Gisleskog P O, Hermann D, Hammarlund-Udenaes M, Karlsson M O
Division of Clinical Pharmacology, GlaxoWellcome Research and Development, Middlesex, England.
Clin Pharmacol Ther. 1998 Dec;64(6):636-47. doi: 10.1016/S0009-9236(98)90054-6.
To develop a pharmacokinetic-pharmacodynamic model that characterizes the conversion of testosterone to dihydrotestosterone (DHT) by 5 alpha-reductase types 1 and 2 and the irreversible inhibition of 5 alpha-reductase by finasteride, a 5 alpha-reductase type 2 inhibitor and by GI198745 (dutasteride), a potent and specific dual 5 alpha-reductase inhibitor.
Healthy men (n = 48) received doses of 0.1 to 40 mg GI198745 (n = 4 subjects per dose), 5 mg finasteride (n = 8), or placebo (n = 8) in a parallel-group study. Plasma concentrations of GI198745, finasteride, and DHT were measured frequently up to 8 weeks after dosing. Models were fitted with mixed-effects modeling with the NONMEM program.
The pharmacodynamics were well described with a model that accounted for the rates of DHT formation and elimination, 5 alpha-reductase turnover, relative capacity of the 2 5 alpha-reductase isozymes, and the rates of irreversible inhibition of one (finasteride) or both (GI198745) types of 5 alpha-reductase. The model indicated that type 2 5 alpha-reductase contributed approximately 80% of plasma DHT. GI198745 was about 3-fold more potent than finasteride on 5 alpha-reductase type 2. Nearly full blockade of both isozymes was achieved at doses of 10 mg or more GI198745, although the potency of this agent on 5 alpha-reductase type 1 was less than on type 2.
A physiologically based model for the turnover and irreversible inhibition of 5 alpha-reductase and for formation and elimination of DHT described the data well. This model helps explain differences in the rates of onset and offset of effect and offers a way to determine the relative potency of the irreversible 5 alpha-reductase inhibitors.
建立一个药代动力学-药效学模型，该模型能够描述1型和2型5α-还原酶将睾酮转化为双氢睾酮（DHT）的过程，以及5α-还原酶2型抑制剂非那雄胺和强效特异性5α-还原酶双重抑制剂GI198745（度他雄胺）对5α-还原酶的不可逆抑制作用。
在一项平行组研究中，48名健康男性接受了0.1至40mg的GI198745（每剂量4名受试者）、5mg非那雄胺（8名受试者）或安慰剂（8名受试者）。在给药后长达8周的时间内，频繁测量血浆中GI198745、非那雄胺和DHT的浓度。使用NONMEM程序通过混合效应建模对模型进行拟合。
用一个考虑了DHT生成和消除速率、5α-还原酶周转、两种5α-还原酶同工酶的相对能力以及一种（非那雄胺）或两种（GI198745）类型的5α-还原酶不可逆抑制速率的模型，能够很好地描述药效学特征。该模型表明，2型5α-还原酶对血浆DHT的贡献约为80%。GI198745对2型5α-还原酶的效力比非那雄胺高约3倍。在剂量为10mg或更高的GI198745时，两种同工酶几乎完全被阻断，尽管该药物对1型5α-还原酶的效力低于对2型的效力。
一个基于生理学的5α-还原酶周转和不可逆抑制以及DHT生成和消除的模型能够很好地描述数据。该模型有助于解释效应起效和消退速率的差异，并提供了一种确定不可逆5α-还原酶抑制剂相对效力的方法。
