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| Name | Class |
|---|---|
| Pfizer | INDUSTRY |
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This will be an open-label, parallel group, multiple dose study in approximately 48 healthy male or female subjects of African American and Caucasian self-reported race, to assess the effect of CYP3A5 genotype on the PK of MVC and CYP3A5-derived metabolites. Maraviroc and CYP3A5-derived metabolite PK will also be compared between African-Americans and Caucasians in subjects carrying two copies of the dysfunctional CYP3A5 alleles (*3, *6, and/or *7).
This will be an open-label, parallel group, multiple dose study in approximately 48 healthy male or female subjects of African American and Caucasian self-reported race, to assess the effect of CYP3A5 genotype on the PK of MVC and CYP3A5-derived metabolites. Maraviroc and CYP3A5-derived metabolite PK will also be compared between African-Americans and Caucasians in subjects carrying two copies of the dysfunctional CYP3A5 alleles (*3, *6, and/or *7).
Dysfunctional genetic variants for CYP3A5, CYP3A4 and SLCO1B1 will be genotyped for subjects who participate in the pre-screening. Subjects who meet the inclusion/exclusion criteria for study participation will be placed into the study cohorts based on race and the number of functional (*1) and dysfunctional CYP3A5 alleles (*3, *6, and *7) CYP3A5 alleles.
Cohort 1 (n=12; African-American): No CYP3A5*1 alleles (poor metabolizer). Cohort 2 (n=12; African-American): One CYP3A5*1 allele (intermediate metabolizer).
Cohort 3 (n=12; African-American): Two CYP3A5*1 alleles (extensive metabolizer).
Cohort 4 (n=12; Caucasian): No CYP3A5*1 alleles (poor metabolizer).
Study Treatments:
Part 1 Days 1-5: Maraviroc 300 mg BID in fasted state (AM dose only on Day 5). Part 2 (Cohorts 1 and 3 only) Days 1-10: Maraviroc 150 mg QD plus darunavir/cobicistat 800/150 mg QD with food.
Pharmacokinetics of MVC, PF-6857639, PF-6857640 and other hydroxylated metabolites with formation mediated by CYP3A5 (if present) will be assessed on Part 1, Day 5 and Part 2, Days 10-11. Blood samples will be collected for a full PK profile.
Subjects will be confined to the Clinical Research Unit (CRU) the day prior to dosing on Day 1 (Day 0) and discharged on Part 1, Day 6 and on Part 2, Day 11 (Cohorts 1 and 3 only). Subjects enrolled into Cohorts 1 and 3 may be confined to the CRU without the need to be discharged between Part 1 and Part 2.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cohort 1 | Experimental | African-Americans with No CYP3A5*1 alleles (poor metabolizer) |
|
| Cohort 2 | Experimental | African-Americans with One CYP3A5*1 allele (intermediate metabolizer) |
|
| Cohort 3 | Experimental | African-Americans with Two CYP3A5*1 alleles (extensive metabolizer) |
|
| Cohort 4 | Experimental | Caucasians with No CYP3A5*1 alleles (poor metabolizer) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Maraviroc (Part 1) | Drug | 300 mg twice daily x 5 days |
|
| Measure | Description | Time Frame |
|---|---|---|
| Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Maraviroc | AUC (0-12) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
| Part 2: Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Maraviroc | AUC (0-24) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 |
| Part 1: Metabolite to Parent Ratio for Area Under the Concentration-Time Curve From Time 0 to 12 Hours for Maraviroc and Its Metabolites (MRAUC12) | MRAUC12 is the ratio of AUC12 of maraviroc to AUC12 of maraviroc's metabolites. Metabolites of Maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. AUC12 is the area under the plasma concentration-time profile from time 0 to 12 hours post-dose. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
| Measure | Description | Time Frame |
|---|---|---|
| Part 1: Average Plasma Concentration (Cavg) of Maraviroc | Cavg is the average plasma concentration of maraviroc during the 0 to 12 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 12 hours (AUC [0-12]) divided by 12. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Pfizer CT.gov Call Center | Pfizer | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Pfizer New Haven Clinical Research Unit | New Haven | Connecticut | 06511 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 30192390 | Derived | Vourvahis M, McFadyen L, Nepal S, Valluri SR, Fang A, Fate GD, Wood LS, Marshall JC, Chan PLS, Nedderman A, Haynes J, Savage ME, Clark A, Smith KY, Heera J. No Clinical Impact of CYP3A5 Gene Polymorphisms on the Pharmacokinetics and/or Efficacy of Maraviroc in Healthy Volunteers and HIV-1-Infected Subjects. J Clin Pharmacol. 2019 Jan;59(1):139-152. doi: 10.1002/jcph.1306. Epub 2018 Sep 7. |
| Label | URL |
|---|---|
| To obtain contact information for a study center near you, click here. | View source |
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The study was conducted in two parts (Part 1 and 2). Participants were assigned to treatment into 4 cohorts in Part 1 (Cohort 1, 2, 3, 4) and into 2 cohorts in part 2 (Cohort 1, 3).
