Oral vinorelbine pharmacokinetics and absolute bioavailability study in patients with solid tumors

Background: Vinorelbine is a vinca alkaloid obtained by hemi-synthesis, whi ch makes the molecule more lipophilic than the other vincas. An injectable formulation is already marketed for the treatment of non small cell lung ca ncer (NSCLC) and advanced breast cancer (ABC). A new oral form has been dev eloped and its file registration is being submitted. As part of its develop ment, a clinical study was conducted to determine the absolute bioavailabil ity and pharmacokinetics of oral vinorelbine administered as softgel capsul es, and to evaluate its safety profile compared with intravenous administra tion. Patients and methods: Thirty-two patients with solid tumours were included in the study. Patients fasted and were randomised to receive vinorelbine on day 1, either as a 20 minute intravenous (i.v.) infusion of 25 mg/m(2) or as softgel capsules at a dose of 80 mg/m(2). Patients were treated with the alternate route after a one week wash-out period. Blood and urine samples for pharmacokinetic analysis were collected during each vinorelbine adminis tration. Safety was assessed after each administration using the CALGB/expa nded CTC classification. Results: Twenty-four patients were eligible for pharmacokinetic evaluation. Oral vinorelbine was rapidly absorbed at 80 mg/m(2) (T-max 1.4 +/- 0.7 h) and showed a bioavailability of 43 +/- 14, and close to 40% based on AUC(la st) and AUC(inf), respectively. A bioequivalence analysis was conducted on dosage-normalised blood exposures. Equivalence was demonstrated between 80 mg/m(2) oral and 30 mg/m(2) i.v., and between 60 mg/m(2) oral and 25 mg/m(2 ) i.v. The inter-individual variability was equivalent for both routes (CV: 38% and 39% for oral and i.v., respectively). A correlation was found in b oth methods between AUC(last) and % nadir variation in white blood cells (W BC) and polymorphonuclears (PMN). More cases of neutropenia (all grades poo led), leucopenia (grades 3-4 only) and nausea (grades 2-3) were induced by 80 mg/m(2) oral vinorelbine than by 25 mg/m(2) i.v. The greatest intensity of these effects, following oral administration, probably reflects the high er, observed drug exposure. Conclusion: At therapeutic dosage levels, pharmacokinetic behaviour and saf ety profiles were similar for both routes. The absolute bioavailability of the oral vinorelbine (new, soft gelatine capsule) was close to 40%. Inter-i ndividual variability in drug exposure was equivalent in both routes. The p harmacokinetic/pharmacodynamic (PK/PD) relationship in haematological toxic ity was independent of the routes of administration. Reliable, correspondin g doses between oral and i.v. vinorelbine were established, which will resu lt in bioequivalent AUC.