Coadministration of oral cyclosporin a enables oral therapy with paclitaxel

i.v. paclitaxel is inconvenient and associated with significant and poorly predictable side effects largely due to the pharmaceutical vehicle Cremopho r EL. Oral administration may be attractive because it may circumvent the u se of Cremophor EL. However, paclitaxel, as well as many other commonly app lied drugs, has poor bioavailability caused by high affinity for the mdr1 P -glycoprotein drug efflux pump, which is abundantly present in the gastroin testinal tract. Consequently, inhibition of P-glycoprotein by oral cyclospo rin A (CsA) should increase systemic exposure of oral paclitaxel to therape utic levels, A proof-of-concept study was carried out in 14 patients with s olid tumors. Patients received one course of oral paclitaxel of 60 mg/m(2) with or without 15 mg/kg CsA and with i.v. paclitaxel in subsequent courses , The pharmacokinetics of paclitaxel and its major metabolites were determi ned during the first two courses. In addition, levels of CsA, Cremophor EL, and ethanol were measured. Bioavailability of oral paclitaxel in combinati on with CsA was 8-fold higher than after oral paclitaxel alone (P < 0.001). Therapeutic concentrations were achieved on average during 7.4 h, which is comparable with an equivalent i.v. dose. The oral combination was well tol erated and did not induce gastrointestinal toxicity or myelosuppression, Cr emophor EL plasma levels after oral drug administration were undetectable. In conclusion, coadministration of oral CsA increased the systemic exposure of oral paclitaxel from negligible to therapeutic levels. The combination enables treatment with oral paclitaxel. Undetectable Cremophor EL levels af ter oral administration may have a very beneficial influence on the safety of the treatment with oral paclitaxel.