The main purpose of this study is to assess the effect of Pirtobrutinib (LOXO-305) on the heart rate-corrected QT (QTc) interval and to conduct blood tests to measure how much pirtobrutinib (LOXO-305) is in the bloodstream and how the body handles and eliminates pirtobrutinib. The study will also evaluate the safety and tolerability of pirtobrutinib. The study will last up to 71 days, including screening.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
DOUBLE
Enrollment
31
Administered orally
Administered orally
Administered orally
Covance Clinical Research Unit 1341 Mockingbird Lane
Dallas, Texas, United States
Covance Clinical Research Unit 3402 Kinsman Blvd
Madison, Wisconsin, United States
Placebo-corrected Change From Baseline in QT Interval Corrected Using Fridericia's Correction (QTcF) (ΔΔQTcF)
The cardiodynamic assessment was performed through 12-lead electrocardiogram (ECG) extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. Placebo-corrected change from baseline in QTcF (ΔΔQTcF) was calculated based on model-predicted effect.
Time frame: Baseline (Predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Change From Baseline in (Δ) QTcF
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF. Change from baseline in (Δ) QTcF was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Change From Baseline in Heart Rate (ΔHR)
Heart rate is the number of times the ventricles of the heart contract and relax per minute. Change from baseline in heart rate (ΔHR) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Change From Baseline in Pulse Rate (ΔPR)
Pulse rate is number of times heart beats per minute. Pulse rate measurements were performed using the same arm for each reading and measurements were taken after the participant had been resting in the supine position for at least 5 minutes. Change from baseline in pulse rate (ΔPR) was calculated using linear mixed-effects model analysis.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Change From Baseline in QRS Intervals (Δ QRS)
QRS interval in an ECG measured the total time of ventricular depolarization. It begins with Q or R wave and ends at the end of the S wave. Change from baseline in QRS intervals (Δ QRS) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Change From Baseline in Individualized Heart Rate-Corrected QT Interval (ΔQTcS), If a Substantial Heart Rate Effect Was Observed
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcS.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Change From Baseline in Optimized Heart Rate-Corrected QT Interval (ΔQTcI), If a Substantial Heart Rate Effect Was Observed
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcI.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Placebo-corrected Change From Baseline in Heart Rate (ΔΔHR)
Heart rate is the number of times the ventricles of the heart contract and relax per minute. Placebo-corrected change from baseline in heart rate (ΔΔHR) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Placebo-corrected Change From Baseline in Pulse Rate (ΔΔ PR)
Pulse rate is number of times heart beats per minute. Pulse rate measurements were performed using the same arm for each reading and measurements were taken after the participant had been resting in the supine position for at least 5 minutes. Placebo-corrected change from baseline in pulse rate (ΔPR) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Placebo-Corrected Change From Baseline in QRS (ΔΔQRS)
QRS interval in an ECG measured the total time of ventricular depolarization. It begins with Q or R wave and ends at the end of the S wave. Placebo-corrected change from baseline in QRS intervals (ΔΔQRS) was calculated using linear mixed-effects model analysis.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Placebo-corrected Change From Baseline in ΔQTcF (ΔΔQTcF), If a Substantial Heart Rate Effect Was Observed
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcF.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Placebo-corrected Change From Baseline in Individualized Heart Rate-Corrected QT Interval (ΔΔQTcS), If a Substantial Heart Rate Effect Was Observed
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcS.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Placebo-corrected Change From Baseline in Optimized Heart Rate-Corrected QT Interval (ΔΔQTcI), If a Substantial Heart Rate Effect Was Observed
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. The QT interval is the time from electrocardiogram Q wave to the end of the T wave corresponding to electrical systole. QT interval was corrected for heart rate using QTcI.
Time frame: Baseline (predose), 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12 and 24 hours post-dose
Number of Participants With Potentially Clinically Significant Electrocardiogram (ECG) Changes
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. Number of participants with potentially clinically significant ECG changes were reported.
Time frame: Baseline up to Day 33
Number of Participants With Treatment Emergent Changes in T-wave Morphology and U-wave Presence
The cardiodynamic assessment was performed through 12-lead ECG extracted from continuous recordings at pre-specified time points. Participants rested in supine position for at least 10 minutes prior to and 5 minutes after each time point for ECG extractions. Number of participants with treatment emergent changes in T-wave morphology and U-wave presence were reported.
Time frame: Baseline up to Day 33
Pharmacokinetic (PK): Percentage of AUC0-inf Extrapolated (AUC%Extrap) of Pirtobrutinib
PK: %AUCextrap was defined as percentage extrapolation for AUC0-inf.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
PK: Mean Residence Time (MRT) of Pirtobrutinib
PK: MRT was calculated by the area under the first moment curve divided by the area under the concentration time curve.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
PK: Apparent Volume of Distribution at the Terminal Phase (Vz/F) of Pirtobrutinib
PK: Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F was calculated as (CL/F)/Lambda Z. Where, CL/F is the apparent total clearance and lambda Z is the apparent terminal elimination rate constant.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
PK: Time to Maximum Observed Plasma Concentration (Tmax) of Pirtobrutinib
PK: Tmax was defined as the time to reach maximum observed plasma concentration (Cmax) for pirtobrutinib.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
PK: Apparent Plasma Terminal Elimination Half-life (t1/2) of Pirtobrutinib
PK: t1/2 was defined as the terminal elimination phase half-life for pirtobrutinib.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
PK: Maximum Observed Concentration (Cmax) of Pirtobrutinib
PK: Cmax was defined as the maximum plasma concentration for pirtobrutinib.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
PK: Area Under the Concentration-time Curve, From Time 0 to 24 Hours Post-dose (AUC0-24) of Pirtobrutinib
PK: AUC(0-24) was defined as the area under the plasma concentration-time curve from 0 time to 24 hours post-dose.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24 hours post-dose
PK: Area Under the Concentration-time Curve, From Time 0 to the Last Measurable Concentration (AUC0-t) of Pirtobrutinib
PK: AUC(0-t) was defined as the area under the plasma concentration-time curve from 0 time to last measurable point for pirtobrutinib.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
PK: Apparent Systemic Clearance (CL/F) of Pirtobrutinib
PK: Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as (Dose/AUC(0-inf))/F. Where AUC(0-inf) is the area under the plasma concentration-time curve from zero to infinity and F is the bioavailability of the drug.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
PK: Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity (AUC0-inf) of Pirtobrutinib
PK: AUC(0-inf) was defined as the area under the plasma concentration-time curve from 0 to infinity for pirtobrutinib.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose
PK: Apparent Terminal Elimination Rate Constant (λZ) of Pirtobrutinib
PK: Terminal elimination rate constant, calculated as the negative of the slope of the log-linear regression of the natural logarithm concentration-time curve during the terminal phase.
Time frame: Pre-dose and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8.5, 12, 24, 48, 72, and 96 hours post-dose