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| ID | Type | Description | Link |
|---|---|---|---|
| C5341029 | Other Identifier | Alias Study Number |
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This research study is examining multiple doses of voxelotor (a study drug intended for treatment of sickle cell disease) and how it interacts with additional substrates (substrates are drugs or other substances that are metabolized by cytochrome enzymes. The substrates used in this study are FDA approved medications). The study will help to determine the safety and tolerability of the study drugs taken together, as well as the pharmacokinetics (PK) on how your body processes and responds to the combination of the study drug and substrates. Although these drugs are FDA approved, their use in this study is experimental.
This is an open-label, fixed-sequence, 2-period evaluation study. This means the study doctor and participants in the study will know what study drugs they are taking. There will be approximately 46 healthy male and female participants between the ages of 18 - 55. There will be two parts of the study: parts A and B.
Part A will consist of 26 healthy male and female participants (at least 20% African American). For Part A, participant involvement is expected to last approximately 81 days, including a 33-day screening period and a 48-day on study period (consisting of 2 study treatment periods, a washout period lasting 7 to 14 days, and the Follow-up visit).
Part B will consist of 20 healthy male and female participants (at least 20% African American). For Part B, participant involvement is expected to last approximately 68 days, including a 33-day screening period and a 35-day on study period (consisting of 2 study treatment periods, a washout period lasting 7 to 14 days, and the Follow-up visit).
You will only be allowed to be in one part of the study.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part A | Experimental | To evaluate the effect of multiple doses of voxelotor on the plasma pharmacokinetics (PK) of a single dose of bupropion, repaglinide, flurbiprofen, omeprazole, and midazolam |
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| Part B | Experimental | To evaluate the effect of multiple doses of voxelotor on the plasma PK of a single dose of metformin, furosemide, and rosuvastatin |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Voxelotor | Drug | Drug drug interaction |
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| Measure | Description | Time Frame |
|---|---|---|
| Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively | |
| Part A: Cmax for Repaglinide | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively | |
| Part A: Cmax for Flurbiprofen | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively | |
| Part A: Cmax for Omeprazole | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively | |
| Part A: Cmax for Midazolam | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively | |
| Part A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion | AUCt was calculated using the linear/log trapezoidal rule. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
| Part A: AUCt for Repaglinide | AUCt was calculated using the linear/log trapezoid rule. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively |
| Measure | Description | Time Frame |
|---|---|---|
| Part A: Cmax for 6-Hydroxybupropion | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively | |
| Part A: Cmax for 5-Hydroxyomeprazole | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Measure | Description | Time Frame |
|---|---|---|
| Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs [probe substrates]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events. |
Inclusion Criteria:
1. Males or females ≥ 18 and ≤ 55 years of age inclusive, at the time of signing the informed consent.
2. No clinically significant findings as assessed by review of medical and surgical history, vital signs assessments, 12-lead electrocardiograms (ECG), physical examination, and clinical laboratory evaluations conducted at screening and day of admission. A single repeat measurement/test may be performed to confirm eligibility based upon initial vital signs, ECG, or clinical laboratory tests abnormalities.
3. Body mass Index (BMI) ≥ 18.0 and ≤ 30.0 kg/m2, and body weight ≥ 50 kg at screening and Period 1 Day -1. BMI = weight (kg)/(height [m])2
4. Females of childbearing potential must agree to use a highly effective method of contraception or practice abstinence from 2 weeks prior to study start through 30 days after the last dose of study drug. A highly effective method of contraception is defined as one that results in a low documented failure rate when used consistently and correctly such as: condom plus use of an intrauterine device; intrauterine system or hormonal method of contraception (oral, injected, implanted, or transdermal) for their female partner; or sexual abstinence. Males must be surgically sterilized, or agree to practice true abstinence, or use acceptable contraception if sexually active with a female partner of childbearing potential, throughout the study, and for at least 30 days after the last dose of study drug.
5. Males must agree not to donate sperm during the study and for 30 days following last dose of study drug.
Exclusion Criteria:
Positive pregnancy test or is lactating.
History or presence of clinically significant allergic diseases (except for untreated,
asymptomatic, seasonal allergies) at time of screening in the opinion of the Investigator.
