Development of a Tumour Growth Inhibition Model to Elucidate the Effects of Ritonavir on Intratumoural Metabolism and Anti-tumour Effect of Docetaxel in a Mouse Model for Hereditary Breast Cancer
Journal Title: The AAPS Journal - Year 2016, Vol 18, Issue 2
Abstract
In a mouse tumour model for hereditary breast cancer, we previously explored the anti-cancer effects of docetaxel, ritonavir and the combination of both and studied the effect of ritonavir on the intratumoural concentration of docetaxel. The objective of the current study was to apply pharmacokinetic (PK)-pharmacodynamic (PD) modelling on this previous study to further elucidate and quantify the effects of docetaxel when co-administered with ritonavir. PK models of docetaxel and ritonavir in plasma and in tumour were developed. The effect of ritonavir on docetaxel concentration in the systemic circulation of Cyp3a knock-out mice and in the implanted tumour (with inherent Cyp3a expression) was studied, respectively. Subsequently, we designed a tumour growth inhibition model that included the inhibitory effects of both docetaxel and ritonavir. Ritonavir decreased docetaxel systemic clearance with 8% (relative standard error 0.4%) in the co-treated group compared to that in the docetaxel only-treated group. The docetaxel concentration in tumour tissues was significantly increased by ritonavir with mean area under the concentration-time curve 2.5-fold higher when combined with ritonavir. Observed tumour volume profiles in mice could be properly described by the PK/PD model. In the co-treated group, the enhanced anti-tumour effect was mainly due to increased docetaxel tumour concentration; however, we demonstrated a small but significant anti-tumour effect of ritonavir addition (p value <0.001). In conclusion, we showed that the increased anti-tumour effect observed when docetaxel is combined with ritonavir is mainly caused by enhanced docetaxel tumour concentration and to a minor extent by a direct anti-tumour effect of ritonavir.
Authors and Affiliations
Huixin Yu, Jeroen J. M. A. Hendrikx, Sven Rottenberg, Jan H. M. Schellens, Jos H. Beijnen, Alwin D. R. Huitema
Keywords
Related Articles
- EP ID EP680847
- DOI 10.1208/s12248-015-9838-1
- Views 43
- Downloads 0
Mechanisms of methamphetamine-induced dopaminergic neurotoxicity
Methamphetamine (METH) is a powerful stimulant of abuse with potent addictive and neurotoxic properties. More than 2.5 decades ago, METH-induced damage to dopaminergic neurons was described. Since then, numerous advancem...
Antidrug Antibody Assay Validation: Industry Survey Results
Immunogenicity of biopharmaceutical products has attracted considerable attention from the industrial, academia, and regulatory organizations. Many methods exist to detect and characterize level of antidrug antibody resp...
Population pharmacokinetics/pharmacodynamics of anesthetics
In this article we review how population pharmacokinetic/pharmacodynamic (PD) modeling has evolved in the specialty of anesthesiology, how anesthesiology benefited from the mixed-effects approach, and which features of m...
Evaluation of sucrose esters as alternative surfactants in microencapsulation of proteins by the solvent evaporation method
Sucrose esters (SE) are surfactants with potential pharmaceutical applications because of their low toxicity, biocompatibility, and excellent biodegradability. The objective of the study was to investigate SE as alternat...
Phytochemicals from Cruciferous Vegetables, Epigenetics, and Prostate Cancer Prevention
Epidemiological evidence has demonstrated a reduced risk of prostate cancer associated with cruciferous vegetable intake. Follow-up studies have attributed this protective activity to the metabolic products of glucosinol...