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

Healthy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06180967
• Other study ID #: LOXO-BTK-20008
• Secondary ID: J2N-OX-JZND
• Status: Completed
• Phase: Phase 1
• Start date: September 3, 2020
• Est. completion date: October 20, 2020

Study information

• Verified date: December 2023
• Source: Eli Lilly and Company
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 15
• Est. completion date: October 20, 2020
• Est. primary completion date: October 20, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Midazolam Syrup
Administered Orally.
• Midazolam Solution
Administered IV bolus.
• Pirtobrutinib
Administered Orally.

Locations

Country	Name	City	State
United States	Covance Clinical Research Unit	Daytona Beach	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Eli Lilly and Company	Loxo Oncology, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Apparent Terminal Elimination Rate Constant (?Z): 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
Primary	Apparent Systemic Clearance (CL/F; Oral Midazolam)		Predose through 24 hours post dose alone on Day 3 and with LOXO-305 on Day 17
Primary	Total Clearance (CL; IV midazolam)		Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15
Primary	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
Primary	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
Primary	Volume of Distribution (Vz, IV Midazolam)		Predose through 24 hours postdose alone on Day 1 and with LOXO-305 on Day 15
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	Apparent Terminal Elimination Rate Constant (?Z): 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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)