Pharmacokinetic–pharmacodynamic (PK-PD) modeling and simulation of serdemetan-induced QTc effects in a first-in-human study.

Abstract

e13011 Background: Serdemetan is a compound that can cause replicative stress type responses in tumor cells and it has been administered to patients with solid tumors. ECG data from an ongoing first-in-human study revealed effects on QT interval, related to serdemetan exposure. The aim of this project was to develop a PK-PD model to quantify the observed effects on QTc interval. Furthermore, model-based simulations were performed with different dosing scenarios to support the dose and regimen selection of next study cohorts. Methods: Clinical data from 36 subjects (doses from 4-300 mg QD) from the phase I study JNJ-26854165-CAN-1001 were used for PK and PKPD modeling. Plasma concentrations were used as input for the pharmacokinetic modeling. QTcF data were used as input for the PK-PD model. Modeling and simulations were performed using nonlinear mixed effect modeling in NONMEM version 6.2. Results: A two-compartment model with combined first- and zero-order absorption best described the pharmacokinetics of serdemetan after oral solution and tablet formulation. A small effect of food intake was observed on the absorption. QTcF effects over time were described by several components, including baseline QTc, heart rate correction (Fridericia's formulae), circadian rhythm, and the drug-induced effect, as described by a linear function of the plasma concentration. The developed PK-PD model was used to address the impact of different dosing schedules (QD, BID, Q2D) on the number of patients with a delta QTcF of > 60 ms. Simulations indicated that BID dosing had increased safety margin for QTcF effects, compared to QD or less frequent dosing at the proposed therapeutic range. Conclusions: PK-PD modeling enables the quantification of QTcF effects of serdemetan in a first-in-human study. Optimization of treatment schedules can be facilitated based upon simulation scenarios as proposed by the PK-PD model. PK-PD modeling in an early stage in drug development can be a valuable tool for dose and schedule selection. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Johnson & Johnson