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

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

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 Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Pirtobrutinib; Drug: Midazolam Solution; Drug: Midazolam Syrup

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Daytona Beach, Florida, United States, 32117
      • Covance Clinical Research Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Midazolam (Intravenous [IV] Bolus); 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; Administered IV bolus.
Experimental: Midazolam Oral; 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; Administered Orally.
Experimental: Pirtobrutinib; Multiple oral doses of Pirtobrutinib once a day (QD) will be administered on Days 5 through Day 17.	Drug: Pirtobrutinib; Administered Orally.; Other Names: LOXO-305; LY3527727

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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)

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Collaborators: Loxo Oncology, Inc.
• Investigators: Study Director: Renee Ward, MD, PhD, Loxo Oncology, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2020
• Primary Completion (Actual): October 20, 2020
• Study Completion (Actual): October 20, 2020

Study Registration Dates

• First Submitted: December 13, 2023
• First Submitted That Met QC Criteria: December 13, 2023
• First Posted (Actual): December 26, 2023

Study Record Updates

• Last Update Posted (Actual): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 13, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Tranquilizing Agents; Psychotropic Drugs; Protein Kinase Inhibitors; Hypnotics and Sedatives; Adjuvants, Anesthesia; Anti-Anxiety Agents; GABA Modulators; GABA Agents; Midazolam; Pirtobrutinib
• Other Study ID Numbers: LOXO-BTK-20008; J2N-OX-JZND (Other Identifier: Eli Lilly and Company)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No