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| ID | Title | Description |
|---|---|---|
| FG000 | Part 1 and Part 2: Cohort 1 -No CYP3A5*1 Alleles | African-American participants with no CYP3A5*1 alleles, received maraviroc 300 milligram (mg) tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1, followed by maraviroc 150 mg tablet once daily along with darunavir/cobicistat 800/150 mg tablet once daily from Day 1 to Day 10 in Part 2. |
| FG001 | Part 1: Cohort 2 - One CYP3A5*1 Allele | African-American participants with one CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. |
| FG002 | Part 1 and 2: Cohort 3 - Two CYP3A5*1 Alleles | African-American participants with two CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1, followed by maraviroc 150 mg tablet once daily along with darunavir/cobicistat 800/150 mg tablet once daily from Day 1 to Day 10 in Part 2. |
| FG003 | Part 1: Cohort 4 - No CYP3A5*1 Alleles | Caucasian participants with no CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Part 1 (6 Days) |
| |||||||||||||
| Part 2 (11 Days) |
|
Safety analysis set included all participants who received at least 1 dose of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | Part 1 and Part 2: Cohort 1 -No CYP3A5*1 Alleles | African-American participants with no CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1, followed by maraviroc 150 mg tablet once daily along with darunavir/cobicistat 800/150 mg tablet once daily from Day 1 to Day 10 in Part 2. |
| Units | Counts |
|---|---|
| Participants |
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| 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 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Maraviroc | AUC (0-12) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose. | Pharmacokinetic (PK) parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram*hour per milliliter (ng*hr/mL) | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
|
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Adverse events were collected and reported for Part 1 and Part 2 separately.
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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 1: Cohort 1- No CYP3A5*1 Alleles | African-American participants with no CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dry mouth | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
As per change in planned analysis, calculation of metabolite PK parameters and statistical analyses were not conducted in Part 2, since substantial number of PK samples were below limit of quantitation, considered as non-reliable by investigator.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Pfizer ClinicalTrials.gov Call Center | Pfizer, Inc. | 1-800-718-1021 | ClinicalTrials.gov_Inquiries@pfizer.com |
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| ID | Term |
|---|---|
| D000077592 | Maraviroc |
| D000069454 | Darunavir |
| D000069547 | Cobicistat |
| C000711687 | cobicistat mixture with darunavir |
| ID | Term |
|---|---|
| D003510 | Cyclohexanes |
| D003516 | Cycloparaffins |
| D006840 | Hydrocarbons, Alicyclic |
| D006844 | Hydrocarbons, Cyclic |
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| Maraviroc (Part 2) | Drug | 150 mg once daily x 10 days |
|
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| Darunavir/cobicistat (Part 2) | Drug | 800/150 mg once daily x 10 days |
|
|
| Part 2: Average Plasma Concentration (Cavg) of Maraviroc |
Cavg is the average plasma concentration of maraviroc during the 0 to 24 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 24 hours (AUC [0-24]) divided by 24. |
| Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Maraviroc | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
| Part 2: Maximum Observed Plasma Concentration (Cmax) of Maraviroc | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 |
| Part 1: Plasma Concentration of Maraviroc at 12 Hours Post-dose | 12 hours post-dose on Day 5 |
| Part 2: Plasma Concentration of Maraviroc at 24 Hours Post-dose | 24 hours post-dose on Day 10 |
| Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
| Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 |
| Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Metabolites of Maraviroc | AUC (0-12) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose. Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
| Part 1: Average Plasma Concentration (Cav) of Metabolites of Maraviroc | Cavg is the average plasma concentration of metabolites of maraviroc during the 0 to 12 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 12 hours (AUC [0-12]) divided by 12. Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
| Part 1: Maximum Observed Plasma Concentration (Cmax) of Metabolites of Maraviroc | Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
| Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metabolites of Maraviroc | Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
