Merck Sharp & Dohme Corp, Whitehouse Station, NJ, USA.
AAPS J. 2013 Apr;15(2):498-504. doi: 10.1208/s12248-012-9443-5. Epub 2013 Jan 25.
Rolofylline is a potent, selective adenosine A1 receptor antagonist that was under development for the treatment of patients with acute congestive heart failure and renal impairment. Rolofylline is metabolized primarily to the pharmacologically active M1-trans and M1-cis metabolites (metabolites) by cytochrome P450 (CYP) 3A4. The aim of this investigation was to provide a pharmacokinetic (PK) model for rolofylline and metabolites following intravenous administration to healthy volunteers. Data included for this investigation came from a randomized, double-blind, dose-escalation trial in four groups of healthy volunteers (N=36) where single doses of rolofylline, spanning 1 to 60 mg ,were infused over 1-2 h. The rolofylline and metabolite data were analyzed simultaneously using NONMEM. The simultaneous PK model comprised, in part, a two-compartment linear PK model for rolofylline, with estimates of clearance and volume of distribution at steady-state of 24.4 L/h and 239 L, respectively. In addition, the final PK model contained provisions for both conversion of rolofylline to metabolites and stereochemical conversion of M1-trans to M1-cis. Accordingly, the final model captured known aspects of rolofylline metabolism and was capable of simultaneously describing the PK of rolofylline and metabolites in healthy volunteers.
罗洛司非林是一种强效、选择性的腺嘌呤 A1 受体拮抗剂，曾在开发用于治疗急性充血性心力衰竭和肾功能损害的患者。罗洛司非林主要通过细胞色素 P450（CYP）3A4 代谢为具有药理活性的 M1-反式和 M1-顺式代谢物（代谢物）。本研究的目的是提供罗洛司非林和代谢物在健康志愿者静脉给药后的药代动力学（PK）模型。本研究的数据来自于一项在四组健康志愿者（N=36）中进行的随机、双盲、剂量递增试验，其中罗洛司非林的单剂量为 1 至 60mg，输注时间为 1 至 2 小时。使用 NONMEM 同时分析罗洛司非林和代谢物数据。同时 PK 模型部分包括罗洛司非林的两室线性 PK 模型，稳态时清除率和分布容积的估计值分别为 24.4L/h 和 239L。此外，最终 PK 模型还包含了罗洛司非林转化为代谢物以及 M1-反式转化为 M1-顺式的立体化学转化的规定。因此，最终模型捕获了罗洛司非林代谢的已知方面，并能够同时描述健康志愿者中罗洛司非林和代谢物的 PK。
