Clinical trial NCT06180967: A Drug Drug Interaction (DDI) Study of Pirtobrutinib (LOXO-305) and Different Formulations of Midazolam in Healthy Participants
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
Collaborators: name: Loxo Oncology, Inc.
First posted: 2023-12-26
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: BASIC_SCIENCE

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
timeFrame: 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)
measure: PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
timeFrame: 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)
measure: PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
timeFrame: 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)
measure: PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
timeFrame: 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)
measure: PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration
timeFrame: 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)
measure: PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration
timeFrame: 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)
measure: PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration
timeFrame: 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)
measure: PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration
timeFrame: 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)
measure: PK: Volume of Distribution (Vz) of Midazolam Following Intravenous Dose Administration
timeFrame: 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)
measure: PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
timeFrame: 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)
measure: PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
timeFrame: 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)
measure: PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
timeFrame: 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)
measure: PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
timeFrame: 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)
measure: PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration
timeFrame: 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)
Secondary outcomes:
measure: PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib
timeFrame: 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)
measure: PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib
timeFrame: 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)
measure: PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib
timeFrame: 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)
measure: PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib
timeFrame: Period 2: 24-hour post-dose on Day 14, Day 15, and Day 17
measure: PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib
timeFrame: 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)
measure: PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib
timeFrame: 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)
measure: PK: Accumulation Ratio (RAUC) of Pirtobrutinib
timeFrame: 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)
Other outcomes:
Locations:
city: Daytona Beach
country: United States
facility: Covance Clinical Research Unit
state: Florida
Study officials:
affiliation: Loxo Oncology, Inc.
name: Renee Ward, MD, PhD
role: STUDY_DIRECTOR
References: