An Adaptive Physiologically Based Pharmacokinetic-Driven Design to Investigate the Effect of Itraconazole and Rifampicin on the Pharmacokinetics of Molibresib (GSK525762) in Healthy Female Volunteers

Kylie Riddell, Aarti Patel, Gary Collins, Yanyan Zhou, Dan Schramek, Brandon E Kremer, Geraldine Ferron-Brady, Kylie Riddell, Aarti Patel, Gary Collins, Yanyan Zhou, Dan Schramek, Brandon E Kremer, Geraldine Ferron-Brady

Abstract

Molibresib (GSK525762), an orally bioavailable small molecule with 2 major equipotent active metabolites, is being developed for the treatment of cancers. Molibresib is a substrate of cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp). To enable administering safe doses of molibresib to healthy volunteers, this 2-part randomized, open-label, crossover drug-drug interaction trial was conducted as an adaptive design study using physiologically based pharmacokinetic (PBPK) modeling and simulation to predict the lowest doses of molibresib that could be safely administered alone (10 mg) or with itraconazole and rifampicin (strong inhibitors and inducers of CYP3A and P-gp, respectively). PBPK simulation guided the molibresib dose (5 mg) to be administered along with itraconazole in part 1. Itraconazole increased total exposure (AUC) of molibresib by 4.15-fold with a 66% increase in Cmax , whereas the total AUC and Cmax for the 2 major active metabolites of molibresib decreased by about 70% and 87%, respectively. A second PBPK simulation was conducted with part 1 data to also include the active metabolites to update the recommendation for the molibresib dose (20 mg) with rifampicin. With rifampicin, the AUC and Cmax of molibresib decreased by approximately 91% and 80%, respectively, whereas the AUC of the 2 active metabolites decreased to a lesser extent (8%), with a 2-fold increase in Cmax . The results of this study confirmed the in vitro data that molibresib is a substrate for CYP3A4. The adaptive design, including Simcyp simulations, allowed evaluation of 2 drug interactions of an oncology drug in a single trial, thus minimizing time and exposures administered to healthy subjects.

Keywords: GSK525762; Simcyp; drug-drug interaction; itraconazole; molibresib; pharmacokinetics; rifampicin.

Conflict of interest statement

All authors are employees of GSK, hold company stock, and meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Editorial support (development of the first draft, assembling tables and figures, collating author comments, and referencing) was provided by Guissou Dabiri, PhD, and was funded by GSK.

© 2020 Glaxo Group Limited. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
PBPK simulation workflow.
Figure 2
Figure 2
Adaptive study design.
Figure 3
Figure 3
Observed and Simcyp‐simulated molibresib concentration‐time profile after a single 60‐ or 100‐mg dose (BET115521).
Figure 4
Figure 4
Dose‐normalized mean molibresib, active metabolite, and total active moiety concentration‐versus‐time plots when molibresib is administered alone (open symbols) or in combination (closed symbols).
Figure 5
Figure 5
Observed and Simcyp‐simulated molibresib (A) and GSK3529246 (B) concentration‐time profiles after a single 10‐mg dose.

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