| Part 1: Plasma Concentration of Metabolites of Maraviroc at 12 Hour Post-dose | Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | 12 hour post-dose on Day 5 |
| Part 1: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 6 days that were absent before treatment or that worsened relative to pre-treatment state. | Baseline up to end of study (up to 6 days) |
| Part 2: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 11 days that were absent before treatment or that worsened relative to pretreatment state. | Baseline up to end of study (up to 11 days) |
| Part 1: Number of Participants With Clinically Significant Vital Sign Abnormalities | Criteria for clinically significant vital sign abnormalities included supine/sitting pulse rate of less than (<) 40 beats per minute (bpm) or greater than (>)120 bpm, standing pulse rate of <40 bpm or >140 bpm, supine systolic blood pressure (SBP) and standing SBP of <90 millimeter of mercury (mm Hg), greater than or equal to (>=) 30 mm Hg, supine diastolic blood pressure (DBP) and standing DBP of <50 mm Hg, >=20 mm Hg. | Baseline up to Day 6 |
| Part 2: Number of Participants With Clinically Significant Vital Sign Abnormalities | Criteria for clinically significant vital sign abnormalities included supine/sitting pulse rate of <40 bpm or >120 bpm, standing pulse rate of <40 bpm or >140 bpm, supine SBP and standing SBP of <90 mm Hg, >=30 mm Hg, supine DBP and standing DBP of <50 mm Hg, >=20 mm Hg. | Baseline up to Day 11 |
| Part 1: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities | Criteria for ECG abnormalities: Maximum PR interval of >=300 milliseconds (msec), maximum QRS interval >=140 msec, maximum QTCF interval (Fridericia's correction) of 450 to <480 msec, 480 to <500 msec and >=500 msec, maximum increase of >=25 percent for baseline values of >200 msec and >=50 percent for baseline values of less than or equal to (<=) 200 msec for PR interval, maximum increase from baseline of >=50 percent for QRS interval, maximum increase from baseline of >=30 msec to <60 msec and maximum increase from baseline of >60 msec in QTCF interval (Fridericia's Correction). | Baseline up to Day 6 |
| Part 2: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities | Criteria for ECG abnormalities: Maximum PR interval of >=300 msec, maximum QRS interval >=140 msec, maximum QTCF interval (Fridericia's correction) of 450 to <480 msec, 480 to <500 msec and >=500 msec, maximum increase of >=25 percent for baseline values of >200 msec and >=50 percent for baseline values of <=200 msec for PR interval, maximum increase from baseline of >=50 percent for QRS interval, maximum increase from baseline of >=30 msec to <60 msec and maximum increase from baseline of >60 msec in QTCF interval (Fridericia's Correction). | Baseline up to Day 11 |
| Part 1: Number of Participants With Laboratory Abnormalities | Criteria: Hemoglobin; hematocrit; red blood cell count: <0.8*lower limit of normal, (LLN), mean corpuscular volume; mean corpuscular hemoglobin concentration; mean platelet volume:<0.9*LLN or >1.1* upper limit of normal (ULN), platelet: <0.5*LLN or >1.75*ULN, white blood cells <0.6*LLN or >1.5*ULN, lymphocyte; neutrophil: <0.8*LLN or >1.2*ULN, basophil; eosinophil; monocyte:>1.2*ULN, bilirubin (total, direct, indirect) >1.5*ULN, aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase:>3.0*ULN, total protein; albumin:<0.8*LLN or >1.2*ULN; creatinine: >1.3*ULN, uric acid>1.2*ULN, sodium<0.95*LLN or >1.05*ULN, potassium; chloride; calcium; bicarbonate:<0.9*LLN or >1.1*ULN, glucose <0.6*LLN or >1.5*ULN, urine specific gravity <1.003, urine pH <4.5 or >8, urine glucose or ketones (qualitative) >=1, urine protein; urine blood/hemoglobin >=1, urobilinogen; bilirubin; nitrite; leukocyte esterase >=1. | Baseline up to Day 6 |
| Part 2: Number of Participants With Laboratory Abnormalities | Criteria: Hemoglobin; hematocrit; red blood cell count: <0.8*LLN, mean corpuscular volume; mean corpuscular hemoglobin concentration; mean platelet volume: <0.9*LLN or >1.1*ULN, platelet: <0.5*LLN or >1.75*ULN, white blood cells <0.6*LLN or >1.5*ULN, lymphocyte; neutrophil: <0.8*LLN or >1.2*ULN, basophil; eosinophil; monocyte: >1.2*ULN, bilirubin (total, direct, indirect) >1.5*ULN, aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase: >3.0*ULN, total protein; albumin: <0.8*LLN or >1.2*ULN; creatinine: >1.3*ULN, uric acid >1.2*ULN, sodium<0.95*LLN or >1.05*ULN, potassium; chloride; calcium; bicarbonate:<0.9*LLN or >1.1*ULN, glucose <0.6*LLN or >1.5*ULN, urine specific gravity <1.003, urine pH <4.5 or >8, urine glucose or ketones (qualitative) >=1, urine protein; urine blood/hemoglobin >=1, urobilinogen; bilirubin; nitrite; leukocyte esterase >=1. | Baseline up to Day 11 |
| COMPLETED |
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| NOT COMPLETED |
|
| BG001 |
| Part 1: Cohort 2 - One CYP3A5*1 Allele |
African-American participants with one CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. |
