A Study of Carbon-14-Labelled [14C] LOXO-305 (Pirtobrutinib) in Healthy Male Participants

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the absorption, metabolism, and excretion (AME) profiles of pirtobrutinib (LOXO-305), to identify and characterize metabolites of pirtobrutinib (LOXO-305), and to assess the safety and tolerability of [14C] LOXO-305 in Part 1. To determine the absolute bioavailability of pirtobrutinib (LOXO-305), to evaluate the plasma concentration of total radioactivity, to evaluate the urinary excretion of [14C] LOXO-305 and total radioactivity, to evaluate the fecal excretion of [14C] LOXO-305 and total radioactivity, and to assess the safety and tolerability of pirtobrutinib (LOXO-305), and [14C] LOXO-305 in Part 2. Blood tests will be performed to check how much pirtobrutinib (LOXO-305) and [14C] LOXO-305 gets into the bloodstream and how long it takes the body to eliminate it. The study will last up to approximately 60 days for Part 1 and approximately 47 days for Part 2.

Official Title
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A Phase I, Open-label, Two-part Study of the Absorption, Metabolism, Excretion, and the Absolute Bioavailability of [14C]-LOXO-305 in Healthy Male Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: [14C]-LOXO-305
* Drug: LOXO-305
* Drug: [14C]-LOXO-305


