A Study of Effect of Multiple Doses of LOXO-305 on the Pharmacokinetics of Single Oral Doses of CYP1A2, CYP2C9, CYP2C19 Substrates 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 CYP1A2, CYP2C9, and CYP2C19 Substrates Using a Probe Drug Cocktail in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06215430
• Other study ID #: LOXO-BTK-20010
• Secondary ID: J2N-OX-JZNE
• Status: Completed
• Phase: Phase 1
• Start date: January 11, 2021
• Est. completion date: April 15, 2021

Study information

• Verified date: January 2024
• 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 evaluate the effect of LOXO-305 on single oral dose of caffeine cytochrome P450 1A2 (CYP1A2) substrate, S-warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate) when administered as multiple doses by collecting the blood samples and conducting the blood tests to measure how much LOXO-305 is in the bloodstream and how the body handles and eliminates LOXO-305 in adult healthy participants. The study will also evaluate the safety and tolerability of LOXO-305. The study will be conducted in two periods. Participants will stay in this study for up to 67 days, including screening.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 16
• Est. completion date: April 15, 2021
• Est. primary completion date: April 15, 2021
• 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/m^2), 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 23-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.
• 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).

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Caffeine Tablet
Administered orally.
• Omeprazole capsule
Administered orally.
• Warfarin tablet
Administered orally.
• LOXO-305
Administered orally.

Locations

Country	Name	City	State
United States	Covance Clinical Research Unit	Dallas	Texas

