Rowinsky E K, Noe D A, Trump D L, Winer E P, Lucas V S, Wargin W A, Hohneker J A, Lubejko B, Sartorius S E, Ettinger D S
Johns Hopkins Oncology Center, Division of Pharmacology and Experimental Therapeutics, Baltimore MD 21287-8934.
J Clin Oncol. 1994 Sep;12(9):1754-63. doi: 10.1200/JCO.1994.12.9.1754.
The feasibility of administering vinorelbine (Navelbine, Burroughs Wellcome Co, Research Triangle Park, NC), a semisynthetic vinca alkaloid with broad activity, as a liquid-filled gelatin capsule was evaluated in a bioavailability (F) and pharmacokinetic study.
Each of 17 cancer patients had pharmacokinetic studies performed after receiving vinorelbine 30 mg/m2 intravenously (IV), which is the maximum-tolerated dose (MTD) for weekly IV administration, and twice after receiving the oral formulation at a nominal dose of 100 mg/m2. Subsequently, these patients and 10 other subjects received the oral formulation at a dose of 100 mg/m2/wk to evaluate the feasibility of chronic oral administration.
Plasma drug disposition was well described by a triphasic model. Mean central volume of distribution and steady-state volume of distribution (Vss) were large (0.66 +/- 0.46 L/kg and 20.02 +/- 8.55 L/kg, respectively); the mean harmonic terminal half-life (t1/2) was long (18 hours); and the high mean clearance (CI) rate (0.80 +/- 0.68 L/h/kg) approached hepatic blood flow. F was low (0.27 +/- 12), and absorption was rapid (mean time of maximum plasma concentration [Tmax], 0.91 +/- 0.22 hours). Absorption parameters after the first and second oral doses were similar, with mean F values of 0.27 +/- 0.14 and 0.25 +/- 0.11, respectively. Coefficients of variability (CVs) for F, maximum plasma concentration (Cmax), and Tmax were 32%, 42%, and 78%, respectively, indicating moderate intraindividual variability. The pharmacologic profile of this oral formulation indicates that there is a large first-pass effect. Neutropenia was the principal toxicity of oral vinorelbine. Grade 3 or 4 neutropenia occurred in 63% of patients, but only 11% developed neutropenia and infection. Nausea, vomiting, and diarrhea were also common with oral administration, but these effects were rarely severe and could be ameliorated by using a divided-dose schedule and/or prophylactic antiemetic and antidiarrheal agents. The mean nominal oral dose was 82 mg/m2, and the mean percentage of intended dose that was received was 92%. Although dose escalations were permitted for negligible toxicity, doses were not escalated to greater than 100 mg/m2/wk in any patient. Vinorelbine given as a liquid-filled gelatin capsule at 100 mg/m2 provided equivalent pharmacologic exposure as 30 mg/m2 IV.
The oral administration of vinorelbine, specifically as a liquid-filled, soft gelatin capsule, is a feasible route of administration. Weekly oral dosing at 100 mg/m2 induces a consistent degree of myelosuppression, but the high frequency of grade 3 or 4 neutropenia, albeit brief and uncomplicated, warrants the recommendation of a slightly lower starting dose, ie, 80 mg/m2/d, for subsequent phase II evaluations, especially in heavily pretreated patients.
在一项生物利用度（F）和药代动力学研究中，评估了将长春瑞滨（诺维本，百时美施贵宝公司，北卡罗来纳州三角研究园）作为明胶软胶囊给药的可行性，长春瑞滨是一种具有广泛活性的半合成长春花生物碱。
17例癌症患者在接受静脉注射长春瑞滨30mg/m²（这是每周静脉给药的最大耐受剂量[MTD]）后进行了药代动力学研究，并在接受标称剂量为100mg/m²的口服制剂后进行了两次药代动力学研究。随后，这些患者和另外10名受试者接受了100mg/m²/周的口服制剂，以评估长期口服给药的可行性。
血浆药物处置情况可用三相模型很好地描述。平均中央分布容积和稳态分布容积（Vss）较大（分别为0.66±0.46L/kg和20.02±8.55L/kg）；平均调和末端半衰期（t1/2）较长（18小时）；高平均清除率（CI）（0.80±0.68L/h/kg）接近肝血流量。F较低（0.27±0.12），吸收迅速（平均达峰时间[Tmax]为0.91±0.22小时）。首次和第二次口服给药后的吸收参数相似，平均F值分别为0.27±0.14和0.25±0.11。F、最大血浆浓度（Cmax）和Tmax的变异系数（CV）分别为32%、42%和78%，表明个体内变异程度中等。该口服制剂的药理特征表明存在较大的首过效应。中性粒细胞减少是口服长春瑞滨的主要毒性。63%的患者发生3级或4级中性粒细胞减少，但只有11%的患者出现中性粒细胞减少和感染。恶心、呕吐和腹泻在口服给药时也很常见，但这些影响很少严重，可通过采用分剂量给药方案和/或预防性使用止吐药和止泻药来缓解。平均标称口服剂量为82mg/m²，接受的预期剂量平均百分比为92%。尽管允许在毒性可忽略不计的情况下增加剂量，但在任何患者中剂量均未增加至超过100mg/m²/周。以100mg/m²的明胶软胶囊形式给药的长春瑞滨提供了与30mg/m²静脉注射等效的药理暴露。
口服长春瑞滨，特别是作为明胶软胶囊给药，是一种可行的给药途径。每周口服100mg/m²可诱导一致程度的骨髓抑制，但3级或4级中性粒细胞减少的高发生率，尽管短暂且无并发症，仍需要推荐稍低的起始剂量，即80mg/m²/日，用于后续的II期评估，尤其是在预处理严重的患者中。