| BG002 | Part 1 and 2: Cohort 3 - Two CYP3A5*1 Alleles | African-American participants with two CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1, followed by maraviroc 150 mg tablet once daily along with darunavir/cobicistat 800/150 mg tablet once daily from Day 1 to Day 10 in Part 2. |
| BG003 | Part 1: Cohort 4 - No CYP3A5*1 Alleles | Caucasian participants with no CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Cohort 2- One CYP3A5*1 Allele |
African-American participants with one CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. |
| OG002 | Cohort 3- Two CYP3A5*1 Alleles | African-American participants with two CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. |
| OG003 | Cohort 4- No CYP3A5*1 Alleles | Caucasian participants with no CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. |
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| Primary | Part 2: Area Under The Plasma Concentration-Time Curve From Time 0 to 24 Hours (AUC [0-24]) of Maraviroc | AUC (0-24) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 24 hours post-dose. | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. Data for Part 2 was planned to be analyzed only in Cohorts 1 and 3, as pre specified in protocol. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 |
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| Primary | Part 1: Metabolite to Parent Ratio for Area Under the Concentration-Time Curve From Time 0 to 12 Hours for Maraviroc and Its Metabolites (MRAUC12) | MRAUC12 is the ratio of AUC12 of maraviroc to AUC12 of maraviroc's metabolites. Metabolites of Maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. AUC12 is the area under the plasma concentration-time profile from time 0 to 12 hours post-dose. | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Geometric Mean | Geometric Coefficient of Variation | ratio | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
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| Secondary | Part 1: Average Plasma Concentration (Cavg) of Maraviroc | Cavg is the average plasma concentration of maraviroc during the 0 to 12 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 12 hours (AUC [0-12]) divided by 12. | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanogram per milliliter (ng/mL) | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
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| Secondary | Part 2: Average Plasma Concentration (Cavg) of Maraviroc | Cavg is the average plasma concentration of maraviroc during the 0 to 24 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 24 hours (AUC [0-24]) divided by 24. | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. Data for Part 2 was planned to be analyzed only in Cohorts 1 and 3, as pre specified in protocol. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 |
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| Secondary | Part 1: Maximum Observed Plasma Concentration (Cmax) of Maraviroc | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
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| Secondary | Part 2: Maximum Observed Plasma Concentration (Cmax) of Maraviroc | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. Data for Part 2 was planned to be analyzed only in Cohorts 1 and 3, as pre specified in protocol. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 |
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| Secondary | Part 1: Plasma Concentration of Maraviroc at 12 Hours Post-dose | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 12 hours post-dose on Day 5 |
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| Secondary | Part 2: Plasma Concentration of Maraviroc at 24 Hours Post-dose | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. Data for Part 2 was planned to be analyzed only in Cohorts 1 and 3, as pre specified in protocol. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 24 hours post-dose on Day 10 |
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| Secondary | Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Median | Full Range | hour | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
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| Secondary | Part 2: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Maraviroc | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. Data for Part 2 was planned to be analyzed only in Cohorts 1 and 3, as pre specified in protocol. | Posted | Median | Full Range | hour | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12, 24 hours post-dose on Day 10 |
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| Secondary | Part 1: Area Under The Plasma Concentration-Time Curve From Time 0 to 12 Hours (AUC [0-12]) of Metabolites of Maraviroc | AUC (0-12) is the area under the plasma concentration versus time curve from time zero (pre-dose) to 12 hours post-dose. Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng*hr/mL | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
