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.