Study of Pirtobrutinib (LOXO-305) in Participants With Impaired Liver Function and Healthy Participants

An Open-label, Nonrandomized, Single-dose, Parallel-group, Safety, Tolerance, and Pharmacokinetic Study of LOXO-305 Administered to Fasted Hepatically Impaired Male and Female Subjects and Fasted Matched-control Healthy Subjects

The main purpose of this study is to measure how much of pirtobrutinib (LOXO-305) gets into the bloodstream and how long it takes the body to eliminate it in participants with impaired liver function and healthy participants. The side effects and tolerability of pirtobrutinib will also be evaluated. Participation could last about 46 days.

Study Overview

• Status: Completed
• Conditions: Hepatic Insufficiency; Healthy
• Intervention / Treatment: Drug: Pirtobrutinib

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Anaheim, California, United States, 92801
      • Orange County Research Institute
    • Tustin, California, United States, 92780
      • Orange County Research Center
  • Florida
    • Edgewater, Florida, United States, 32132
      • Riverside Clinical Research
    • Miami, Florida, United States, 33014
      • Clinical Pharmacology of Miami
    • Miami, Florida, United States, 33147
      • Advanced Pharma Clinical Research
    • Orlando, Florida, United States, 32809
      • Orlando Clinical Research Center
  • Texas
    • San Antonio, Texas, United States, 78215
      • The Texas Liver Institute
    • San Antonio, Texas, United States, 78229
      • Pinnacle Clinical Research

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Participants with mild, moderate or severe hepatic impairment and healthy participants with normal hepatic function
• Males and females of non-childbearing potential.
• Within body mass index (BMI) range 18.5 to 40.0 kilograms per square meter (kg/m²).
• Participants will be in good health, based on medical history, physical examination findings, vital signs, 12 lead electrocardiogram (ECG), and clinical laboratory tests, as determined by the Investigator (or designee).
• Able to comply with all study procedures, including the 8-night stay at the Clinical Research Unit and follow-up phone call.

Exclusion Criteria:

• History or presence of any of the following, deemed clinically significant by the Investigator (or designee), and/or Sponsor:

  1. pancreatitis
  2. peptic ulcer disease
  3. intestinal malabsorption
  4. gastric reduction surgery
  5. history or presence of clinically significant cardiovascular disease.
• Participants with out-of-range, at-rest vital signs.
• Abnormal laboratory values determined to be clinically significant by the Investigator (or designee).
• Clinically significant abnormality, as determined by the Investigator (or designee), from physical examination.
• Participation in any other investigational study drug trial involving administration of any investigational drug in the past 30 days or 5 half-lives, whichever was longer, prior to the first dose administration (Day 1).
• Use or intention to use any prescription or over-the-counter medications within 14 days prior to the first dose administration (Day 1) and through end of trial.
• History or presence, upon clinical evaluation, of any illness that, in the opinion of the Investigator, would interfere with the ability to provide informed consent or comply with study instructions, or that might confound the interpretation of the study results, or put the participant at undue risk.
• Donation of blood from 56 days prior to Screening, plasma or platelets from 4 weeks prior to Screening.
• Receipt of blood products within 2 months prior to Check-in (Day -1).
• Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, biliary, renal, hematological, pulmonary, cardiovascular (including any prior history of cardiomyopathy or cardiac failure), gastrointestinal (GI), neurological, or psychiatric disorder (as determined by the Investigator).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pirtobrutinib (Normal Hepatic Function); Participants received a single dose of Pirtobrutinib 200 milligrams (mg) administered orally on Day 1.	Drug: Pirtobrutinib; Administered orally; Other Names: LOXO-305, LY3527727
Experimental: Pirtobrutinib (Mild Hepatic Impairment); Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1.	Drug: Pirtobrutinib; Administered orally; Other Names: LOXO-305, LY3527727
Experimental: Pirtobrutinib (Moderate Hepatic Impairment); Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1.	Drug: Pirtobrutinib; Administered orally; Other Names: LOXO-305, LY3527727
Experimental: Pirtobrutinib (Severe Hepatic Impairment); Participants received a single dose of Pirtobrutinib 200 mg administered orally on Day 1.	Drug: Pirtobrutinib; Administered orally; Other Names: LOXO-305, LY3527727

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (PK): Maximum Observed Concentration (Cmax) of Pirtobrutinib	PK: Cmax of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib	PK: Tmax of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Area Under the Concentration Versus Time Curve From Time Zero to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib	PK: AUC0-t of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity (AUC0-inf) of Pirtobrutinib	PK: AUC0-inf of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Pirtobrutinib	PK: %AUCextrap of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Apparent Plasma Terminal Elimination Half-life (t½) of Pirtobrutinib	PK: t½ of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib	PK: CL/F of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of Pirtobrutinib	PK: Vz/F of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Mean Residence Time (MRT) of Pirtobrutinib	MRT is the average time a drug molecule stays in the body, calculated from the AUC0-inf.	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Unbound Cmax (Cmax,u) of Pirtobrutinib	Cmax,u was calculated by multiplying Cmax by Fu (i.e., Cmax*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Unbound AUC0-t (AUC0-t,u) of Pirtobrutinib	AUC0-t,u was calculated by multiplying AUC0-t by Fu (i.e., AUC0-t*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Unbound AUC0-inf (AUC0-inf,u) of Pirtobrutinib	AUC0-inf,u was calculated by multiplying AUC0-inf by Fu (i.e., AUC0-inf*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Unbound CL/F (CL/F,u) of Pirtobrutinib	CL/F,u was calculated by multiplying CL/F by Fu (i.e., CL/F*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Unbound Vz/F (Vz/F,u) of Pirtobrutinib	Vz/F,u was calculated by multiplying Vz/F by Fu (i.e., Vz/F*Fu). Fu represents the unbound fraction, which is the portion of the drug in the bloodstream that is unbound to plasma proteins. It is expressed as a decimal and will be calculated from protein binding concentration data as the unbound drug concentration divided by the total drug concentration in plasma. The concentrations of total and unbound drug were determined in a sample of predose plasma fortified with a known concentration of drug.	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Normal Hepatic Function)	PK: λZ of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Mild Hepatic Function)	PK: λZ of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Moderate Hepatic Function)	PK: λZ of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)
PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib (Severe Hepatic Function)	PK: λZ of pirtobrutinib	Day 1 (predose, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hours postdose)

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): December 18, 2020
• Primary Completion (Actual): December 30, 2021
• Study Completion (Actual): December 30, 2021

Study Registration Dates

• First Submitted: December 11, 2023
• First Submitted That Met QC Criteria: January 3, 2024
• First Posted (Actual): January 5, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: November 19, 2024
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Tyrosine Kinase Inhibitors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Pirtobrutinib
• Other Study ID Numbers: LOXO-BTK-20012; J2N-OX-JZNF (Other Identifier: Eli Lilly and Company)

Drug and device information, study documents

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