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| Secondary | Part 1: Average Plasma Concentration (Cav) of Metabolites of Maraviroc | Cavg is the average plasma concentration of metabolites of maraviroc during the 0 to 12 hour time period. It was calculated as area under the plasma concentration-time curve from 0 to 12 hours (AUC [0-12]) divided by 12. Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
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| Secondary | Part 1: Maximum Observed Plasma Concentration (Cmax) of Metabolites of Maraviroc | Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
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| Secondary | Part 1: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Metabolites of Maraviroc | Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Median | Full Range | hour | Pre-dose, 0.5, 1, 2, 3, 4, 6, 9, 12 hours post-dose on Day 5 |
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| Secondary | Part 1: Plasma Concentration of Metabolites of Maraviroc at 12 Hour Post-dose | Metabolites of maraviroc included PF-6857639, PF-6857640, PF-06927572 and PF-06927573. | PK parameter analysis set included all randomized and treated participants who had at least 1 of the PK parameters of primary interest. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | 12 hour post-dose on Day 5 |
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| Secondary | Part 1: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 6 days that were absent before treatment or that worsened relative to pre-treatment state. | Safety analysis set included all participants who received at least 1 dose of study drug. | Posted | Number | participants | Baseline up to end of study (up to 6 days) |
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| Secondary | Part 2: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 11 days that were absent before treatment or that worsened relative to pretreatment state. | Safety analysis set included all participants who received at least 1 dose of study drug. Data for Part 2 was planned to be analyzed only in Cohorts 1 and 3, as pre specified in protocol. | Posted | Number | participants | Baseline up to end of study (up to 11 days) |
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| Secondary | Part 1: Number of Participants With Clinically Significant Vital Sign Abnormalities | Criteria for clinically significant vital sign abnormalities included supine/sitting pulse rate of less than (<) 40 beats per minute (bpm) or greater than (>)120 bpm, standing pulse rate of <40 bpm or >140 bpm, supine systolic blood pressure (SBP) and standing SBP of <90 millimeter of mercury (mm Hg), greater than or equal to (>=) 30 mm Hg, supine diastolic blood pressure (DBP) and standing DBP of <50 mm Hg, >=20 mm Hg. | Safety analysis set included all participants who received at least 1 dose of study drug. | Posted | Number | participants | Baseline up to Day 6 |
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| Secondary | Part 2: Number of Participants With Clinically Significant Vital Sign Abnormalities | Criteria for clinically significant vital sign abnormalities included supine/sitting pulse rate of <40 bpm or >120 bpm, standing pulse rate of <40 bpm or >140 bpm, supine SBP and standing SBP of <90 mm Hg, >=30 mm Hg, supine DBP and standing DBP of <50 mm Hg, >=20 mm Hg. | Safety analysis set included all participants who received at least 1 dose of study drug. Data for Part 2 was planned to be analyzed only in Cohorts 1 and 3, as pre specified in protocol. | Posted | Number | participants | Baseline up to Day 11 |
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| Secondary | Part 1: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities | Criteria for ECG abnormalities: Maximum PR interval of >=300 milliseconds (msec), maximum QRS interval >=140 msec, maximum QTCF interval (Fridericia's correction) of 450 to <480 msec, 480 to <500 msec and >=500 msec, maximum increase of >=25 percent for baseline values of >200 msec and >=50 percent for baseline values of less than or equal to (<=) 200 msec for PR interval, maximum increase from baseline of >=50 percent for QRS interval, maximum increase from baseline of >=30 msec to <60 msec and maximum increase from baseline of >60 msec in QTCF interval (Fridericia's Correction). | Safety analysis set included all participants who received at least 1 dose of study drug. | Posted | Number | participants | Baseline up to Day 6 |
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| Secondary | Part 2: Number of Participants With 12-Lead Electrocardiogram (ECG) Abnormalities | Criteria for ECG abnormalities: Maximum PR interval of >=300 msec, maximum QRS interval >=140 msec, maximum QTCF interval (Fridericia's correction) of 450 to <480 msec, 480 to <500 msec and >=500 msec, maximum increase of >=25 percent for baseline values of >200 msec and >=50 percent for baseline values of <=200 msec for PR interval, maximum increase from baseline of >=50 percent for QRS interval, maximum increase from baseline of >=30 msec to <60 msec and maximum increase from baseline of >60 msec in QTCF interval (Fridericia's Correction). | Safety analysis set included all participants who received at least 1 dose of study drug. Data for Part 2 was planned to be analyzed only in Cohorts 1 and 3, as pre specified in protocol. | Posted | Number | participants | Baseline up to Day 11 |
