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

Summary

Background

Vinorelbine is a vinca alkaloid obtained by hemisynthesis, which makes the molecule more lipophilic than the other vincas An injectable formulation is already marketed for the treatment of non small cell lung cancer (NSCLC) and advanced breast cancer (ABC) A new oral form has been developed and its file registration is being submitted As part of its development, a clinical study was conducted to determine the absolute bioavailability and pharmacokinetics of oral vinorelbine administered as softgel capsules, and to evaluate its safety profile compared with intravenous administration.

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 (ı v) infusion of 25 mg/m² or as softgel capsules at a dose of 80 mg/m² 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 administration. Safety was assessed after each administration using the CALGB/expanded CTC classification

Results

Twenty-four patients were eligible for pharmacokinetic evaluation. Oral vinorelbine was rapidly absorbed at 80 mg/m² (T_max 14 ± 07 h) and showed a bioavailability of 43 ± 14, and close to 40% based on AUC_last and AUC_inf, respectively A bioequivalence analysis was conducted on dosage-normalised blood exposures Equivalence was demonstrated between 80 mg/m² oral and 30 mg/m² ı v, and between 60 mg/m² oral and 25 mg/m² ı v The inter-individual variability was equivalent for both routes (CV 38% and 39% for oral and ı v, respectively) A correlation was found in both methods between AUC_last and % nadir variation in white blood cells (WBC) and polymorphonuclears (PMN) More cases of neutropenia (all grades pooled), leucopenia (grades 3–4 only) and nausea (grades 2–3) were induced by 80 mg/m² oral vinorelbine than by 25 mg/m² ı v The greatest intensity of these effects, following oral administration, probably reflects the higher, observed drug exposure.

Conclusion

At therapeutic dosage levels, pharmacokinetic behaviour and safety profiles were similar for both routes The absolute bioavailability of the oral vinorelbine (new, soft gelatine capsule) was close to 40% Inter-individual variability in drug exposure was equivalent in both routes The pharmacokinetic/pharmacodynamic (PKVPD) relationship in haematological toxicity was independent of the routes of administration Reliable, corresponding doses between oral and ı v vinorelbine were established, which will result in bioequivalent AUC