History or presence of conditions which, in the opinion of the Investigator, are known to interfere with the absorption, distribution, metabolism, or excretion of drugs, such as previous surgery on the gastrointestinal tract (including removal of parts of the stomach, bowel, liver, or pancreas). Participants who have a history of cholecystectomy and appendectomy are eligible for enrollment.
Any signs and/or symptoms of acute illness at screening or Day -1.
Abnormal ECG in any of the single ECGs collected at screening or Day -1, including QTcF > 430 msec for males and > 450 msec for females, or any cardiac rhythm other than sinus rhythm that is interpreted by the Investigator to be clinically significant. A single repeat measurement may be performed to re-evaluate ECG abnormalities (ie, to confirm that a participant is eligible). All the single ECGs must be not clinically significant to qualify for enrollment into the study.
Resting bradycardia (HR < 45 bpm) or resting tachycardia (HR > 100 bpm) at screening or Day -1. A single repeat measurement may be performed to re-evaluate vital signs abnormalities(ie, to confirm that a participant is ineligible). Each of the readings must be not clinically significant to qualify for enrollment into the study.
Hypertension, defined as resting (supine) systolic blood pressure (BP) > 140 mmHg or resting diastolic BP > 90 mmHg at screening or Day -1. A single repeat measurement may be performed to re-evaluate vital signs abnormalities (ie, to confirm that a participant is eligible). Each of the readings must be not clinically significant to qualify for enrollment into the study.
Use of prescription medications (with the exception of contraception), any over the counter drugs including herbal preparations including St. John's wort or dietary supplements, or any drugs that induce or inhibit study drug specific CYP450(s) within 14 days or 5 half-lives, whichever is longer, prior to Day -1, or requires continuing use during study participation.
Prior exposure to voxelotor/Oxbryta® within the past month.
Clinically significant anemia, or has donated blood or blood components exceeding 400 mL within 90 days prior to screening.
Positive screen for human immunodeficiency virus 1 (HIV-1) and HIV -2 antibodies, hepatitis A virus antibody, hepatitis B surface antigen, or hepatitis C virus antibody.
History or presence of contraindication to the use of midazolam including but not limited to hypersensitivity to benzodiazepines or formulation ingredients, acute narrow-angle glaucoma, myasthenia gravis, severe respiratory insufficiency, or sleep apnea syndrome.
Poor CYP2C9 or CYP2C19 metabolizer (determined at screening or available historical data).
Participant has an allergy or sensitivity to voxelotor, bupropion, repaglinide, flurbiprofen, omeprazole, or midazolam.
Part B only
History of statin-induced myopathy or serious hypersensitivity reaction to other 3-hydroxy-3-methylglutaryl coenzyme A, reductase inhibitors (statins).
Heterozygous or homozygous variant allele carriers of SLCO1B1 (c.521T>C, rs4149056), encoding the hepatic uptake transporter OATP1B1, resulting in decreased transport activity.
Participant has an allergy or sensitivity to voxelotor, metformin, furosemide, or rosuvastatin.
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| Name | Affiliation | Role |
|---|---|---|
| Pfizer CT.gov Call Center | Pfizer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| ICON Early Phase Services, LLC | San Antonio | Texas | 78209 | United States |
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| Label | URL |
|---|---|
| To obtain contact information for a study center near you, click here. | View source |
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Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical\_trials/trial\_data\_and\_results/data\_requests.
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A total of 44 participants (26 in Part A and 18 in Part B) were enrolled in the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Part A:Treatment Sequence ABCDEFG | On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (bupropion 150 milligrams [mg], flurbiprofen 50 mg, omeprazole 20 mg, and midazolam 2 mg) and on Day 4, participants received a single oral dose of repaglinide 0.5 mg (Treatment B). Period 1 for Part A was of 5 days. In Period 2, participants were administered once daily oral dose of voxelotor 1500 mg (Treatment C) for 13 days. On Day 2, a single oral dose of bupropion 150 mg (Treatment D) was administered immediately following voxelotor administration. On Day 4, single oral dose of Treatment E (flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg) was administered immediately following voxelotor administration. Participants received Treatment F (single oral dose of repaglinide 0.5 mg) and Treatment G (single oral dose of bupropion 150 mg) on Day 6 and Day 12, immediately following voxelotor administration. Period 2 for Part A was of 15 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 28. |
| FG001 | Part B: Treatment Sequence ABCD | On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg). Period 1 for Part B was of 4 days. In Period 2, from Day 1 to Day 3, participants were administered Treatment B (oral doses of voxelotor 1500 mg) orally for 3 days. On Day 4, participants were administered Treatment C (single oral doses of metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg) immediately following voxelotor administration. On Day 5, participants were administered Treatment D (single oral dose of voxelotor 1500 mg). Period 2 for Part B was of 7 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 18. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1 |
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| Washout Period |
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| Period 2 |
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Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs [probe substrates]).
