title: 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.
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.affiliation: Department of Pharmacy & Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek/Slotervaart Hospital, Louwesweg 6, PO Box 90440, 1006 BK, Amsterdam, The Netherlands. h.yu@nki.nl.
authors.forename: Huixin
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Pharmacy & Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek/Slotervaart Hospital, Louwesweg 6, PO Box 90440, 1006 BK, Amsterdam, The Netherlands.|Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jeroen J M A
authors.initials: JJ
authors.lastname: Hendrikx
authors.affiliation: Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Institute of Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Rottenberg
authors.affiliation: Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands.|Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.affiliation: Department of Pharmacy & Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek/Slotervaart Hospital, Louwesweg 6, PO Box 90440, 1006 BK, Amsterdam, The Netherlands.|Utrecht Institute of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.affiliation: Department of Pharmacy & Pharmacology, Netherlands Cancer Institute-Antoni van Leeuwenhoek/Slotervaart Hospital, Louwesweg 6, PO Box 90440, 1006 BK, Amsterdam, The Netherlands.
authors.forename: Alwin D R
authors.initials: AD
authors.lastname: Huitema
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000077143:Docetaxel; D005260:Female; D051379:Mice; D018345:Mice, Knockout; D019438:Ritonavir / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects* / Q000502:physiology
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D019438:Ritonavir
keywords: anti-cancer effect; co-administration; docetaxel; pharmacokinetic-pharmacodynamic modelling; ritonavir