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

Eli Lilly and Company15 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Enrollment

Conditions

Healthy

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

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compound, food, or other substance, unless approved by the Investigator (or designee) * Have previously completed or withdrawn from any other study investigating Pirtobrutinib (LOXO-305) and have previously received the investigational product

Outcomes

Primary Outcomes

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.

Time frame: 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.

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.

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.

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.

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.

PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration

PK: CL/F of midazolam following oral dose administration was reported.

PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration

PK: Vz/F of midazolam following oral dose administration was reported.

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.

PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration

PK: CL of midazolam following intravenous dose administration was reported.

Time frame: 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.

PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration

PK: Vss of midazolam following intravenous dose administration was reported.

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.

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.

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.

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.

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.

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.

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.

Secondary Outcomes

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.

Time frame: 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: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib

PK: AUCtau of Pirtobrutinib was reported.

PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib

PK: Cmax of Pirtobrutinib was reported.

PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib

PK: Ctrough of Pirtobrutinib before multiple oral doses administration was reported.

Time frame: 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.

PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib

PK: CL,ss/F of Pirtobrutinib was reported.

Time frame: 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.

Time frame: 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)