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| Secondary | Part 1: Number of Participants With Laboratory Abnormalities | Criteria: Hemoglobin; hematocrit; red blood cell count: <0.8*lower limit of normal, (LLN), mean corpuscular volume; mean corpuscular hemoglobin concentration; mean platelet volume:<0.9*LLN or >1.1* upper limit of normal (ULN), platelet: <0.5*LLN or >1.75*ULN, white blood cells <0.6*LLN or >1.5*ULN, lymphocyte; neutrophil: <0.8*LLN or >1.2*ULN, basophil; eosinophil; monocyte:>1.2*ULN, bilirubin (total, direct, indirect) >1.5*ULN, aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase:>3.0*ULN, total protein; albumin:<0.8*LLN or >1.2*ULN; creatinine: >1.3*ULN, uric acid>1.2*ULN, sodium<0.95*LLN or >1.05*ULN, potassium; chloride; calcium; bicarbonate:<0.9*LLN or >1.1*ULN, glucose <0.6*LLN or >1.5*ULN, urine specific gravity <1.003, urine pH <4.5 or >8, urine glucose or ketones (qualitative) >=1, urine protein; urine blood/hemoglobin >=1, urobilinogen; bilirubin; nitrite; leukocyte esterase >=1. | Safety analysis set included all participants who received at least 1 dose of study drug. | Posted | Number | participants | Baseline up to Day 6 |
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| Secondary | Part 2: Number of Participants With Laboratory Abnormalities | Criteria: Hemoglobin; hematocrit; red blood cell count: <0.8*LLN, mean corpuscular volume; mean corpuscular hemoglobin concentration; mean platelet volume: <0.9*LLN or >1.1*ULN, platelet: <0.5*LLN or >1.75*ULN, white blood cells <0.6*LLN or >1.5*ULN, lymphocyte; neutrophil: <0.8*LLN or >1.2*ULN, basophil; eosinophil; monocyte: >1.2*ULN, bilirubin (total, direct, indirect) >1.5*ULN, aspartate aminotransferase; alanine aminotransferase; alkaline phosphatase: >3.0*ULN, total protein; albumin: <0.8*LLN or >1.2*ULN; creatinine: >1.3*ULN, uric acid >1.2*ULN, sodium<0.95*LLN or >1.05*ULN, potassium; chloride; calcium; bicarbonate:<0.9*LLN or >1.1*ULN, glucose <0.6*LLN or >1.5*ULN, urine specific gravity <1.003, urine pH <4.5 or >8, urine glucose or ketones (qualitative) >=1, urine protein; urine blood/hemoglobin >=1, urobilinogen; bilirubin; nitrite; leukocyte esterase >=1. | Safety analysis set included all participants who received at least 1 dose of study drug. Data for Part 2 was planned to be analyzed only in Cohorts 1 and 3, as pre specified in protocol. | Posted | Number | participants | Baseline up to Day 11 |
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| 0 |
| 11 |
| 3 |
| 11 |
| EG001 | Part 1: Cohort 2- One CYP3A5*1 Allele | African-American participants with two CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. | 0 | 12 | 0 | 12 |
| EG002 | Part 1: Cohort 3- Two CYP3A5*1 Alleles | African-American participants with two CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. | 0 | 12 | 0 | 12 |
| EG003 | Part 1: Cohort 4 - No CYP3A5*1 Alleles | Caucasian participants with no CYP3A5*1 alleles, received maraviroc 300 mg tablet orally twice daily from Day 1 to Day 4 and once only in the morning of Day 5 in Part 1. | 0 | 12 | 3 | 12 |
| EG004 | Part 2: Cohort 1- No CYP3A5*1 Alleles | African-American participants with no CYP3A5*1 alleles, received maraviroc 150 mg tablet orally once daily along with darunavir/cobicistat 800/150 mg tablet once daily from Day 1 to Day 10 in Part 2 . | 0 | 11 | 2 | 11 |
| EG005 | Part 2: Cohort 3- Two CYP3A5*1 Alleles | African-American participants with two CYP3A5*1 alleles, received maraviroc 150 mg tablet orally once daily along with darunavir/cobicistat 800/150 mg tablet once daily from Day 1 to Day 10 in Part 2 . | 0 | 12 | 1 | 12 |
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Ear discomfort | Ear and labyrinth disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Flatulence | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Pain | General disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Thirst | General disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Pollakiuria | Renal and urinary disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Polyuria | Renal and urinary disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Throat irritation | Respiratory, thoracic and mediastinal disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Hot flush | Vascular disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Abdominal pain upper | Gastrointestinal disorders | MedDRA 18.1 | Non-systematic Assessment |
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| Somnolence | Nervous system disorders | MedDRA 18.1 | Non-systematic Assessment |
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Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications 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.