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| ID | Title | Description |
|---|---|---|
| BG000 | Part A:Treatment Sequence ABCDEFG | On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg, and midazolam 2 mg) and on Day 4, participants received a single oral dose of repaglinide 0.5 mg (Treatment B). Period 1 for Part A was of 5 days. In Period 2, participants were administered once daily oral dose of voxelotor 1500 mg (Treatment C) for 13 days. On Day 2, a single oral dose of bupropion 150 mg (Treatment D) was administered immediately following voxelotor administration. On Day 4, single oral dose of Treatment E (flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg) was administered immediately following voxelotor administration. Participants received Treatment F (single oral dose of repaglinide 0.5 mg) and Treatment G (single oral dose of bupropion 150 mg) on Day 6 and Day 12, immediately following voxelotor administration. Period 2 for Part A was of 15 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 28. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Part A: Maximum Observed Plasma Concentration (Cmax) for Bupropion | Pharmacokinetic (PK) evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | Nanogram per milliliter (ng/mL) | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
|
Part A: from start of study drug on Day 1 up to Day 28 (for a maximum of 30 days). Part B: from start of study drug on Day 1 up to Day 18 (for a maximum of 20 days)
Safety population included all participants who received any amount of study drug (voxelotor or cocktail drugs [probe substrates]). As prespecified in the statistical analysis plan, safety data is reported period-wise.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Part A: Period 1 | On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (bupropion 150 mg, flurbiprofen 50 mg, omeprazole 20 mg, and midazolam 2 mg) and on Day 4, participants received a single oral dose of repaglinide 0.5 mg (Treatment B). Period 1 for Part A was of 5 days. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA v26.0 | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pfizer ClinicalTrials.gov Call Center | Pfizer Inc. | 1-800-718-1021 | ClinicalTrials.gov_Inquiries@pfizer.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Mar 2, 2023 | Sep 27, 2024 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 10, 2023 | Sep 27, 2024 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D000755 | Anemia, Sickle Cell |
| ID | Term |
|---|---|
| D000745 | Anemia, Hemolytic, Congenital |
| D000743 | Anemia, Hemolytic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
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| ID | Term |
|---|---|
| C000628792 | voxelotor |
| D016642 | Bupropion |
| C072379 | repaglinide |
| D005480 | Flurbiprofen |
| D009853 | Omeprazole |
| D008874 | Midazolam |
| D008687 | Metformin |
| D005665 | Furosemide |
| D000068718 | Rosuvastatin Calcium |
| ID | Term |
|---|---|
| D011427 | Propiophenones |
| D007659 | Ketones |
| D009930 | Organic Chemicals |
| D011422 | Propionates |
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| Bupropion | Drug | Drug drug interaction |
|
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| Repaglinide | Drug | Drug drug interaction |
|
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| Flurbiprofen | Drug | Drug drug interaction |
|
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| Omeprazole | Drug | Drug drug interaction |
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| Midazolam | Drug | Drug drug interaction |
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| Metformin | Drug | Drug drug interaction |
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| Furosemide | Drug | Drug drug interaction |
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| Rosuvastatin | Drug | Drug drug interaction |
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| Part A: AUCt for Flurbiprofen | AUCt was calculated using the linear/log trapezoid rule. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: AUCt for Omeprazole | AUCt was calculated using the linear/log trapezoid rule. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: AUCt for Midazolam | AUCt was calculated using the linear/log trapezoid rule. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
| Part A: AUCinf for Repaglinide | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively |
| Part A: AUCinf for Flurbiprofen | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: AUCinf for Omeprazole | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: AUCinf for Midazolam | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part B: Cmax for Metformin | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: Cmax for Furosemide | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: Cmax for Rosuvastatin | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: AUCt for Metformin | AUCt was calculated using the linear/log trapezoid rule. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: AUCt for Furosemide | AUCt was calculated using the linear/log trapezoid rule. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: AUCt for Rosuvastatin | AUCt was calculated using the linear/log trapezoid rule. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Day 1 and Day 4 for Treatment A and Treatment C, respectively |
| Part B: AUCinf for Metformin | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: AUCinf for Furosemide | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: AUCinf for Rosuvastatin | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part A: Cmax for 1-Hydroxymidazolam | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: AUCt for 6-Hydroxybupropion | AUCt was calculated using the linear/log trapezoid rule. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
| Part A: AUCt for 5-Hydroxyomeprazole | AUCt was calculated using the linear/log trapezoid rule. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: AUCt for 1-Hydroxymidazolam | AUCt was calculated using the linear/log trapezoid rule. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: AUCinf for 6-Hydroxybupropion | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
