Oral paclitaxel and concurrent cyclosporin A: targeting clinically relevant systemic exposure to paclitaxel.

摘要: Oral paclitaxel is not inherently bioavailable because of the overexpression P-glycoprotein by intestinal cells and significant first-pass extraction cytochrome P450-dependent processes. This study sought to simulate toxicological pharmacological profile a clinically relevant schedule administered on i.v. dosing schedules in patients with advanced solid malignancies using oral cyclosporin A, an inhibitor both P450 CYP3A. Nine were treated single course its parenteral formulation at dose level 180, 360, or 540 mg. Cyclosporin A was 5 mg/kg p.o. 1 h before concurrently paclitaxel. Blood sampling performed evaluate pharmacokinetics paclitaxel, 6-α-hydroxypaclitaxel, 3-ρ-hydroxypaclitaxel, A. The pharmacokinetic behavior characterized compartmental noncompartmental methods. Modelestimated parameters used concentrations after once daily twice administration A. Aside from unpleasant taste, regimen well tolerated, there no grade 3 4 drug-related toxicities. systemic exposure as assessed maximum plasma concentration ( C max) area under versus time curve (AUC) values, did increase increased 180 mg, substantial interindividual variability (4–6-fold) each level. Mean max values approached achieved schedules, averaging 268 ± 164 ng/ml. AUC averaged 3306 1977 ng·h/ml, which significantly lower than schedules. However, computer simulations derived present demonstrated that pharmacodynamically steady-state least 0.06 μm would be protracted Paclitaxel metabolites detectable three patients, 6-α-hydroxypaclitaxel:paclitaxel 3-ρ-hydroxypaclitaxel:paclitaxel ratios 0.63 0.86, respectively; these substantially higher reported paclitaxel. Oral humans when combination treatment, this biologically attained treatment failed achieve sufficiently high drug pharmacodynamic effects. In contrast, effects are likely multiple paclitaxel-cyclosporin