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Must have Body mass index (BMI) within the range of 18.5 to 32.0 kilograms per square meter (kg/m²), inclusive Male 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 Participants who are capable of fathering a child must agree to use contraception from the time of the dose administration through 6 months after the last dose of LOXO-305 administration History of a minimum of 1 bowel movement per day 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 (HBV) 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) Part 1 only: Participation in a radiolabeled drug study where exposures are known to the Investigator (or designee) within the previous 4 months prior to Check-in (Day -1) or participation in a radiolabeled drug study where exposures are not known to the Investigator (or designee) within the previous 6 months prior to Check-in (Day -1). Part 2 only: Participation in any other radiolabeled investigational study drug trial within 12 months prior to Check-in (Day -1). Any previous radiolabeled study drug must have been received more than 12 months prior to Check-in (Day -1).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This is a 2-part study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: [14C]-LOXO-305<br>A single dose of [14C]-LOXO-305 oral solution will be administered | Drug: [14C]-LOXO-305<br>* Administered orally<br>* Other names: LY3527727;|
| Experimental: Part 2: LOXO-305<br>A single dose of LOXO-305 oral tablets will be administered | Drug: LOXO-305<br>* Administered orally<br>* Other names: LY3527727;|
| Experimental: Part 2: [14C]-LOXO-305<br>A single dose of [14C]-LOXO-305 intravenously (IV) solution will be administered | Drug: [14C]-LOXO-305<br>* Administered IV<br>* Other names: LY3527727;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Area Under the Concentration-time Curve, From Time 0 Extrapolated to Infinity (AUC0-inf) of LOXO-305 Following a Single Oral Dose of [14C]-LOXO-305 | AUC0-inf of LOXO-305 following a single oral dose of [14C]-LOXO-305. | Pre-dose up to 264 hours post-dose | 
| Part 1: Area Under the Concentration-time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of [14C]-LOXO-305 | AUC0-t of LOXO-305 following a single oral dose of [14C]-LOXO-305. | Pre-dose up to 264 hours post-dose | 
| Part 1: Maximum Observed Plasma Concentration (Cmax) of LOXO-305 Following a Single Oral Dose of [14C]-LOXO-305 | Cmax of LOXO-305 following a single oral dose of [14C]-LOXO-305. | Pre-dose up to 264 hours post-dose | 
| Part 1: Time to Maximum Observed Plasma Concentration (Tmax) of LOXO-305 Following a Single Oral Dose of [14C]-LOXO-305 | Tmax of LOXO-305 following a single oral dose of [14C]-LOXO-305. | Pre-dose up to 264 hours post-dose | 
| Part 1: Apparent Terminal Elimination Half-life (t1/2) of [14C]-LOXO-305 | t1/2 of LOXO-305 following a single oral dose of [14C]-LOXO-305. | Pre-dose up to 264 hours post-dose | 
| Part 1: Apparent Systemic Clearance (CL/F) of [14C]-LOXO-305 | CL/F of [14C]-LOXO-305. | Pre-dose up to 264 hours post-dose | 
| Part 1: Apparent Volume of Distribution (Vz/F) of [14C]-LOXO-305 | Vz/F of [14C]-LOXO-305. | Pre-dose up to 264 hours post-dose | 
| Part 1: Ratio of AUC0-inf of Plasma LOXO-305 Relative to AUC0-inf of Plasma Total Radioactivity | Ratio of AUC0-inf of plasma LOXO-305 relative to AUC0-inf of plasma total radioactivity. | Pre-dose up to 264 hours post-dose | 
| Part 1: Ratio of AUC0-inf of Whole Blood Total Radioactivity to AUC0-inf of Plasma Total Radioactivity | Ratio of AUC0-inf of whole blood total radioactivity to AUC0-inf of plasma total radioactivity. | Pre-dose up to 264 hours post-dose | 
| Part 1: Cumulative Amount Excreted in Urine (Aeu) and Feces (Aef) Collection of Total Radioactivity | Cumulative amount excreted in urine and feces collection for total radioactivity. | Pre-dose up to 264 hours post-dose | 
| Part 1: Percentage of Dose Excreted in Urine (feu) and Feces (fef) Collection of Total Radioactivity | Percentage of dose excreted in urine and feces collection per sampling interval of total radioactivity. | Pre-dose up to 264 hours post-dose | 
| Part 1: Changes in Metabolic Profile of LOXO-305 | Metabolites are identified by comparison with known standards and by liquid chromatography/tandem mass spectrometry. | Pre-dose up to 264 hours post-dose | 
| Part 1: Number of Participants with LOXO-305 Metabolites | Metabolites are identified by comparison with known standards and by liquid chromatography/tandem mass spectrometry. | Pre-dose up to 264 hours post-dose | 
| Part 2: Area Under the Concentration-time Curve, From Time 0 Extrapolated to Infinity (AUC0-inf) of LOXO-305 and Total Radioactivity in Plasma | AUC0-inf of LOXO-305 and total radioactivity in plasma following oral administration of LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Area Under the Concentration-time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of LOXO-305 and Total Radioactivity in Plasma | AUC0-t of LOXO-305 and total radioactivity in plasma following oral administration of LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Maximum Observed Plasma Concentration (Cmax) of LOXO-305 and Total Radioactivity in Plasma | Cmax of LOXO-305 and Total Radioactivity in plasma following oral administration of LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of LOXO-305 and Total Radioactivity in Plasma | Tmax of LOXO-305 and total radioactivity in plasma following oral administration of LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Apparent Terminal Elimination Half-life (t1/2) of LOXO-305 and Total Radioactivity in Plasma | t1/2 of LOXO-305 and total radioactivity in plasma following oral administration of LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Apparent Systemic Clearance (CL/F) of LOXO-305 and Total Radioactivity in Plasma | CL/F of LOXO-305 and total radioactivity in plasma following oral administration of LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Apparent Volume of Distribution (Vz/F) of LOXO-305 and Total Radioactivity in Plasma | Vz/F of LOXO-305 and total radioactivity in plasma following oral administration of LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Absolute Bioavailability of LOXO-305 and Total Radioactivity in Plasma | Absolute bioavailability of LOXO-305 and total radioactivity in plasma following oral administration of LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Area Under the Concentration-time Curve, From Time 0 Extrapolated to Infinity (AUC0-inf) of [14C]-LOXO-305 in Plasma | AUC0-inf of [14C]-LOXO-305 in plasma following IV administration of [14C]-LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Area Under the Concentration-time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of [14C]-LOXO-305 in Plasma | AUC0-t of [14C]-LOXO-305 in plasma following IV administration of [14C]-LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Maximum Observed Plasma Concentration (Cmax) of [14C]-LOXO-305 in Plasma | Cmax of [14C]-LOXO-305 in plasma following IV administration of [14C]-LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Time to Maximum Observed Plasma Concentration (Tmax) of [14C]-LOXO-305 in Plasma | Tmax of [14C]-LOXO-305 in plasma following IV administration of [14C]-LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Apparent Terminal Elimination Half-life (t1/2) of [14C]-LOXO-305 in Plasma | t1/2 of [14C]-LOXO-305 in plasma following IV administration of [14C]-LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Total Clearance (CL) of [14C]-LOXO-305 in Plasma | CL of [14C]-LOXO-305 in plasma following IV administration of [14C]-LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Volume of Distribution (Vz) of [14C]-LOXO-305 in Plasma | Vz of [14C]-LOXO-305 in plasma following IV administration of [14C]-LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Volume of Distribution at Steady State (Vss) of [14C]-LOXO-305 in Plasma | Vss of [14C]-LOXO-305 in plasma following IV administration of [14C]-LOXO-305. | Pre-dose up to 192 hours post-dose | 
| Part 2: Cumulative Amount Excreted in Urine (Aeu) and Feces (Aef) of [14C]-LOXO-305 and Total Radioactivity in Urine and Feces Collections | Cumulative amount excreted in urine and feces of [14C]-LOXO-305 and total radioactivity in urine collections. | Pre-dose up to 192 hours post-dose | 
| Part 2: Renal clearance (CLR) of [14C]-LOXO-305 and Total Radioactivity | CLR of [14C]-LOXO-305 and total radioactivity in urine collections. | Pre-dose up to 192 hours post-dose | 
| Part 2: Cumulative Percentage of Dose Excreted in Urine (feu) and Feces (fef) of [14C]-LOXO-305 and Total Radioactivity in Urine and Feces Collections | Cumulative percentage of dose excreted in urine and feces of [14C]-LOXO-305 and total radioactivity in urine and feces collections. | Pre-dose up to 192 hours post-dose |