| Part A: AUCinf for 5-Hydroxyomeprazole | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: AUCinf for 1-Hydroxymidazolam | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion | The time that Cmax was observed. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
| Part A: Tmax for 6-Hydroxybupropion | The time that Cmax was observed for 6-Hydroxybupropion. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
| Part A: Tmax for Repaglinide | The time that Cmax was observed for Repaglinide. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively |
| Part A: Tmax for Flurbiprofen | The time that Cmax was observed for Flurbiprofen. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: Tmax for Omeprazole | The time that Cmax was observed for Omeprazole. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: Tmax for 5-Hydroxyomeprazole | The time that Cmax was observed for 5-Hydroxyomeprazole. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: Tmax for Midazolam | The time that Cmax was observed for Midazolam. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: Tmax for 1-Hydroxymidazolam | The time that Cmax was observed for 1-Hydroxymidazolam. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: Terminal Elimination Half-life (T½) for Bupropion | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
| Part A: t1/2 6-Hydroxybupropion | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
| Part A: T1/2 for Repaglinide | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively |
| Part A: T1/2 for Flurbiprofen | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: T1/2 for Omeprazole | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: T1/2 for 5-Hydroxyomeprazole | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: T1/2 for Midazolam | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: T1/2 for 1-Hydroxymidazolam | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
| Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
| Part B: Tmax for Metformin | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: Tmax for Furosemide | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: Tmax for Rosuvastatin | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: T½ for Metformin | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: T½ for Furosemide | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| Part B: T½ for Rosuvastatin | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
| From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) |
| Part B: Number of Participants With TEAEs and SAEs | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs [probe substrates]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events. | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) |
| Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests | The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator. | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) |
| Part A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations | A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator. | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) |
| Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs | Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator. | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) |
| Part B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests | The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator. | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) |
| Part B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations | A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator. | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) |
| Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs | Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator. | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) |
| NOT COMPLETED |
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| NOT COMPLETED |
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| BG001 | Part B: Treatment Sequence ABCD | On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg). Period 1 for Part B was of 4 days. In Period 2, from Day 1 to Day 3, participants were administered Treatment B (oral doses of voxelotor 1500 mg) orally for 3 days. On Day 4, participants were administered Treatment C (single oral doses of metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg) immediately following voxelotor administration. On Day 5, participants were administered Treatment D (single oral dose of voxelotor 1500 mg). Period 2 for Part B was of 7 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 18. |
| BG002 | Total | Total of all reporting groups |
| Years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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On Period 2 Day 2, participants were administered Treatment D (single oral dose of bupropion 150 mg) administered immediately following voxelotor. |
| OG002 | Part A: Period 2: Treatment G | On Period 2 Day 12, participants were administered Treatment G (single oral dose of bupropion 150 mg) administered immediately following voxelotor. |
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| Primary | Part A: Cmax for Repaglinide | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/ml | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively |
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| Primary | Part A: Cmax for Flurbiprofen | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/ml | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Primary | Part A: Cmax for Omeprazole | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/ml | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Primary | Part A: Cmax for Midazolam | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/ml | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Primary | Part A: Area Under the Plasma Concentration-Time Curve From Time Zero (0) to the Time of the Last Quantifiable Concentration (AUCt) for Bupropion | AUCt was calculated using the linear/log trapezoidal rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hour* nanogram/milliliter (h*ng/mL) | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
