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| ID | Type | Description | Link |
|---|---|---|---|
| J2N-OX-JZND | Other Identifier | Eli Lilly and Company |
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| Name | Class |
|---|---|
| Loxo Oncology, Inc. | INDUSTRY |
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The main purpose of this study is to assess the effect of Pirtobrutinib (LOXO-305) on how fast different formulations of midazolam gets into the blood stream and how long it takes the body to remove it when administered in healthy participants. The study will also access how much endogenous coproporphyrins I and III as biomarkers of OATP1B1 and OATP1B3 is in the bloodstream and how the body handles and eliminates them following single and multiple oral doses of Pirtobrutinib. Safety and tolerability of Pirtobrutinib will also be evaluated. For each participant, the total duration of the study will be 59 days, including screening.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Midazolam (Intravenous [IV] Bolus) | Experimental | A single IV bolus dose of midazolam will be administered in the morning following a 10-hour fast prior to dosing and a 4-hour fast postdose on Day 1 and Day 15. |
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| Midazolam Oral | Experimental | A single oral dose of midazolam will be administered in the morning following a 10-hour fast prior to dosing and a 4-hour fast postdose on Day 3 and Day 17. |
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| Pirtobrutinib | Experimental | Multiple oral doses of Pirtobrutinib once a day (QD) will be administered on Days 5 through Day 17. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Midazolam Syrup | Drug | Administered Orally. |
| |
| Midazolam Solution |
| Measure | Description | Time Frame |
|---|---|---|
| Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-hydroxymidazolam (1-OH-midazolam) Following Oral Dose Administration | PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: AUC(0-inf) of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: Cmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| Measure | Description | Time Frame |
|---|---|---|
| PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | PK: AUC0-t of Pirtobrutinib was reported. | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Renee Ward, MD, PhD | Loxo Oncology, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Covance Clinical Research Unit | Daytona Beach | Florida | 32117 | United States |
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The study consisted of 2 periods: Period 1 and Period 2. A total of 15 healthy participants were enrolled in the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Period 1: All Participants: Midazolam (IV + Oral Dose) |
A washout period of 2 days between midazolam IV dose and midazolam oral dose on Day 1 and Day 3 was observed. |
| FG001 | Period 2: All Participants: Pirtobrutinib + Midazolam (IV + Oral Dose) |
A washout period of 2 days between midazolam IV dose and midazolam oral dose on Day 15 and Day 17 was observed. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Period 1: Day 1 to Day 4 |
| ||||||||||||||||
| Period 2: Day 5 to Day 20 |
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All participants who received at least 1 dose of study drug.
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| ID | Title | Description |
|---|---|---|
| BG000 | All Participants: Midazolam (IV + Oral Dose) + Pirtobrutinib | All participants in the study who received:
|
| 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 | Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-hydroxymidazolam (1-OH-midazolam) Following Oral Dose Administration | PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Hours*nanograms per milliliter (h*ng/mL) | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
|
From Day 1 up to 7 days post end of treatment (i.e., up to Day 30)
All participants who received at least 1 dose of study drugs (pirtobrutinib, IV midazolam, or oral midazolam). Participants were classified into groups based on actual treatment received.
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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 | Period 1: IV Midazolam 250 mcg | Participants received a single IV bolus dose of midazolam 250 mcg solution on Day 1. |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Constipation | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chief Medical Officer | Eli Lilly and Company | 08005455979 | ClinicalTrials.gov@lilly.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 | Sep 13, 2020 | Jan 21, 2025 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Oct 16, 2020 | Jan 21, 2025 | SAP_001.pdf |
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| ID | Term |
|---|---|
| C000723100 | pirtobrutinib |
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| Drug |
Administered IV bolus. |
|
| Pirtobrutinib | Drug | Administered Orally. |
|
|
| PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration |
PK: tmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. |
| Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: λz of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration | PK: CL/F of midazolam following oral dose administration was reported. | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration | PK: Vz/F of midazolam following oral dose administration was reported. | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: t½ of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration | PK: CL of midazolam following intravenous dose administration was reported. | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Volume of Distribution (Vz) of Midazolam Following Intravenous Dose Administration | PK: Vz of midazolam following intravenous dose administration was reported. | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration | PK: Vss of midazolam following intravenous dose administration was reported. | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: AUC0-inf of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: Cmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: tmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: λz of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: t1/2 of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
| PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib | PK: AUCtau of Pirtobrutinib was reported. | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) |
| PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib | PK: Cmax of Pirtobrutinib was reported. | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) |
| PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib | PK: Ctrough of Pirtobrutinib before multiple oral doses administration was reported. | Period 2: 24-hour post-dose on Day 14, Day 15, and Day 17 |
| PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | PK: tmax of Pirtobrutinib was reported. | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) |
| PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib | PK: CL,ss/F of Pirtobrutinib was reported. | Period 2: Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) |
| PK: Accumulation Ratio (RAUC) of Pirtobrutinib | RAUC was ratio of Day 14 AUCtau to Day 5 AUCtau. | Period 2: Day 5 and Day 14 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose) |
| COMPLETED |
|
| NOT COMPLETED |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants | No |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants | No |
|
| Race (NIH/OMB) | Count of Participants | Participants | No |
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| Region of Enrollment | Count of Participants | Participants | No |
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| OG001 | Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg (Day 17) | Participants who received pirtobrutinib 200 mg tablets orally followed by a single oral dose of midazolam 500 mcg syrup on Day 17. |
|
|
| Primary | PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: AUC(0-inf) of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
|
|
|
| Primary | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | percentage of AUC0-inf | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
|
|
|
