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Completed

NCT Number: NCT06180967

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

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.

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Key information

Conditions

Healthy

Age range

18 year–55 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1

Primary location

Covance Clinical Research Unit

Daytona Beach, Florida, 32117, United States

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Midazolam Syrup

Drug

Administered Orally.

Midazolam Solution

Drug

Administered IV bolus.

Pirtobrutinib

Drug

Administered Orally.

Other names: LOXO-305, LY3527727

Primary outcomes

  1. 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

    Time frame: 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)

    PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.

  2. 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

    Time frame: 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)

    PK: AUC(0-inf) of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.

  3. PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration

    Time frame: 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)

    PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.

  4. PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration

    Time frame: 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)

    PK: Cmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.

  5. PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration

    Time frame: 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)

    PK: tmax of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.

  6. PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration

    Time frame: 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)

    PK: λz of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.

  7. PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration

    Time frame: 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)

    PK: CL/F of midazolam following oral dose administration was reported.

  8. PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration

    Time frame: 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)

    PK: Vz/F of midazolam following oral dose administration was reported.

  9. PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration

    Time frame: 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)

    PK: t½ of midazolam and its metabolite 1-OH-midazolam following oral dose administration was reported.

  10. PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration

    Time frame: 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)

    PK: CL of midazolam following intravenous dose administration was reported.

  11. PK: Volume of Distribution (Vz) of Midazolam Following Intravenous Dose Administration

    Time frame: 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)

    PK: Vz of midazolam following intravenous dose administration was reported.

  12. PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration

    Time frame: 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)

    PK: Vss of midazolam following intravenous dose administration was reported.

  13. 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

    Time frame: 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)

    PK: AUC0-t of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.

  14. 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

    Time frame: 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)

    PK: AUC0-inf of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.

  15. PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration

    Time frame: 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)

    PK: %AUCextrap of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.

  16. PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration

    Time frame: 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)

    PK: Cmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.

  17. PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration

    Time frame: 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)

    PK: tmax of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.

  18. PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration

    Time frame: 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)

    PK: λz of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.

  19. PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration

    Time frame: 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)

    PK: t1/2 of midazolam and its metabolite 1-OH-midazolam following intravenous dose administration was reported.

Secondary outcomes

  1. PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib

    Time frame: 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)

    PK: AUC0-t of Pirtobrutinib was reported.

  2. PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib

    Time frame: 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)

    PK: AUCtau of Pirtobrutinib was reported.

  3. PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib

    Time frame: 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)

    PK: Cmax of Pirtobrutinib was reported.

  4. PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib

    Time frame: Period 2: 24-hour post-dose on Day 14, Day 15, and Day 17

    PK: Ctrough of Pirtobrutinib before multiple oral doses administration was reported.

  5. PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib

    Time frame: 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)

    PK: tmax of Pirtobrutinib was reported.

  6. PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib

    Time frame: 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)

    PK: CL,ss/F of Pirtobrutinib was reported.

  7. PK: Accumulation Ratio (RAUC) of Pirtobrutinib

    Time frame: 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)

    RAUC was ratio of Day 14 AUCtau to Day 5 AUCtau.

Sponsors and collaborators

Lead sponsor

Eli Lilly and Company

Industry

Collaborators

  • Loxo Oncology, Inc.

Registry information

Official study 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

Important dates

Study start
2020
Primary completion
2020
Study completion
2020
First posted
Dec 26, 2023
Registry last updated
Feb 24, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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