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

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 druginduced 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 pre specification of the concentration-QTc model should be reconsidered for drugs with circadian rhythm modulation potential.Circadian rhythm represents a biological process exhibiting 24-hour cycles, which plays a critical role for the optimal functioning of organisms. Disruption of the circadian rhythm is observed in patients with Alzheimer's disease (AD) and various types of mood disorders as evidenced by sleep-cycle alterations. [1][2][3][4] Therefore, entrainment of misaligned circadian behavior is a promising target for the treatment of AD or major depressive disorder. 5,6 The circadian system of the body is regulated by an endogenous biological clock located in the suprachiasmatic nucleus of the anterior hypothalamus. The suprachiasmatic nucleus ensures rhythmic expression of the clock genes period (PER1, PER2, and PER3) and cryptochrome (CRY1 and CRY2), which are ultimately translated into physiological circadian rhythm. 7 Casein kinases 1 (CK1) δ/ε were shown to phosphorylate CRY and PER proteins, leading to proteasome-mediated degradation and inhibition of circadian locomotor output cycles kaput (CLOCK)/brain, muscle Arnt-like 1(BMAL1) transcriptional activity, acting as a negative feedback for clock genes. 8 A mutation in the human CK1 δ gene has been linked to familial advanced sleep phase syndrome characterized by early sleep and early morning awakening. 9 Also, CK1-inhibiting

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

“…To the Editor: In the Letter to the Editor regarding: "Assumption checking is essential," the authors questioned satisfaction of assumptions required for applying the prespecified linear mixed effect (LME) model, and our conclusion on reconsidering the LME model when drug-induced circadian rhythm change is expected. 1 We appreciate the authors' investigation of exploratory plots. We believe the basic assumptions are met in part (i) and consideration of exploring alternative models based on known pharmacology is warranted in part (ii) because exploratory plots may not be sensitive to identify all characteristics of drug effects on QT.…”

“…Response Letter to the Editor: "Assumption Checking Before Application of the Prespecified QT Linear Mixed Effect Model is Essential" Yeamin Huh 1, *, Steve Riley 1…”

Concentration‐QTc Modeling of the DPP‐4 Inhibitor HSK7653 in a First‐in‐Human Study of Chinese Healthy Volunteers

“…Unlike TQT studies that only examine 1 or 2 dose groups, C‐QTc modeling, utilizing high‐quality ECG data from early‐phase clinical trials, could provide a more comprehensive assessment of the relationship between drug concentration and QTc interval 2 . In addition, the C‐QTc model has played a key role in evaluating the risk of drugs in both general and special populations 3–6 …”

“…2 In addition, the C-QTc model has played a key role in evaluating the risk of drugs in both general and special populations. [3][4][5][6] Cofrogliptin (HSK7653) is a long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor for the treatment of patients with type 2 diabetes mellitus (T2DM). It was chemically synthesized by Haisco Pharmaceutical Group Co. Ltd. (Chengdu, China).…”

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

“…In the paper, titled "Evaluation of QT Liability for PF-05251749 in the Presence of Potential Circadian Rhythm Modification," 1 the authors presented results from assessment of QT-liability based on (i) clinical data and (ii) simulations using models for a drug that affects QT circadian rhythm.…”