| Primary | PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: Cmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | nanograms per milliliter (ng/mL) | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
|
|
|
| Primary | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: tmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Median | Full Range | Hours | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
|
|
|
| Primary | PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: λz of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | one per hour (1/h) | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
|
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| Primary | PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration | PK: CL/F of midazolam following oral dose administration was reported. | All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters per hour (L/h) | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
|
|
|
| Primary | PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration | PK: Vz/F of midazolam following oral dose administration was reported. | All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
|
|
|
| Primary | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration | PK: t½ of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported. | All participants who received at least 1 dose of oral midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Period 1: Day 3 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
|
|
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| Primary | PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration | PK: CL of midazolam following intravenous dose administration was reported. | All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
|
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| Primary | PK: Volume of Distribution (Vz) of Midazolam Following Intravenous Dose Administration | PK: Vz of midazolam following intravenous dose administration was reported. | All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
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| Primary | PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration | PK: Vss of midazolam following intravenous dose administration was reported. | All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Liters | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
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| Primary | PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
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| Primary | PK: Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: AUC0-inf of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. Here, 'Number analyzed' signifies participants with available data for each specified category. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
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| Primary | PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. Here, 'Number analyzed' signifies participants with available data for each specified category. | Posted | Geometric Mean | Geometric Coefficient of Variation | percentage of AUC0-inf | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
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| Primary | PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: Cmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
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| Primary | PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: tmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Median | Full Range | hours | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
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| Primary | PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: λz of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | 1/h | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
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| Primary | PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration | PK: t1/2 of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported. | All participants who received at least 1 dose of IV midazolam had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Period 1: Day 1 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose); Period 2: Day 15 (pre-dose, 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 and 24 hours post-dose) |
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| Secondary | PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib | PK: AUC0-t of Pirtobrutinib was reported. | The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) |
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| Secondary | PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib | PK: AUCtau of Pirtobrutinib was reported. | The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) |
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| Secondary | PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib | PK: Cmax of Pirtobrutinib was reported. | The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) |
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| Secondary | PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib | PK: Ctrough of Pirtobrutinib before multiple oral doses administration was reported. | The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Period 2: 24-hour post-dose on Day 14, Day 15, and Day 17 |
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| Secondary | PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib | PK: tmax of Pirtobrutinib was reported. | The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Median | Full Range | hours | Period 2: Day 5, Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) |
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| Secondary | PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib | PK: CL,ss/F of Pirtobrutinib was reported. | The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | Period 2: Day 14 and Day 15 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose), Day 17 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, and 100 hours post-dose) |
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| Secondary | PK: Accumulation Ratio (RAUC) of Pirtobrutinib | RAUC was ratio of Day 14 AUCtau to Day 5 AUCtau. | The PK population included all participants who received at least 1 dose of pirtobrutinib had at least 1 quantifiable PK concentration, and for whom at least 1 PK parameter was computed. | Posted | Geometric Mean | Geometric Coefficient of Variation | Ratio | Period 2: Day 5 and Day 14 (pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, and 24 hours post-dose) |
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| 0 |
| 15 |
| 0 |
| 15 |
| 1 |
| 15 |
| EG001 | Period 1: Oral Midazolam 500 mcg | Participants received a single oral dose of midazolam 500 mcg syrup on Day 3 | 0 | 15 | 0 | 15 | 0 | 15 |
| EG002 | Period 2: Pirtobrutinib 200 mg | Participants received pirtobrutinib 200 mg tablets orally QD from Day 5 through Day 17. | 0 | 15 | 0 | 15 | 3 | 15 |
| EG003 | Period 2: Pirtobrutinib 200 mg + IV Midazolam 250 mcg | Participants received pirtobrutinib 200 mg tablets orally followed by IV bolus dose of midazolam 250 mcg solution on Day 15. | 0 | 15 | 0 | 15 | 1 | 15 |
| EG004 | Period 2: Pirtobrutinib 200 mg + Oral Midazolam 500 mcg | Participants received pirtobrutinib 200 mg tablets orally followed by oral dose of midazolam 500 mcg syrup on Day 17. | 0 | 15 | 0 | 15 | 0 | 15 |
| Flatulence | Gastrointestinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Injection site pain | General disorders | MedDRA 23.0 | Systematic Assessment |
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| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 23.0 | Systematic Assessment |
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| Pollakiuria | Renal and urinary disorders | MedDRA 23.0 | Systematic Assessment |
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| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 23.0 | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA 23.0 | Systematic Assessment |
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Not provided
| Metabolite: 1-OH-medazolam |
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| Metabolite: 1-OH-medazolam |
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