Steady‐state population pharmacokinetics of terizidone and its metabolite cycloserine in patients with drug‐resistant tuberculosis

药代动力学 环丝氨酸 分配量 人口 药理学 代谢物 医学 肺结核 活性代谢物 内科学 病理 环境卫生
作者
Mwila Mulubwa,Pierre Mugabo
出处
期刊:British Journal of Clinical Pharmacology [Wiley]
卷期号:85 (9): 1946-1956 被引量:5
标识
DOI:10.1111/bcp.13975
摘要

Aims Despite terizidone being part of the second-line recommended drugs for treatment of drug-resistant tuberculosis (DR-TB), information on its pharmacokinetics is scarce. The aim of this study was to describe the steady-state population pharmacokinetics (PPK) of terizidone and its primary metabolite cycloserine in patients with DR-TB and determine the effect of patient characteristics. Methods This clinical study involved 39 adult DR-TB patients admitted to Brewelskloof Hospital in Cape Town, South Africa for intensive treatment phase. Blood samples were collected at predose and 0.5, 1, 2, 3, 3.5, 4, 8, 16 and 24 hours after drug administration. The estimation of PPK parameters was performed using nonlinear mixed-effects modelling software Monolix 2018R1. Free-fat mass was used to perform allometric scaling on disposition parameters. Results A 1-compartment model best described the pharmacokinetics of terizidone and cycloserine. A modified transit compartment model described the absorption of terizidone. The parameters of terizidone model were mean transit time (1.7 h), absorption rate constant (2.97 h-1 ), apparent volume of distribution (Vp/F: 13.4 L) and apparent total clearance (0.51 L h-1 ). In the joint model, apparent fraction of terizidone converted to cycloserine was 0.29 while apparent clearance of terizidone via other routes and apparent cycloserine clearance was 0.1 L h-1 and 2.94 L h-1 , respectively. Serum albumin had significant effect on Vp/F. Conclusions The developed PPK model described well the concentration-time profile for terizidone and cycloserine in DR-TB patients. High albumin concentration was associated with low Vp/F.

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