Institut Claudius Regaud, Toulouse, France.
Clin Pharmacokinet. 2012 Jun 1;51(6):357-64. doi: 10.2165/11599300-000000000-00000.
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.
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).
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.
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.
The high bioavailability and low inter-individual variability are favourable pharmacokinetic properties, which could be valuable for further clinical development of oral vinflunine.
长春氟宁是一种新型微管抑制剂，目前已在欧洲和其他一些国家注册，作为二线治疗转移性尿路上皮细胞癌的静脉制剂。基于有利的非临床结果，启动了口服制剂的临床开发。
通过两项连续试验研究了患者的绝对口服生物利用度：第一项试验使用填充有溶出长春氟宁的软明胶胶囊（SLCaps），第二项研究则考察了含有长春氟宁的硬明胶胶囊作为配方粉末（HPCaps）的情况。
每项药代动力学试验均按照随机交叉设计进行。患者在第 1 天接受 120mg/m2 的口服（SLCaps 或 HPCaps）或静脉长春氟宁给药，在 2 周洗脱期后切换至另一途径给药。采集 168 小时的血样。对每位患者和给药途径进行药代动力学分析，得出 SLCaps 和 HPCaps 的绝对口服生物利用度。
共纳入 12 名和 22 名患者，分别接受 SLCaps 和 HPCaps 治疗。两种口服制剂的长春氟宁吸收均迅速。口服给药时，与食物同服，血药浓度在 2.5 小时达峰，然后与静脉药代动力学特征相似地下降。绝对生物利用度较高，分别为 58.3±14.4%（SLCaps）和 57.3±11%（HPCaps），个体间变异性有限（变异系数分别为 25%和 19%，SLCaps 和 HPCaps）。未检测到顺序或周期效应。胃肠耐受性良好。主要的药物相关不良事件是乏力、疲劳、便秘和中性粒细胞减少症，多为 1 级或 2 级。未报告 4 级和药物相关的严重不良事件。
高生物利用度和低个体间变异性是有利的药代动力学特征，这可能对进一步开发口服长春氟宁具有重要意义。
