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(2) 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 microM (T>0.1 microM) of oral paclitaxel. The mean (+/-SD) AUC and T>0.1 microM values of oral paclitaxel with CsA 10 mg/kg were 4.29+/-0.88 microM x h and 12.0+/-2.1 h, respectively. With CsA 5 mg/kg these values were 2.75+/-0.63 microM x 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 microM values of oral paclitaxel. Because CsA 10 mg/kg resulted in similar paclitaxel AUC and T>0.1 microM 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.
The objective of this study was to evaluate the pharmacokinetics of oral cyclosporin A (CsA) when co-administered to enhance the oral absorption of paclitaxel. Patients received oral paclitaxel in doses of 60-360 mg/m(2) in combination with a dose of oral CsA of 15 mg/kg. Dose escalation of paclitaxel from 60 to 300 mg/m(2) resulted in a significant decrease in the area under the concentration-time curve (AUC) of CsA from 24.4+/-9.9 to 17.6+/-2.8 mg/l.h (p=0.03) (n=28). In conclusion, increases in the paclitaxel dose resulted in a decrease in the AUC of CsA. This observation may be explained by the increase in the co-solvent Cremophor EL of paclitaxel causing reduced absorption of CsA.
The purpose of our study was to investigate the pharmacokinetics of Cremophor EL following administration of escalating doses of Taxol (paclitaxel dissolved in Cremophor EL/ethanol) to non-small cell lung cancer (NSCLC) patients. Patients with NSCLC stage IIIb or IV without prior chemotherapy treatment were eligible for treatment with paclitaxel and carboplatin in a dose-finding phase I study. The starting dose of paclitaxel was 100 mg/m2 and doses were escalated with steps of 25 mg/m2, which is equal to a starting dose of Cremophor EL of 8.3 ml/m2 with dose increments of 2.1 ml/m2. Carboplatin dosages were 300, 350 or 400 mg/m2. Pharmacokinetic sampling was performed during the first and the second course, and the samples were analyzed using a validated high-performance liquid chromatographic assay. A total of 39 patients were included in this pharmacokinetic part of the study. The doses of paclitaxel were escalated up to 250 mg/m2 (20.8 ml/m2 Cremophor EL). Pharmacokinetic analyses revealed a low elimination-rate of Cremophor EL (CI=37.8-134 ml/h/m2; t 1/2=34.4-61.5 h) and a volume of distribution similar to the volume of the central blood compartment (Vss=4.96-7.85 l). In addition, a dose-independent clearance of Cremophor EL was found indicating linear kinetics. Dose adjustment using the body surface area, however, resulted in a non-linear increase in systemic exposure. The use of body surface area in calculations of Cremophor EL should therefore be re-evaluated.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.