Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Br J Clin Pharmacol. 2011 Jul;72(1):51-62. doi: 10.1111/j.1365-2125.2011.03940.x.
This study was designed to characterize the population pharmacokinetics of isoniazid in South African pulmonary tuberculosis patients.
Concentration-time measurements obtained from 235 patients receiving oral doses of isoniazid as part of routine tuberculosis chemotherapy in two clinical studies were pooled and subjected to nonlinear mixed-effects analysis.
A two-compartmental model, including first-order absorption and elimination with allometric scaling, was found to describe the observed dose-exposure relationship for oral isoniazid adequately. A mixture model was used to characterize dual rates of isoniazid elimination. Estimates of apparent clearance in slow and fast eliminators were 9.70 and 21.6 l h(-1) , respectively. The proportion of fast eliminators in the population was estimated to be 13.2%. Central volume of distribution was estimated to be 10% smaller in female patients and clearance was found to be 17% lower in patients with HIV. Variability in absorption rate (90%) was completely interoccasional in nature, whereas in relative bioavailability, interoccasional variability (8.4%) was lower than interindividual variability (26%). Oral doses, given once daily according to dosing policies at the time, were sufficient to reach therapeutic concentrations in the majority of the studied population, regardless of eliminator phenotype. Simulations suggested that current treatment guidelines (5 mg kg(-1) ) may be suboptimal in fast eliminators with low body weight.
A population pharmacokinetic model was developed to characterize the highly variable pharmacokinetics of isoniazid in a South African pulmonary tuberculosis patient population. Current treatment guidelines may lead to underexposure in rapid isoniazid eliminators.
本研究旨在描述南非肺结核患者异烟肼的群体药代动力学特征。
将 235 例患者接受异烟肼口服剂量的浓度-时间测量值作为常规结核病化疗的一部分进行汇总，并进行非线性混合效应分析。
发现包括一阶吸收和消除以及比例缩放的两室模型能够充分描述口服异烟肼的观察到的剂量-暴露关系。使用混合模型来描述异烟肼消除的双重速率。在缓慢和快速消除者中，表观清除率的估计值分别为 9.70 和 21.6 l/h。人群中快速消除者的比例估计为 13.2%。女性患者的中心分布容积估计小 10%，HIV 患者的清除率低 17%。吸收速率的变异性（90%）完全是偶然的，而在相对生物利用度方面，偶然变异性（8.4%）低于个体间变异性（26%）。根据当时的给药政策，每天一次给予口服剂量，足以使大多数研究人群达到治疗浓度，无论消除者表型如何。模拟表明，目前的治疗指南（5mg/kg）可能不适用于体重较轻的快速消除者。
开发了一个群体药代动力学模型来描述南非肺结核患者异烟肼高度可变的药代动力学。目前的治疗指南可能导致快速异烟肼消除者暴露不足。
