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

Citation
Cd. Britten et al., Oral paclitaxel and concurrent cyclosporin A: Targeting clinically relevant systemic exposure to paclitaxel, CLIN CANC R, 6(9), 2000, pp. 3459-3468
Citations number
53
Categorie Soggetti
Oncology
Journal title
CLINICAL CANCER RESEARCH
ISSN journal
10780432 → ACNP
Volume
6
Issue
9
Year of publication
2000
Pages
3459 - 3468
Database
ISI
SICI code
1078-0432(200009)6:9<3459:OPACCA>2.0.ZU;2-C
Abstract
Oral paclitaxel is not inherently bioavailable because of the overexpressio n of P-glycoprotein by intestinal cells and the significant first-pass extr action by cytochrome P450-dependent processes. This study sought to simulat e the toxicological and pharmacological profile of a clinically relevant sc hedule of paclitaxel administered on clinically relevant i.v. dosing schedu les in patients with advanced solid malignancies using oral paclitaxel admi nistered with cyclosporin A, an inhibitor of both P-glycoprotein and P450 C YP3A. Nine patients were treated with a single course of oral paclitaxel in its p arenteral formulation at a paclitaxel dose Level of 180, 360, or 540 mg. Cy closporin A was administered at a dose of 5 mg/kg p.o. 1 h before and concu rrently with oral paclitaxel. Blood sampling was performed to evaluate the pharmacokinetics of paclitaxel, 6-alpha-hydroxypaclitaxel, 3-rho-hydroxypac litaxel, and cyclosporin A. The pharmacokinetic behavior of paclitaxel was characterized using both compartmental and noncompartmental methods. Model- estimated parameters were used to simulate paclitaxel concentrations after once daily and twice daily oral administration of paclitaxel and cyclospori n A. Aside from an unpleasant taste, the oral regimen was well tolerated, and th ere were no grade 3 or 4 drug-related toxicities. The systemic exposure to paclitaxel, as assessed by maximum plasma concentration (C-max) and area un der the plasma concentration versus time curve (AUC) values, did not increa se as the dose of paclitaxel was increased from 180 to 540 mg, and there wa s substantial interindividual variability (4-6-fold) at each dose level. Me an paclitaxel C-max values approached plasma concentrations achieved with c linically relevant parenteral dose schedules, averaging 268 +/- 164 ng/ml. AUC values averaged 3306 +/- 1977 ng.h/ ml, which was significantly lower t han AUC values achieved with clinically relevant i.v. paclitaxel dose sched ules. However, computer simulations using pharmacokinetic parameters derive d from the present study demonstrated that pharmacodynamically relevant ste ady-state plasma paclitaxel concentrations of at least 0.06 mu M would be a chieved after protracted once daily and twice daily dosing with oral paclit axel and cyclosporin A. Paclitaxel metabolites were detectable in three pat ients, and the 6-alpha-hydroxypaclitaxel: paclitaxel and 3-rho-hydroxypacli taxel:paclitaxel AUC ratios averaged 0.63 and 0.86, respectively; these val ues were substantially higher than values reported in patients treated with i.v. paclitaxel. Oral paclitaxel was bioavailable in humans when administered in combination with oral cyclosporin A 5 mg/kg 1 h before and concurrently with paclitaxe l treatment, and plasma paclitaxel concentrations achieved with this schedu le were biologically relevant and approached concentrations attained with c linically relevant parenteral dose schedules. However, treatment of patient s with oral paclitaxel using a single oral dose administration schedule fai led to achieve sufficiently high systemic drug exposure and pharmacodynamic effects. In contrast, computer simulations demonstrated that clinically re levant pharmacodynamic effects are likely to be achieved with multiple once daily and twice daily oral paclitaxel-cyclosporin A dosing schedules.