A Drug Drug Interaction (DDI) Study of Pirtobrutinib (LOXO-305) and Different Formulations of Midazolam in Healthy Participants

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I, Open Label, Fixed-sequence Drug Interaction Study to Investigate the Effect of Multiple Oral Doses of LOXO-305 on the Pharmacokinetics of a Single Dose of Intravenous and Oral Midazolam (CYP3A4 Substrate) in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: Midazolam Syrup
* Drug: Midazolam Solution
* Drug: Pirtobrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have Body mass index (BMI) within the range of 18.0 to 32.0 kilograms per square meter (kg/m²), inclusive Male and female participants in good health, determined by no clinically significant findings from medical history, 12-lead Electrocardiogram (ECG), vital sign measurements, or clinical laboratory evaluations as assessed by the investigator Female participants of non-childbearing potential and male participants who follow standard contraceptive methods Must have comply with all study procedures, including the 8-night stay at the Clinical Research Unit (CRU) and follow-up phone call Exclusion Criteria: History or presence of any diseases or conditions of clinical significance by the Investigator (or designee) and/or Sponsor Positive serologic test for hepatitis B surface antigen (HBsAg), hepatitis B virus immunoglobulin M (HBV IgM) core antibody, hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) antibody at Screening Positive polymerase chain reaction (PCR) test for COVID-19 at Screening or Check-in (Day -1) Known ongoing alcohol and/or drug abuse within 2 years prior to Screening History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee) Have previously completed or withdrawn from any other study investigating Pirtobrutinib (LOXO-305) and have previously received the investigational product

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midazolam (Intravenous [IV] Bolus)<br>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. | Drug: Midazolam Solution<br>* Administered IV bolus.<br>|
| Experimental: Midazolam Oral<br>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. | Drug: Midazolam Syrup<br>* Administered Orally.<br>|
| Experimental: Pirtobrutinib<br>Multiple oral doses of Pirtobrutinib once a day (QD) will be administered on Days 5 through Day 17. | Drug: Pirtobrutinib<br>* Administered Orally.<br>* Other names: LY3527727;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t): Midazolam and its Metabolite 1-OH-Midazolam Following Oral Dose |  | Predose through 24 hours post dose alone on Day 3 and with LOXO-305 on Day 17 | 
| Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf): Midazolam and its Metabolite 1-OH-Midazolam Following Oral Dose |  | Predose through 24 hours post dose alone on Day 3 and with LOXO-305 on Day 17 | 
| Percentage Extrapolation for AUC0-inf (%AUCextrap): Midazolam and its Metabolite 1-OH-Midazolam Following Oral Dose |  | Predose through 24 hours post dose alone on Day 3 and with LOXO-305 on Day 17 | 
| Maximum Observed Plasma Concentration (Cmax): Midazolam and its Metabolite 1-OH-Midazolam Following Oral Dose |  | Predose through 24 hours post dose alone on Day 3 and with LOXO-305 on Day 17 | 
| Time To Maximum Observed Plasma Concentration (tmax): Midazolam and its Metabolite 1-OH-Midazolam Following Oral Dose |  | Predose through 24 hours post dose alone on Day 3 and with LOXO-305 on Day 17 | 
| Apparent Terminal Elimination Rate Constant (λZ): Midazolam and its Metabolite 1-OH-Midazolam Following Oral Dose |  | Predose through 24 hours post dose alone on Day 3 and with LOXO-305 on Day 17 | 
| Apparent Systemic Clearance (CL/F; Oral Midazolam) |  | Predose through 24 hours post dose alone on Day 3 and with LOXO-305 on Day 17 | 
| Total Clearance (CL; IV midazolam) |  | Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15 | 
| Apparent Plasma Terminal Elimination Half-Life (t½): Midazolam and its Metabolite 1-OH-Midazolam Following Oral Dose |  | Predose through 24 hours post dose alone on Day 3 and with LOXO-305 on Day 17 | 
| Apparent Volume of Distribution (Vz/F; Oral Midazolam) |  | Predose through 24 hours post dose alone on Day 3 and with LOXO-305 on Day 17 | 
| Volume of Distribution (Vz, IV Midazolam) |  | Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15 | 
| Volume of Distribution at Steady State (Vss; IV Midazolam) |  | Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15 | 
| Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t): Midazolam and its Metabolite 1-OH-Midazolam Following IV Dose |  | Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15 | 
| Area Under the Concentration-Time From Time 0 Extrapolated To Infinity (AUC0-inf): Midazolam and its Metabolite 1-OH-Midazolam Following IV Dose |  | Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15 | 
| Percentage Extrapolation for AUC0-inf (%AUCextrap): Midazolam and its Metabolite 1-OH-Midazolam Following IV Dose |  | Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15 | 
| Maximum Observed Plasma Concentration (Cmax): Midazolam and its Metabolite 1-OH-Midazolam Following IV Dose |  | Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15 | 
| Time To Maximum Observed Plasma Concentration (tmax): Midazolam and its Metabolite 1-OH-Midazolam Following IV Dose |  | Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15 | 
| Apparent Terminal Elimination Rate Constant (λZ): Midazolam and its Metabolite 1-OH-Midazolam Following IV Dose |  | Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib |  | Predose through 24 hours postdose alone on Day 5 and Day 14, and on Day 15 with IV midazolam, and Day 17, 19, 20, and 21 (up to 100 hours post-LOXO-305 dose on Day 17) | 
| Area Under the Concentration during a dosing interval (AUCtau) of Pirtobrutinib |  | Predose through 24 hours postdose alone on Day 5 and Day 14, and on Day 15 with IV midazolam, and Day 17, 19, 20, and 21 (up to 100 hours post-LOXO-305 dose on Day 17) | 
| Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib |  | Predose through 24 hours postdose alone on Day 5 and Day 14, and on Day 15 with IV midazolam, and Day 17, 19, 20, and 21 (up to 100 hours post-LOXO-305 dose on Day 17) | 
| Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib |  | Predose through 24 hours postdose alone on Day 5 and Day 14, and on Day 15 with IV midazolam, and Day 17, 19, 20, and 21 (up to 100 hours post-LOXO-305 dose on Day 17) | 
| Time To Maximum Observed Plasma Concentration (tmax) of Pirtobrutinib |  | Predose through 24 hours postdose alone on Day 5 and Day 14, and on Day 15 with IV midazolam, and Day 17, 19, 20, and 21 (up to 100 hours post-LOXO-305 dose on Day 17) | 
| Apparent Systemic Clearance at Steady State (CL,ss/F) of Pirtobrutinib |  | Predose through 24 hours postdose alone on Day 5 and Day 14, and on Day 15 with IV midazolam, and Day 17, 19, 20, and 21 (up to 100 hours post-LOXO-305 dose on Day 17) | 
| Accumulation Ratio (RAUC) of Pirtobrutinib |  | Predose through 24 hours postdose alone on Day 5 and Day 14, and on Day 15 with IV midazolam, and Day 17, 19, 20, and 21 (up to 100 hours post-LOXO-305 dose on Day 17) |