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 (AUC) From Hour 0 to 24 Hours Post-Dose (AUC0-24): Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Area Under the Concentration Time Curve (AUC) From Hour 0 to 24 Hours Post-Dose (AUC0-24): Omeprazole		Predose through 48 hours postdose following administration alone on Day 1 (Period 1) and predose through 48 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Area Under the Concentration Time Curve (AUC) From Hour 0 to 24 Hours Post-Dose (AUC0-24): Warfarin		Predose through 120 hours postdose following administration alone on Day 1 (Period 1) and predose through 120 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Area Under the Concentration Time Curve (AUC) From Hour 0 to 24 Hours Post-Dose (AUC0-24): LOXO-305		0 hours and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (prior to dosing on Day16), 48 (prior to dosing on Day17), 72 (prior to dosing on Day18), 96 (prior to dosing on Day19), 120,144,168,&192 hours postdose on Day15 and/or Day 23
Primary	AUC From hour 0 to the Last Measurable Concentration (AUC0-t): Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Area Under the Concentration Time Curve (AUC) From hour 0 to the Last Measurable Concentration (AUC0-t): Omeprazole		Predose through 48 hours postdose following administration alone on Day 1 (Period 1) and predose through 48 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Area Under the Concentration Time Curve (AUC) From hour 0 to the Last Measurable Concentration (AUC0-t): Warfarin		Predose through 120 hours postdose following administration alone on Day 1 (Period 1) and predose through 120 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Area Under the Concentration Time Curve (AUC) From hour 0 to the Last Measurable Concentration (AUC0-t): LOXO-305		0 hours and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (prior to dosing on Day 16), 48 (prior to dosing on Day 17), 72 (prior to dosing on Day 18), 96 (prior to dosing on Day 19), 120, 144, 168, & 192 hours postdose on Day 15 and/or Day 23
Primary	Area Under the Concentration Time Curve (AUC) from hour 0 extrapolated to infinity (AUC0-inf): Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Area Under the Concentration Time Curve (AUC) from hour 0 extrapolated to infinity (AUC0-inf): Omeprazole		Predose through 48 hours postdose following administration alone on Day 1 (Period 1) and predose through 48 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Area Under the Concentration Time Curve (AUC) from hour 0 extrapolated to infinity (AUC0-inf): Warfarin		Predose through 120 hours postdose following administration alone on Day 1 (Period 1) and predose through 120 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Area Under the Concentration Time Curve (AUC) from hour 0 extrapolated to infinity (AUC0-inf): LOXO-305		0 hours and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (prior to dosing on Day 16), 48 (prior to dosing on Day 17), 72 (prior to dosing on Day 18), 96 (prior to dosing on Day 19), 120, 144, 168, & 192 hours postdose on Day 15 and/or Day 23
Primary	Percentage Extrapolation for AUC0-inf (%AUCextrap): Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Percentage Extrapolation for AUC0-inf (%AUCextrap): Omeprazole		Predose through 48 hours postdose following administration alone on Day 1 (Period 1) and predose through 48 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Percentage Extrapolation for AUC0-inf (%AUCextrap): Warfarin		Predose through 120 hours postdose following administration alone on Day 1 (Period 1) and predose through 120 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Percentage Extrapolation for AUC0-inf (%AUCextrap): LOXO-305		0 hours and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (prior to dosing on Day 16), 48 (prior to dosing on Day 17), 72 (prior to dosing on Day 18), 96 (prior to dosing on Day 19), 120, 144, 168, & 192 hours postdose on Day 15 and/or Day 23
Primary	Apparent Systemic Clearance (CL/F): Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Apparent Systemic Clearance (CL/F): Omeprazole		Predose through 48 hours postdose following administration alone on Day 1 (Period 1) and predose through 48 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Apparent Systemic Clearance (CL/F): Warfarin		Predose through 120 hours postdose following administration alone on Day 1 (Period 1) and predose through 120 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Apparent Systemic Clearance (CL/F): LOXO-305		0 hours and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (prior to dosing on Day 16), 48 (prior to dosing on Day 17), 72 (prior to dosing on Day 18), 96 (prior to dosing on Day 19), 120, 144, 168, & 192 hours postdose on Day 15 and/or Day 23
Primary	Maximum Observed Plasma Concentration: Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Maximum Observed Plasma Concentration: Omeprazole		Predose through 48 hours postdose following administration alone on Day 1 (Period 1) and predose through 48 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Maximum Observed Plasma Concentration: Warfarin		Predose through 120 hours postdose following administration alone on Day 1 (Period 1) and predose through 120 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Maximum Observed Plasma Concentration: LOXO-305		0 hours and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (prior to dosing on Day 16), 48 (prior to dosing on Day 17), 72 (prior to dosing on Day 18), 96 (prior to dosing on Day 19), 120, 144, 168, & 192 hours postdose on Day 15 and/or Day 23
Primary	Time to Maximum Observed Plasma Concentration (tmax): Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Time to Maximum Observed Plasma Concentration (tmax): Omeprazole		Predose through 48 hours postdose following administration alone on Day 1 (Period 1) and predose through 48 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Time to Maximum Observed Plasma Concentration (tmax): Warfarin		Predose through 120 hours postdose following administration alone on Day 1 (Period 1) and predose through 120 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Time to Maximum Observed Plasma Concentration (tmax): LOXO-305		0 hours and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (prior to dosing on Day 16), 48 (prior to dosing on Day 17), 72 (prior to dosing on Day 18), 96 (prior to dosing on Day 19), 120, 144, 168, & 192 hours postdose on Day 15 and/or Day 23
Primary	Apparent Terminal Elimination Rate Constant (?Z): Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Apparent Terminal Elimination Rate Constant (?Z): Omeprazole		Predose through 48 hours postdose following administration alone on Day 1 (Period 1) and predose through 48 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Apparent Terminal Elimination Rate Constant (?Z): Warfarin		Predose through 120 hours postdose following administration alone on Day 1 (Period 1) and predose through 120 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Apparent Terminal Elimination Rate Constant (?Z): LOXO-305		0 hours and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (prior to dosing on Day 16), 48 (prior to dosing on Day 17), 72 (prior to dosing on Day 18), 96 (prior to dosing on Day 19), 120, 144, 168, & 192 hours postdose on Day 15 and/or Day 23
Primary	Apparent Volume of Distribution at Terminal Phase (Vz/F): Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Apparent Volume of Distribution at Terminal Phase (Vz/F): Omeprazole		Predose through 48 hours postdose following administration alone on Day 1 (Period 1) and predose through 48 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Apparent Volume of Distribution at Terminal Phase (Vz/F): Warfarin		Predose through 120 hours postdose following administration alone on Day 1 (Period 1) and predose through 120 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Apparent Volume of Distribution at Terminal Phase (Vz/F): LOXO-305		0 hours and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (prior to dosing on Day 16), 48 (prior to dosing on Day 17), 72 (prior to dosing on Day 18), 96 (prior to dosing on Day 19), 120, 144, 168, & 192 hours postdose on Day 15 and/or Day 23
Primary	AUC0-24 and AUC0-48 Ratio of Paraxanthine to Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Mean Residence Time (MRT): Caffeine		Predose through 24 hours postdose following administration alone on Day 1 (Period 1) and predose through 24 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Mean Residence Time (MRT): Omeprazole		Predose through 48 hours postdose following administration alone on Day 1 (Period 1) and predose through 48 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Mean Residence Time (MRT): Warfarin		Predose through 120 hours postdose following administration alone on Day 1 (Period 1) and predose through 120 hours postdose following administration with LOXO-305 on Day 15 (Period 2)
Primary	Mean Residence Time (MRT): LOXO-305		0 hours and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24 (prior to dosing on Day 16), 48 (prior to dosing on Day 17), 72 (prior to dosing on Day 18), 96 (prior to dosing on Day 19), 120, 144, 168, & 192 hours postdose on Day 15 and/or Day 23