The effect of different doses of cyclosporin A on the systemic exposure of orally administered paclitaxel

The objective of this study was to define the minimally effective dose of cyclosporin A (CsA) that would result in a maximal increase of the systemic exposure to oral paclitaxel. Six evaluable patients participated in this randomized cross-over study in which they received at two occasions two doses of 90 mg/m oral paclitaxel 7 h apart in combination with 10 or 5 mg/kg CsA. Dose reduction of CsA from 10 to 5 mg/kg resulted in a statistically significant decrease in the area under the plasma concentration-time curve (AUC) and time above the threshold concentrations of 0.1 μM (T>0.1 μM) of oral paclitaxel. The mean (±SD) AUC and T>0.1 μM values of oral paclitaxel with CsA 10 mg/kg were 4.29±0.88 μM·h and 12.0±2.1 h, respectively. With CsA 5 mg/kg these values were 2.75±0.63 μM·h and 7.0±2.1 h, respectively (p = 0.028 for both parameters). In conclusion, dose reduction of CsA from 10 to 5 mg/kg resulted in a significant decrease in the AUC and T>0.1 μM values of oral paclitaxel. Because CsA 10 mg/kg resulted in similar paclitaxel AUC and T>0.1 μM values compared to CsA 15 mg/kg (data which we have published previously), the minimally effective dose of CsA is determined at 10 mg/kg.