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| Primary | Part A: AUCt for Repaglinide | AUCt was calculated using the linear/log trapezoid rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively |
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| Primary | Part A: AUCt for Flurbiprofen | AUCt was calculated using the linear/log trapezoid rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Primary | Part A: AUCt for Omeprazole | AUCt was calculated using the linear/log trapezoid rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Primary | Part A: AUCt for Midazolam | AUCt was calculated using the linear/log trapezoid rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Primary | Part A: Area Under the Plasma Concentration-Time Curve From Time 0 Extrapolated to Infinity (AUCinf) for Bupropion | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hour*nanogram/milliliter | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
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| Primary | Part A: AUCinf for Repaglinide | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively |
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| Primary | Part A: AUCinf for Flurbiprofen | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Primary | Part A: AUCinf for Omeprazole | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Primary | Part A: AUCinf for Midazolam | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Primary | Part B: Cmax for Metformin | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Primary | Part B: Cmax for Furosemide | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Primary | Part B: Cmax for Rosuvastatin | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Primary | Part B: AUCt for Metformin | AUCt was calculated using the linear/log trapezoid rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Primary | Part B: AUCt for Furosemide | AUCt was calculated using the linear/log trapezoid rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Primary | Part B: AUCt for Rosuvastatin | AUCt was calculated using the linear/log trapezoid rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Day 1 and Day 4 for Treatment A and Treatment C, respectively |
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| Primary | Part B: AUCinf for Metformin | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Primary | Part B: AUCinf for Furosemide | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Primary | Part B: AUCinf for Rosuvastatin | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Secondary | Part A: Cmax for 6-Hydroxybupropion | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
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| Secondary | Part A: Cmax for 5-Hydroxyomeprazole | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: Cmax for 1-Hydroxymidazolam | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/ml | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: AUCt for 6-Hydroxybupropion | AUCt was calculated using the linear/log trapezoid rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
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| Secondary | Part A: AUCt for 5-Hydroxyomeprazole | AUCt was calculated using the linear/log trapezoid rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: AUCt for 1-Hydroxymidazolam | AUCt was calculated using the linear/log trapezoid rule. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: AUCinf for 6-Hydroxybupropion | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
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| Secondary | Part A: AUCinf for 5-Hydroxyomeprazole | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: AUCinf for 1-Hydroxymidazolam | AUCinf was calculated as AUClast + Clast/lamda z, where AUClast: area under the plasma concentration-time curve from time 0 to time of the last quantifiable concentration. Clast is the last measurable concentration and lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: Time at Which Cmax Was Observed (Tmax) for Bupropion | The time that Cmax was observed. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
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| Secondary | Part A: Tmax for 6-Hydroxybupropion | The time that Cmax was observed for 6-Hydroxybupropion. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
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| Secondary | Part A: Tmax for Repaglinide | The time that Cmax was observed for Repaglinide. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively |
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| Secondary | Part A: Tmax for Flurbiprofen | The time that Cmax was observed for Flurbiprofen. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: Tmax for Omeprazole | The time that Cmax was observed for Omeprazole. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: Tmax for 5-Hydroxyomeprazole | The time that Cmax was observed for 5-Hydroxyomeprazole. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: Tmax for Midazolam | The time that Cmax was observed for Midazolam. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: Tmax for 1-Hydroxymidazolam | The time that Cmax was observed for 1-Hydroxymidazolam. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: Terminal Elimination Half-life (T½) for Bupropion | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
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| Secondary | Part A: t1/2 6-Hydroxybupropion | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
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| Secondary | Part A: T1/2 for Repaglinide | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours post-dose on Period 1 Day 4 and Period 2 Day 6 for Treatment B and F, respectively |
