Pharmacokinetic/Pharmacodynamic Modeling of Schedule-Dependent Interaction between Docetaxel and Cabozantinib in Human Prostate Cancer Xenograft Models

Abstract

In this work, a semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model to quantitatively describe the antitumor activity of docetaxel (Doc) and cabozantinib (Cab) under monotherapy, concurrent therapy, interval therapy, and different sequential therapy in mouse xenograft models of castration-resistant prostate cancer was developed and evaluated. The pharmacokinetics (PK) of Doc and Cab when administered separately and simultaneously were investigated in nude mice, and PD study was conducted in tumor-bearing mice treated with different dosing schedules. The PK interaction between Doc and Cab was expressed by adding the effect of Cab on the clearance of Doc in the PK model. And the PD interaction between the two drugs was demonstrated by the developed PK/PD model through the combination index "φ" Our results showed that the concurrent therapy and Doc followed by Cab (Doc ∼ Cab) sequential therapy exhibited better tumor inhibitory efficacy than monotherapy. The Cab followed by Doc (Cab ∼ Doc) sequential schedule was less effective than monotherapy, and the interval therapy did not enhance the antitumor efficacy compared with the concurrent therapy. The parameter φ estimated from the PK/PD model quantitatively characterized the action between Doc and Cab. There was no significant PD interaction between Doc and Cab in both the concurrent schedule and the interval schedule, whereas the effect of the two drugs in the "Doc ∼ Cab" and "Cab ∼ Doc" sequential schedule was synergistic and antagonistic, respectively. The proposed model properly described the antitumor effects of Doc and Cab under different treatment schedules and could be used for dose optimization through model-based simulation.