Towards better dose individualisation : metabolic phenotyping to predict cabazitaxel pharmacokinetics in men with prostate cancer
Menée auprès de 10 patients atteints d'un cancer métastatique de la prostate résistant à la castration, cette étude analyse la possibilité d'utiliser le niveau de clairance du midazolam, un sédatif pouvant indiquer le phénotype métabolique du cytochrome P450 3A, pour déterminer les doses de cabazitaxel à administrer et individualiser ainsi le traitement
Background : Cabazitaxel is approved for treatment of castration-resistant metastatic prostate cancer. The current dosing strategy of cabazitaxel is based on body surface area (BSA). Body surface area is known as a poor predictor for total systemic exposure to drugs, since it does not take into account variability in activity of metabolising enzymes, necessary for clearance of drugs. As exposure to cabazitaxel is related to treatment response, it is essential to develop a better individualised dosing strategy.
Methods : Ten patients with metastatic castration-resistant prostate cancer, who received cabazitaxel dosed on BSA as a part of routine palliative care, were enrolled in this study. Midazolam was administered as phenotyping probe for cytochrome P450 isoenzyme 3A (CYP3A). The relationship between midazolam and cabazitaxel clearance was investigated using non-linear mixed effects modelling.
Results : The clearance of Midazolam highly correlated with cabazitaxel clearance (R=0.74). Midazolam clearance significantly (P<0.004) explained the majority (~60%) of the inter-individual variability in cabazitaxel clearance in the studied population.
Conclusions : Metabolic phenotyping of CYP3A using midazolam is a promising strategy to individualise cabazitaxel dosing. Before clinical application, a randomised study is warranted.
British Journal of Cancer , résumé, 2016