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| Secondary | Part A: T1/2 for Flurbiprofen | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: T1/2 for Omeprazole | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: T1/2 for 5-Hydroxyomeprazole | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: T1/2 for Midazolam | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: T1/2 for 1-Hydroxymidazolam | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. Here "Number of Participants Analyzed" signifies the number of participants evaluable for this outcome measure. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight (AUCt M/P) for 6-Hydroxybupropion/Bupropion | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | Ratio | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, and 72 hours post-dose on Period 1 Day 1, Period 2 Day 2 and Period 2 Day 12 for Treatment A, D and G, respectively |
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| Secondary | Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for 5-Hydroxyomeprazole/Omeprazole | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | Ratio | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part A: Ratio of Metabolite to Parent AUCt Corrected for Molecular Weight for Hydroxymidazolam/Midazolam | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Geometric Mean | Geometric Coefficient of Variation | Ratio | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and E, respectively |
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| Secondary | Part B: Tmax for Metformin | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Secondary | Part B: Tmax for Furosemide | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Secondary | Part B: Tmax for Rosuvastatin | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Median | Full Range | Hours | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Secondary | Part B: T½ for Metformin | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Secondary | Part B: T½ for Furosemide | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Secondary | Part B: T½ for Rosuvastatin | T½ was calculated as ln (2)/lambda z; where lamda z: apparent terminal elimination rate constant. | PK evaluable population included all participants who received at least 1 dose of study drug (voxelotor or cocktail drugs [probe substrates]) and had a sufficient PK profile to derive at least 1 PK parameter. | Posted | Mean | Standard Deviation | Hours | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 24, and 48 hours post-dose on Period 1 Day 1 and Period 2 Day 4 for Treatment A and Treatment C, respectively |
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| Other Pre-specified | Part A: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | An adverse event (AE) was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs [probe substrates]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events. | Safety analysis set (SAS) included all participants who received any amount of study drug (voxelotor or cocktail drugs [probe substrates]). As prespecified in the statistical analysis plan, safety data is reported period-wise. | Posted | Count of Participants | Participants | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) |
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| Other Pre-specified | Part B: Number of Participants With TEAEs and SAEs | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product during the course of a clinical investigation. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of an investigational product, whether or not thought to be related to the investigational product. TEAE: any event that was not present before exposure to study drug (voxelotor or cocktail drugs [probe substrates]) or any event already present that worsened in either intensity or frequency after exposure to study drug. An SAE was defined as an AE that at any dose resulted in any of the following outcomes: death; life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or disability; a congenital anomaly/birth defect; other important medical events. | SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs [probe substrates]). As prespecified in the statistical analysis plan, safety data is reported period-wise. | Posted | Count of Participants | Participants | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) |
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| Other Pre-specified | Part A: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests | The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator. | SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs [probe substrates]). As prespecified in the statistical analysis plan, safety data is reported period-wise. | Posted | Count of Participants | Participants | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) |
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| Other Pre-specified | Part A: Number of Participants With Clinically Significant Abnormalities in Physical Examinations | A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator. | SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs [probe substrates]). As prespecified in the statistical analysis plan, safety data is reported period-wise. | Posted | Count of Participants | Participants | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) |
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| Other Pre-specified | Part A: Number of Participants With Clinically Significant Abnormalities in Vital Signs | Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator. | SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs [probe substrates]). As prespecified in the statistical analysis plan, safety data is reported period-wise. | Posted | Count of Participants | Participants | From start of study drug on Day 1 up to Day 28 (for a maximum of 30 days) |
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| Other Pre-specified | Part B: Number of Participants With Clinically Significant Abnormalities in Laboratory Tests | The following laboratory parameters were assessed: hematology: hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet count, red blood cell count, neutrophils, monocytes, lymphocytes, basophils and eosinophils. coagulation: prothrombin time, partial thromboplastin time, international normalized ratio. Serum Chemistry: albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, creatinine, blood urea nitrogen, lactate dehydrogenase. Urinalysis: ketones, pH, protein, blood glucose, bilirubin, chloride, bicarbonate, phosphorous, potassium was assessed. Clinical significance of laboratory abnormalities was determined by investigator. | SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs [probe substrates]). As prespecified in the statistical analysis plan, safety data is reported period-wise. | Posted | Count of Participants | Participants | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) |
