College of Pharmacy, University of Iowa, Iowa City, 52242, USA.
AAPS J. 2011 Dec;13(4):665-73. doi: 10.1208/s12248-011-9304-7. Epub 2011 Oct 25.
Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n = 32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. Telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h(-1). Moderate renal impairment resulted in a 74% decrease in Ka. The population estimates for oral clearance (CL/F) for the two populations were 11.6 and 3.34 L/h, respectively, with 25% of the subjects being allocated to the high-clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmet(est)) was 0.20/L. Apparent volume of distribution of the metabolite compartment (V3/F) was fixed to 1 L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. A two-compartment parent-metabolite model adequately described the pharmacokinetics of telapristone and CDB-4453. The clearance of telapristone was separated into two populations and could be the result of metabolism via polymorphic CYP3A5.
地洛孕素是一种选择性孕激素拮抗剂，目前正在开发用于长期治疗子宫内膜异位症和子宫肌瘤相关症状。采用非线性混合效应模型研究了地洛孕素（CDB-4124）和 CDB-4453 的群体药代动力学。对来自两项临床研究（n=32）的数据进行了分析。采用两室（母体）一室（代谢物）混合模型（具有两个表观清除率群体），并结合一级吸收和消除，可较好地描述地洛孕素和 CDB-4453 的药代动力学。地洛孕素吸收迅速，吸收速率常数（Ka）为 1.26 h-1。中重度肾功能不全使 Ka 降低 74%。两个群体的口服清除率（CL/F）的群体估计值分别为 11.6 和 3.34 L/h，25%的受试者被分配到高清除率组。中央室表观分布容积（V2/F）为 37.4 L，两室间表观清除率（Q/F）为 21.9 L/h，母体的外周表观分布容积（V4/F）为 120 L。地洛孕素转化为 CDB-4453 的分数与 CDB-4453 分布容积的比值（Fmet（est））为 0.20/L。代谢物室的表观分布容积（V3/F）固定为 1 L，代谢物的表观清除率（CLM/F）为 2.43 L/h。两室母体-代谢物模型可较好地描述地洛孕素和 CDB-4453 的药代动力学。地洛孕素的清除率分为两个群体，这可能是由于代谢物经多态性 CYP3A5 代谢所致。
