Janssen Research & Development, LLC, Raritan, NJ, USA.
Clin Pharmacol Drug Dev. 2018 Sep;7(7):699-711. doi: 10.1002/cpdd.412. Epub 2017 Nov 10.
To improve room temperature stability and oral bioavailability of mavatrep (JNJ-39439335, a transient receptor potential vanilloid subtype-1 antagonist), various formulations were initially developed and evaluated in 2 phase 1 open-label, randomized, 3-way crossover studies in healthy participants. Study 1 evaluated 2 new overencapsulated tablet formulations (formulations B and C) relative to an overencapsulated early tablet formulation (formulation A), using mavatrep HCl salt form. Because these tablets were still not room-temperature stable, in study 2: two free-base solid dispersion amorphous formulations (formulations D and E) were evaluated relative to the best encapsulated formulation from study 1 (formulation C) and also food effect. Both studies had screening (∼4 weeks), treatment (study 1: n = 18, 6-sequenced; formulations B and C [2 × 25 mg] versus A [2 × 25 mg]; study 2, part 1: n = 24, formulations D and E [2 × 12.5 mg] versus C [1 × 25 mg]; study 2, part 2: n = 16, best formulation from part 1 fed versus fasted, 2 × 12.5 mg) with a 21-day washout period and a follow-up. Mavatrep exhibited consistent pharmacokinetics across formulations. Following rapid absorption (median t , 1.5-6.5 hours), plasma concentrations declined multiexponentially (mean t , 67-104 hours). The new encapsulated tablet formulation (formulation C, capsule filler: poloxamer 407) was the best formulation (C and AUC values 2-3-fold > than the other 2) from study 1. Using this as a reference in study 2, part 1, only small (<20%) differences in mean C and AUC were observed between the 3 formulations (C, D, and E). Formulation E (gelatin capsule with amorphous solid dispersion [12.5 mg free base], hydroxypropyl methylcellulose, vitamin E polyethylene glycol succinate, silicified microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide) showed improved room-temperature stability and provided the best overall bioavailability with small variability. Small effects of a high-fat meal on oral bioavailability were observed for formulation E, but were not clinically meaningful. Mavatrep safety profiles were similar across formulations and under fasted and fed conditions. No new safety concerns were reported.
为了提高马瓦特雷普（JNJ-39439335，瞬时受体电位香草酸亚型 1 拮抗剂）的室温稳定性和口服生物利用度，在健康参与者中进行了 2 项 1 期开放标签、随机、3 向交叉研究，最初开发并评估了各种制剂。研究 1 评估了 2 种新的包封片剂制剂（制剂 B 和 C）相对于早期包封片剂制剂（制剂 A），使用马瓦特雷普 HCl 盐形式。由于这些片剂仍不稳定在室温下，在研究 2 中：两种游离碱固体分散无定形制剂（制剂 D 和 E）相对于研究 1 中最佳包封制剂（制剂 C）和食物效应进行了评估。这两项研究都有筛选期（约 4 周）和治疗期（研究 1：n = 18，6 个序列；制剂 B 和 C [2×25mg]与 A [2×25mg]；研究 2，第 1 部分：n = 24，制剂 D 和 E [2×12.5mg]与 C [1×25mg]；研究 2，第 2 部分：n = 16，第 1 部分中最佳制剂进食与禁食，2×12.5mg），洗脱期为 21 天，随访期为 21 天。马瓦特雷普在制剂之间表现出一致的药代动力学。快速吸收后（中位数 t ，1.5-6.5 小时），血浆浓度呈多指数下降（平均 t ，67-104 小时）。新的包封片剂制剂（制剂 C，胶囊填充剂：泊洛沙姆 407）是研究 1 中最佳制剂（C 和 AUC 值是其他 2 种的 2-3 倍）。在研究 2 中，第 1 部分中，使用该制剂作为参考，3 种制剂（C、D 和 E）之间仅观察到平均 C 和 AUC 之间较小（<20%）的差异。制剂 E（含有无定形固体分散体的明胶胶囊[12.5mg 游离碱]、羟丙基甲基纤维素、生育酚聚乙二醇琥珀酸酯、硅化微晶纤维素、硬脂酸镁、胶体二氧化硅）表现出改善的室温稳定性，并具有较小的变异性，提供了最佳的整体生物利用度。制剂 E 观察到高脂肪餐对口服生物利用度的小影响，但无临床意义。马瓦特雷普的安全性特征在制剂之间以及空腹和进食条件下相似。未报告新的安全性问题。