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| Other Pre-specified | Part B: Number of Participants With Clinically Significant Abnormalities in Physical Examinations | A complete physical examination included cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and weight were also measured and recorded. Clinical significance of physical examinations was determined by investigator. | SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs [probe substrates]). As prespecified in the statistical analysis plan, safety data is reported period-wise. | Posted | Count of Participants | Participants | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) |
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| Other Pre-specified | Part B: Number of Participants With Clinically Significant Abnormalities in Vital Signs | Vital signs included oral temperature, heart rate, respiratory rate (breaths per minute), and blood pressure. Blood pressure and heart rate were measured in a supine position using completely automated device after at least 5 minutes of rest for the participant in a quiet setting without distractions. Clinical significance of vital signs was determined by investigator. | SAS included all participants who received any amount of study drug (voxelotor or cocktail drugs [probe substrates]). As prespecified in the statistical analysis plan, safety data is reported period-wise. | Posted | Count of Participants | Participants | From start of study drug on Day 1 up to Day 18 (for a maximum of 20 days) |
|
|
|
| 0 |
| 26 |
| 0 |
| 26 |
| 4 |
| 26 |
| EG001 | Part A: Period 2 | In Period 2, participants were administered once daily oral dose of voxelotor 1500 mg (Treatment C) for 13 days. On Day 2, a single oral dose of bupropion 150 mg (Treatment D) was administered immediately following voxelotor administration. On Day 4, single oral dose of Treatment E (flurbiprofen 50 mg, omeprazole 20 mg and midazolam 2 mg) was administered immediately following voxelotor administration. Participants received Treatment F (single oral dose of repaglinide 0.5 mg) and Treatment G (single oral dose of bupropion 150 mg) on Day 6 and Day 12, immediately following voxelotor administration. Period 2 for Part A was of 15 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 28. | 0 | 25 | 0 | 25 | 9 | 25 |
| EG002 | Part B: Period 1 | On Day 1 of Period 1, participants were administered a single oral dose of Treatment A (metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg). Period 1 for Part B was of 4 days. | 0 | 18 | 0 | 18 | 1 | 18 |
| EG003 | Part B: Period 2 | In Period 2, from Day 1 to Day 3, participants were administered Treatment B (oral doses of voxelotor 1500 mg) orally for 3 days. On Day 4, participants were administered Treatment C (single oral doses of metformin 10 mg, furosemide 1 mg, and rosuvastatin 10 mg) immediately following voxelotor administration. On Day 5, participants were administered Treatment D (single oral dose of voxelotor 1500 mg). Period 2 for Part B was of 7 days. There was a washout period of 7 to 14 days in between Period 1 and 2. Participants had a follow-up visit on Day 18. | 0 | 18 | 0 | 18 | 2 | 18 |
| Dizziness | Nervous system disorders | MedDRA v26.0 | Non-systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA v26.0 | Non-systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA v26.0 | Non-systematic Assessment |
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| Constipation | Gastrointestinal disorders | MedDRA v26.0 | Non-systematic Assessment |
|
| Diarrhoea | Gastrointestinal disorders | MedDRA v26.0 | Non-systematic Assessment |
|
| Influenza like illness | General disorders | MedDRA v26.0 | Non-systematic Assessment |
|
| Muscle strain | Injury, poisoning and procedural complications | MedDRA v26.0 | Non-systematic Assessment |
|
| Atrial fibrillation | Cardiac disorders | MedDRA v26.0 | Non-systematic Assessment |
|
| COVID-19 | Infections and infestations | MedDRA v26.0 | Non-systematic Assessment |
|
| Rash | Skin and subcutaneous tissue disorders | MedDRA v26.0 | Non-systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA v26.0 | Non-systematic Assessment |
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| Tooth abscess | Infections and infestations | MedDRA v26.0 | Non-systematic Assessment |
|
Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publication until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
| D006425 |
| Hemic and Lymphatic Diseases |
| D006453 | Hemoglobinopathies |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D000144 |
| Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D001713 | Biphenyl Compounds |
| D001555 | Benzene Derivatives |
| D006841 | Hydrocarbons, Aromatic |
| D006844 | Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D053799 | 2-Pyridinylmethylsulfinylbenzimidazoles |
| D013454 | Sulfoxides |
| D013457 | Sulfur Compounds |
| D011725 | Pyridines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D001562 | Benzimidazoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D001569 | Benzodiazepines |
| D001552 | Benzazepines |
| D001645 | Biguanides |
| D006146 | Guanidines |
| D000578 | Amidines |
| D013424 | Sulfanilamides |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D000814 | Aniline Compounds |
| D000588 | Amines |
| D013450 | Sulfones |
| D005464 | Fluorobenzenes |
| D006845 | Hydrocarbons, Fluorinated |
| D006846 | Hydrocarbons, Halogenated |
| D011743 | Pyrimidines |
| Ratio of Geometric LS Means |
| 0.9494 |
| 2-Sided |
| 90 |
| 0.8759 |
| 1.0291 |
| Other |
| Ratio of Geometric LS Means |
| 0.9371 |
| 2-Sided |
| 90 |
| 0.8643 |
| 1.0162 |
| Other |