Pharmacokinetics of oral cyclosporin A when co-administered to enhance the absorption of orally administered docetaxel

Abstract.

Objective: To evaluate the pharmacokinetics of oral cyclosporin A (CsA) when co-administered to enhance the absorption of orally administered docetaxel. Methods: Patients (n=9) with histological proof of solid cancer received oral docetaxel 75 mg/m² in combination with oral CsA 15 mg/kg. Results: The area under the blood concentration–time curve (AUC) of CsA when combined with docetaxel 75 mg/m² was 31.0±9.3 mg/l h (mean±SD). Compared with literature data of the same dose of CsA, AUC values in our study appear to be substantially higher. In addition, compared with the AUC values of CsA in combination with oral paclitaxel (previously published data), AUC values in this study are approximately 1.5-fold higher. Conclusions: The higher AUC values of CsA obtained in this study compared with literature data may be explained by competitive inhibition of cytochrome P₄₅₀ (CYP) 3A4-mediated metabolism of CsA by docetaxel. In addition, the higher levels of CsA with docetaxel than with paclitaxel co-administration may be explained by the fact that docetaxel is almost exclusively metabolised by CYP 3A4, whereas paclitaxel is predominantly metabolised by CYP 2C8 and to a lesser extent by CYP 3A4.