| D006838 |
| Hydrocarbons |
| D009930 | Organic Chemicals |
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D013449 | Sulfonamides |
| D000577 | Amides |
| D002219 | Carbamates |
| D000144 | Acids, Acyclic |
| D002264 | Carboxylic Acids |
| D013450 | Sulfones |
| D013457 | Sulfur Compounds |
| D005663 | Furans |
| D013844 | Thiazoles |
| PF-6857640 |
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| PF-06927572 |
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| PF-06927573 |
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| Mixed Models Analysis |
| 0.0001 |
| Adjusted Geometric Mean Ratio |
| 164.06 |
| 2-Sided |
| 90 |
| 134.54 |
| 200.06 |
| Superiority or Other |
| Statistical analysis of PF -6857639 was estimated and reported. | Mixed Models Analysis | < 0.0001 | Adjusted Geometric Mean Ratio | 198.49 | 2-Sided | 90 | 162.77 | 242.05 | Superiority or Other |
| Statistical analysis of PF -6857639 was estimated and reported. | Mixed Models Analysis | 0.1061 | Adjusted Geometric Mean Ratio | 120.99 | 2-Sided | 90 | 99.65 | 146.90 | Superiority or Other |
| Statistical analysis of PF -6857639 was estimated and reported. | Mixed Models Analysis | <0.0001 | Adjusted Geometric Mean Ratio | 272.07 | 2-Sided | 90 | 224.08 | 330.33 | Superiority or Other |
| Statistical analysis of PF -6857640 was estimated and reported. | Mixed Models Analysis | 0.3081 | Adjusted Geometric Mean Ratio | 110.22 | 2-Sided | 90 | 94.05 | 129.18 | Superiority or Other |
| Statistical analysis of PF -6857640 was estimated and reported. | Mixed Models Analysis | 0.8583 | Adjusted Geometric Mean Ratio | 101.71 | 2-Sided | 90 | 86.79 | 119.20 | Superiority or Other |
| Statistical analysis of PF -6857640 was estimated and reported. | Mixed Models Analysis | 0.3913 | Adjusted Geometric Mean Ratio | 108.52 | 2-Sided | 90 | 92.60 | 127.17 | Superiority or Other |
| Statistical analysis of PF -6857640 was estimated and reported. | Mixed Models Analysis | 0.4866 | Adjusted Geometric Mean Ratio | 106.69 | 2-Sided | 90 | 91.36 | 124.60 | Superiority or Other |
| Statistical analysis of PF -6857640 was estimated and reported. | Mixed Models Analysis | 0.0590 | Adjusted Geometric Mean Ratio | 119.61 | 2-Sided | 90 | 102.42 | 139.69 | Superiority or Other |
| Statistical analysis of PF -06927572 was estimated and reported. | Mixed Models Analysis | 0.9816 | Adjusted Geometric Mean Ratio | 99.70 | 2-Sided | 90 | 80.47 | 123.53 | Superiority or Other |
| Statistical analysis of PF -06927572 was estimated and reported. | Mixed Models Analysis | 0.6974 | Adjusted Geometric Mean Ratio | 105.12 | 2-Sided | 90 | 84.84 | 130.24 | Superiority or Other |
| Statistical analysis of PF -06927572 was estimated and reported. | Mixed Models Analysis | 0.9363 | Adjusted Geometric Mean Ratio | 101.03 | 2-Sided | 90 | 81.54 | 125.18 | Superiority or Other |
| Statistical analysis of PF -06927572 was estimated and reported. | Mixed Models Analysis | 0.7520 | Adjusted Geometric Mean Ratio | 96.11 | 2-Sided | 90 | 77.94 | 118.52 | Superiority or Other |
| Statistical analysis of PF -06927572 was estimated and reported. | Mixed Models Analysis | 0.9536 | Adjusted Geometric Mean Ratio | 100.73 | 2-Sided | 90 | 81.69 | 124.22 | Superiority or Other |
| Statistical analysis of PF -06927573 was estimated and reported. | Mixed Models Analysis | 0.8241 | Adjusted Geometric Mean Ratio | 97.60 | 2-Sided | 90 | 81.28 | 117.18 | Superiority or Other |
