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 50
- Downloads 0
Novel Lansoprazole-Loaded Nanoparticles for the Treatment of Gastric Acid Secretion-Related Ulcers: In Vitro and In Vivo Pharmacokinetic Pharmacodynamic Evaluation
The objective of this study is to combine nanoparticle design and enteric coating technique to sustain the delivery of an acid-labile drug, lansoprazole (LPZ), in the treatment of acid reflux disorders. Lansoprazole-load...
Dopamine D2 Occupancy as a Biomarker for Antipsychotics: Quantifying the Relationship with Efficacy and Extrapyramidal Symptoms
The online version of this article (doi:10.1208/s12248-010-9247-4) contains supplementary material, which is available to authorized users.
Effect of chloroquine on phagolysosomal fusion in cultured guinea pig alveolar macrophages: Implications in drug delivery
Biomaterials/Tissue Interactions: Possible Solutions to Overcome Foreign Body Response
In recent years, a variety of biomaterial implantable devices has been developed. Of particular significance to pharmaceutical sciences is the progress made on the development of drug/implantable device combination produ...
Pharmacokinetics of 1,4-Butanediol in Rats: Bioactivation to γ-Hydroxybutyric Acid, Interaction with Ethanol, and Oral Bioavailability
1,4-Butanediol (BD), a substance of abuse, is bioactivated to γ-hydroxybutyrate (GHB), but its fundamental pharmacokinetics (PK) have not been characterized. Because this bioactivation is partly mediated by alcoh...