Wenjun Chen, Rong Chen, Jian Li, Liang Li, Tianyan Zhou, Wei Lu
Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Objectives: Achieving better antitumor efficacy by drug combination is a mainstay in oncology. However, the combination efficacy of antitumor drugs might not be a simple synergy. Docetaxel (Doc) is a semi-synthetic taxane microtubule inhibitor, and docetaxel plus prednisone has been the standard first-line chemotherapy in patients with castration-resistant prostate cancer (CRPC) [1]. Cabozantinib (Cab) is an orally bioavailable multi-target tyrosine kinase inhibitor [2] which has been investigated in multiple solid tumors including prostate cancer. The purpose of this study were (1) to develop a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model to describe plasma concentration and the antitumor activity of Doc and Cab, (2) to quantitatively describe and compare the combination effect of Doc and Cab under concurrent therapy and interval therapy, with or without PK interaction considered, and (3) to investigate different sequential therapies in mouse xenograft model of CRPC.
Methods: Pharmacokinetics of Doc and Cab when administered separately and simultaneously were investigated in nude mice, and the plasma concentrations were determined using HPLC-MS/MS. The pharmacodynamic studies of Doc and Cab under monotherapy, concurrent therapy (Doc and Cab were administered simultaneously) and interval therapy (Cab was administered six hours after Doc) were performed in prostate cancer cell PC3 and 22Rv1 tumor-bearing mice, and the antitumor activity of the two drugs under different sequential therapies were investigated in PC3 xenograft model. Based on the experimental data, a semi-mechanistic PK/PD model was developed and evaluated to explore the relationship between plasma concentration and drug effect quantitatively. The proposed PK/PD model was performed using the First Order Conditional Estimation with Interaction (FOCEI) method with NONMEM and validated via VPC.
Results: The concentration-time curve of Doc was fitted by a two-compartment model, while that of Cab was described by a one-compartment model with first-order absorption. The PK interaction between Doc and Cab was expressed by adding the effect of Cab on the clearance of Doc in PK model. Gompertz and logistic model were used as the base model for tumor natural growth dynamics of PC3 and 22Rv1 xenografts, respectively. It was assumed that Doc exhibited direct cell-killing effect while Cab exerted inhibitory effect on tumor carrying capacity (the maximum sustainable tumor volume) instead of damaging tumor cells [3]. The PD interaction between the two drugs was quantitatively characterized through combination index φ. Our experimental results showed that the concurrent administration of Doc and Cab proved better tumor inhibition efficacy than monotherapy in both xenograft models, and the interval therapy did not enhance the anti-tumor efficacy compared with the concurrent therapy. When the PK interaction was ignored, Doc and Cab showed weak synergy in antitumor efficacy with parameter φ greater than one under both concurrent and interval treatment schedules. However, parameter φ estimated were adjacent to one after introducing PK interaction into the model, indicating that there was no significant PD synergism or antagonism between the two drugs. Tumor growth inhibition exhibited different patterns in different sequential schedules. The Doc followed by Cab (Doc ~ Cab) sequential therapy was superior to monotherapy while the Cab followed by Doc (Cab ~ Doc) sequential schedule was less effective. The effect of the two drugs in “Doc ~ Cab” and “Cab ~ Doc” sequential schedule was synergistic and antagonistic respectively since φ estimated were greater than or less than one respectively.
Conclusions: The proposed PK/PD model properly described the plasma concentration and anti-tumor effects of Doc and Cab under different treatment schedules. There was no significant PD interaction between Doc and Cab in both concurrent schedule and interval schedule, while the effect of the two drugs in “Doc ~ Cab” and “Cab ~ Doc” sequential schedule was synergistic and antagonistic, respectively. The enhanced antitumor efficacy of the concurrent and interval regimen could be explained by PK interaction of the two drugs partly.
References:
[1] McKeage K. Docetaxel: a review of its use for the first-line treatment of advanced castration-resistant prostate cancer[J]. Drugs. 2012,72(11):1559-77.
[2] Grüllich C. Cabozantinib: a MET, RET, and VEGFR2 tyrosine kinase inhibitor. Small Molecules in Oncology: Springer; 2014. p. 207-14.
[3] Ouerdani A, Struemper H, Suttle A, Ouellet D, Ribba B. Preclinical modeling of tumor growth and angiogenesis inhibition to describe pazopanib clinical effects in renal cell carcinoma[J]. CPT: pharmacometrics & systems pharmacology. 2015,4(11):660-8.
Reference: PAGE 27 (2018) Abstr 8488 [www.page-meeting.org/?abstract=8488]
Poster: Drug/Disease Modelling - Oncology