Evaluation of QT Liability for PF-05251749 in the Presence of Potential Circadian Rhythm Modification

Overview

Journal CPT Pharmacometrics Syst Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2019 Nov 22

PMID 31749321

Citations 2

Authors

Yeamin Huh

Danny Chen

Steve Riley

Cheng Chang

Timothy Nicholas

Affiliations

Soon will be listed here.

Abstract

PF-05251749 is a dual inhibitor of casein kinase 1 δ/ε, key regulators of circadian rhythm. As a result of its mechanism of action, PF-05251749 may also change the heart rate corrected QT (QTc) circadian rhythm, which may confound detection of drug-induced QTc prolongation. In this analysis, a nonlinear mixed effect model including a multioscillator function was developed in addition to fitting the prespecified linear mixed effect concentration-QTc model, to identify QTc liability of PF-05251749 in the presence of potential circadian rhythm change. The modeling results suggested lack of clinically meaningful QTc prolongation (upper bound of 90% confidence interval for ∆∆QTc < 10 milliseconds) and that the drug-induced QTc circadian rhythm change was not present. However, simulation results indicated that inference of drug-induced QTc prolongation could be misleading if the drug effect on QTc circadian rhythm is not properly addressed. The modeling and simulation results suggest that prespecification of the concentration-QTc model should be reconsidered for drugs with circadian rhythm modulation potential.

Citing Articles

Response Letter to the Editor: "Assumption Checking Before Application of the Prespecified QT Linear Mixed Effect Model is Essential".

Huh Y, Riley S, Nicholas T CPT Pharmacometrics Syst Pharmacol. 2020; 9(7):372-373.

PMID: 32511884 PMC: 7376289. DOI: 10.1002/psp4.12519.

Assumption Checking Before Application of the Prespecified QT Linear Mixed Effect Model is Essential.

Rekic D, Parkinson J, Kimko H CPT Pharmacometrics Syst Pharmacol. 2020; 9(7):371.

PMID: 32424953 PMC: 7376286. DOI: 10.1002/psp4.12517.

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