| Statistical analysis of PF -06927573 was estimated and reported. | Mixed Models Analysis | 0.1261 | Adjusted Geometric Mean Ratio | 118.50 | 2-Sided | 90 | 98.69 | 142.28 | Superiority or Other |
| Statistical analysis of PF -06927573 was estimated and reported. | Mixed Models Analysis | 0.9708 | Adjusted Geometric Mean Ratio | 99.60 | 2-Sided | 90 | 82.95 | 119.59 | Superiority or Other |
| Statistical analysis of PF -06927573 was estimated and reported. | Mixed Models Analysis | 0.1099 | Adjusted Geometric Mean Ratio | 84.05 | 2-Sided | 90 | 70.29 | 100.52 | Superiority or Other |
| Statistical analysis of PF -06927573 was estimated and reported. | Mixed Models Analysis | 0.7913 | Adjusted Geometric Mean Ratio | 97.21 | 2-Sided | 90 | 81.29 | 116.25 | Superiority or Other |
| Adjusted Geometric Mean Ratio |
| 85.84 |
| 2-Sided |
| 90 |
| 72.46 |
| 101.68 |
| Superiority or Other |
| Mixed Models Analysis | < 0.0001 | Adjusted Geometric Mean Ratio | 63.34 | 2-Sided | 90 | 53.47 | 75.04 | Superiority or Other |
| Mixed Models Analysis | 0.0036 | Adjusted Geometric Mean ratio | 73.79 | 2-Sided | 90 | 62.53 | 87.09 | Superiority or Other |
| Mixed Models Analysis | 0.0037 | Adjusted Geometric Mean Ratio | 73.89 | 2-Sided | 90 | 62.61 | 87.20 | Superiority or Other |
| Adjusted Geometric Mean Ratio |
| 87.28 |
| 2-Sided |
| 90 |
| 70.34 |
| 108.28 |
| Superiority or Other |
| Mixed Models Analysis | 0.0004 | Adjusted Geometric Mean Ratio | 61.23 | 2-Sided | 90 | 49.35 | 75.97 | Superiority or Other |
| Mixed Models Analysis | 0.0071 | Adjusted Geometric Mean Ratio | 70.16 | 2-Sided | 90 | 56.81 | 86.63 | Superiority or Other |
| Mixed Models Analysis | 0.0135 | Adjusted Geometric Mean Ratio | 72.37 | 2-Sided | 90 | 58.60 | 89.36 | Superiority or Other |
| Adjusted Geometric Mean Ratio |
| 105.43 |
| 90 |
| 85.28 |
| 130.35 |
| Superiority or Other |
| Mixed Models Analysis | 0.0331 | Adjusted Geometric Mean Ratio | 75.74 | 2-Sided | 90 | 61.26 | 93.64 | Superiority or Other |
| Mixed Models Analysis | 0.0104 | Adjusted Geometric Mean Ratio | 71.84 | 2-Sided | 90 | 58.38 | 88.40 | Superiority or Other |
| Mixed Models Analysis | 0.0104 | Adjusted Geometric Mean Ratio | 71.82 | 2-Sided | 90 | 58.37 | 88.39 | Superiority or Other |
| PF-6857640 |
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| PF-06927572 |
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| PF-06927573 |
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| PF-6857640 |
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| PF-06927572 |
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| PF-06927573 |
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| PF-6857640 |
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| PF-06927572 |
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| PF-06927573 |
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| PF-6857640 |
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| PF-06927572 |
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| PF-06927573 |
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| PF-6857640 |
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| PF-06927572 |
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| PF-06927573 |
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| SAEs |
|