Vinflunine oral pharmacokinetics and absolute bioavailability of soft and hard gelatin capsules: results of two phase I trials.

Background: Vinflunine is a new-generation microtubule inhibitor, which is currently registered in Europe and in some countries elsewhere as an intravenous formulation for the second-line treatment of transitional urothelial cell carcinoma. On the basis of favourable non-clinical results, the clinical development of an oral formulation was initiated.

Objective: The absolute oral bioavailability was investigated in patients through two consecutive trials: the first trial used soft gelatin capsules filled with solubilized vinflunine (SLCaps), while the second study investigated hard gelatin capsules containing vinflunine as a formulated powder (HPCaps).

Study Design: Each pharmacokinetic trial was conducted according to a randomized cross-over design. Patients received 120 mg/m2 of either oral (SLCaps or HPCaps) or intravenous vinflunine on day 1, followed by the alternate dosing route after a 2-week washout period. Blood samples were collected over 168 hours. A pharmacokinetic analysis was conducted for each patient and route of dosing to derive the absolute oral bioavailability of SLCaps and HPCaps.

Results: A total of 12 and 22 patients were enrolled, for SLCaps and HPCaps, respectively. Vinflunine absorption was rapid for both oral formulations. Blood concentrations peaked at 2.5 hours following oral intake with food, and then decreased similarly to the intravenous profile. The mean absolute bioavailability was high, at 58.3 ± 14.4% (SLCaps) and 57.3 ± 11% (HPCaps), with limited inter-individual variability (coefficient of variation = 25% and 19% for SLCaps and HPCaps, respectively). Neither sequence nor period effects were detected. The gastro-intestinal tolerance was satisfactory. The main drug-related adverse events were asthenia, fatigue, constipation and neutropenia, mostly of grade 1 or 2. No grade 4 and no drug-related serious adverse events were reported.

Conclusion: The high bioavailability and low inter-individual variability are favourable pharmacokinetic properties, which could be valuable for further clinical development of oral vinflunine.