Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients
Variability in the population pharmacokinetics of isoniazid in South African tuberculosis patients
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DOI：
10.1111/j.1365-2125.2011.03940.x
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发表时间：
2011-07-01
影响因子：
3.4
通讯作者：
Simonsson, Ulrika S. H.
中科院分区：
文献类型：
--
作者：
Wilkins, Justin J.;Langdon, Grant;Simonsson, Ulrika S. H.
目的：研究南非肺结核患者异烟肼的人群药代动力学特征。方法对两项临床研究中接受口服异烟肼作为常规结核化疗一部分的235例患者的浓度-时间测量数据进行汇总，并进行非线性混合效应分析。结果建立了一阶异速尺度吸收消除双室模型，该模型能较好地描述口服异烟肼的剂量-暴露关系。混合模型用于表征异烟肼消除的双重速率。慢速消除剂和快速消除剂的表观清除率分别为9.70和21.6 l h（-1）。种群中快速消灭者的比例估计为13.2%。据估计，女性患者的中心分布体积要小10%，而HIV患者的清除率要低17%。吸收率的变异性（90%）在本质上完全是间断性的，而相对生物利用度的间断性变异性（8.4%）低于个体间变异性（26%）。根据当时的给药政策，口服剂量每天一次，足以在大多数研究人群中达到治疗浓度，无论消除剂表型如何。模拟表明，目前的治疗指南（5mg kg(-1)）对于低体重的快速消除者可能不是最佳的。结论建立了一个人群药代动力学模型，以表征异烟肼在南非肺结核患者人群中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剂暴露不足。
AIMThis study was designed to characterize the population pharmacokinetics of isoniazid in South African pulmonary tuberculosis patients.METHODSConcentration-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.RESULTSA 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.CONCLUSIONSA 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.