Phase 1
Completed N=15
A Drug Drug Interaction (DDI) Study of Pirtobrutinib (LOXO-305) and Different Formulations of Midazolam in Healthy Participants
Healthy
Source: ClinicalTrials.gov NCT06180967 ↗
Enrolled (actual)
15
Serious AEs
0.0%
Results posted
Feb 2025
Primary outcomePrimary: 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 — 4.81; 8.30; 2.24; 2.52 Hours*nanograms per milliliter (h*ng/mL)
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.
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY 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 |
4.81; 8.30; 2.24; 2.52 | — |
| PRIMARY 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 |
5.31; 9.01; 2.60; 2.92 | — |
| PRIMARY PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration |
8.84; 7.42; 12.9; 12.2 | — |
| PRIMARY PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration |
2.33; 3.68; 1.25; 1.41 | — |
| PRIMARY PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration |
0.750; 0.500; 0.750; 0.500 | — |
| PRIMARY PK: Apparent Terminal Elimination Rate Constant (Lambda [λ] z) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration |
0.316; 0.227; 0.441; 0.419 | — |
| PRIMARY PK: Apparent Systemic Clearance (CL/F) of Midazolam Following Oral Dose Administration |
94.2; 55.5 | — |
| PRIMARY PK: Apparent Volume of Distribution (Vz/F) of Midazolam Following Oral Dose Administration |
298; 244 | — |
| PRIMARY PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-Midazolam Following Oral Dose Administration |
2.20; 3.05; 1.57; 1.65 | — |
| PRIMARY PK: Total Clearance (CL) of Midazolam Following Intravenous Dose Administration |
26.0; 23.1 | — |
| PRIMARY PK: Volume of Distribution (Vz) of Midazolam Following Intravenous Dose Administration |
113; 105 | — |
| PRIMARY PK: Volume of Distribution at Steady State (Vss) of Midazolam Following Intravenous Dose Administration |
78.2; 76.1 | — |
| PRIMARY 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 |
8.89; 10.1; 1.39; 1.21 | — |
| PRIMARY 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 |
9.62; 10.8; 2.13; 1.62 | — |
| PRIMARY PK: Percentage Extrapolation for AUC0-inf (%AUCextrap) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration |
7.13; 6.44; 19.6; 24.7 | — |
| PRIMARY PK: Maximum Observed Plasma Concentration (Cmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration |
6.96; 6.91; 0.512; 0.475 | — |
| PRIMARY PK: Time to Maximum Observed Plasma Concentration (Tmax) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration |
0.0833; 0.0833; 0.750; 0.750 | — |
| PRIMARY PK: Apparent Terminal Elimination Rate Constant (λz) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration |
0.229; 0.221; 0.224; 0.282 | — |
| PRIMARY PK: Apparent Plasma Terminal Elimination Half-life (t½) of Midazolam and Its Metabolite 1-OH-midazolam Following Intravenous Dose Administration |
3.02; 3.13; 3.09; 2.46 | — |
| SECONDARY PK: Area Under the Concentration-Time Curve From Hour 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib |
54800; 114000; 115000; 211000 | — |
| SECONDARY PK: Area Under the Concentration-time Curve During a Dosing Interval (AUCtau) of Pirtobrutinib |
55000; 114000; 116000; 118000 | — |
| SECONDARY PK: Maximum Observed Plasma Concentration (Cmax) of Pirtobrutinib |
4880; 8120; 8620; 8750 | — |
| SECONDARY PK: Concentration Observed at the End Of the Dosing Interval (Ctrough) of Pirtobrutinib |
3060; 3180; 3050 | — |
| SECONDARY PK: Time To Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib |
2.50; 3.00; 3.00; 3.00 | — |
| SECONDARY PK: Apparent Systemic Plasma Clearance at Steady State (CL,ss/F) of Pirtobrutinib |
1.75; 1.72; 1.69 | — |
| SECONDARY PK: Accumulation Ratio (RAUC) of Pirtobrutinib |
2.08 | — |
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
Data sourced from ClinicalTrials.gov (NCT06180967). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication. Informational only — not medical advice.