Clofazimine pharmacokinetics in patients with TB: dosing implications.
Clofazimine pharmacokinetics in patients with TB: dosing implications.
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DOI：
10.1093/jac/dkaa310
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发表时间：
2020-11-01
期刊：
影响因子：
--
通讯作者：
Denti P
中科院分区：
文献类型：
--
作者：
Abdelwahab MT;Wasserman S;Brust JCM;Gandhi NR;Meintjes G;Everitt D;Diacon A;Dawson R;Wiesner L;Svensson EM;Maartens G;Denti P
氯法齐明被广泛用作耐药结核病方案的关键成分，但推荐剂量没有证据。需要来自相关患者群体的药代动力学数据来提供剂量优化信息。为了确定氯法齐明的暴露，评估变量对变异性的影响，并模拟南非结核病患者不同剂量策略的暴露。临床和药代动力学数据是从两项研究中登记的肺结核患者获得的，这两项研究的样本密集和稀疏，持续时间长达6个 月。用LC-MS/MS测定血药浓度，并用非线性混合效应模型进行解释。对人体尺寸描述参数和其他潜在协变量进行了药代动力学参数测试。我们模拟了不同的给药方案，以安全地缩短达到日均浓度超过推定目标浓度0.25 mg/L的时间。我们分析了139名参与者的1570名氯法齐明浓度；79名(57%)患有耐药结核病，54名(39%)感染了艾滋病毒。氯法齐明的药代动力学符合三房室模型。典型受试者的血气清晰度为11.5 L/h，外周血容量为10 500 L。女性在治疗的头几个月中观察到较低的血浆暴露，这是由于较高的体脂比例所解释的。基于模型的模拟估计，在典型的结核病参与者中，每天200 mg的负荷剂量持续2 周将实现比目标有效浓度早37 天的平均日浓度。氯法齐明分布广泛，消除半衰期较长。性情受体内脂肪含量的影响很大，对患有结核病的妇女有潜在的剂量影响。
Clofazimine is in widespread use as a key component of drug-resistant TB regimens, but the recommended dose is not evidence based. Pharmacokinetic data from relevant patient populations are needed to inform dose optimization. To determine clofazimine exposure, evaluate covariate effects on variability, and simulate exposures for different dosing strategies in South African TB patients. Clinical and pharmacokinetic data were obtained from participants with pulmonary TB enrolled in two studies with intensive and sparse sampling for up to 6 months. Plasma concentrations were measured by LC-MS/MS and interpreted with non-linear mixed-effects modelling. Body size descriptors and other potential covariates were tested on pharmacokinetic parameters. We simulated different dosing regimens to safely shorten time to average daily concentration above a putative target concentration of 0.25 mg/L. We analysed 1570 clofazimine concentrations from 139 participants; 79 (57%) had drug-resistant TB and 54 (39%) were HIV infected. Clofazimine pharmacokinetics were well characterized by a three-compartment model. Clearance was 11.5 L/h and peripheral volume 10 500 L for a typical participant. Lower plasma exposures were observed in women during the first few months of treatment, explained by higher body fat fraction. Model-based simulations estimated that a loading dose of 200 mg daily for 2 weeks would achieve average daily concentrations above a target efficacy concentration 37 days earlier in a typical TB participant. Clofazimine was widely distributed with a long elimination half-life. Disposition was strongly influenced by body fat content, with potential dosing implications for women with TB.
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DOI：
10.5588/ijtld.16.0073
发表时间：
2016-12-01
影响因子：
4
作者：
O'Donnell, M. R.;Padayatchi, N.;Metcalfe, J. Z.
通讯作者：
Metcalfe, J. Z.
DOI：
10.1164/rccm.201909-1874st
发表时间：
2019-11-15
影响因子：
24.7
作者：
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通讯作者：
Seaworth, Barbara
DOI：
10.1007/s10928-017-9542-0
发表时间：
2017-12-01
影响因子：
2.5
作者：
Dosne, Anne-Gaelle;Bergstrand, Martin;Karlsson, Mats O.
通讯作者：
Karlsson, Mats O.
影响因子：
4.9
作者：
Swanson, Rosemary V.;Adamson, John;Almeida, Deepak V.
通讯作者：
Almeida, Deepak V.
DOI：
10.4269/ajtmh.1974.23.1110
发表时间：
1974-01-01
影响因子：
3.3
作者：
BANERJEE, DK;ELLARD, GA;WATERS, MFR
通讯作者：
WATERS, MFR