Infectious Disease Pharmacokinetics Laboratory, University of Florida, Gainesville, Florida, USA.
Clinical Pharmacy Department, King Saud University College of Pharmacy, Riyadh, Saudi Arabia.
Antimicrob Agents Chemother. 2018 Aug 27;62(9). doi: 10.1128/AAC.00008-18. Print 2018 Sep.
Optimal doses for antituberculosis (anti-TB) drugs in children have yet to be established. In 2010, the World Health Organization (WHO) recommended revised dosages of the first-line anti-TB drugs for children. Pharmacokinetic (PK) studies that investigated the adequacy of the WHO revised dosages to date have yielded conflicting results. We performed population PK modeling using data from one of these studies to identify optimal dosage ranges. Ghanaian children with tuberculosis on recommended therapy with rifampin (RIF), isoniazid (INH), pyrazinamide (PZA), and ethambutol (EMB) for at least 4 weeks had blood samples collected predose and at 1, 2, 4, and 8 hours postdose. Drug concentrations were determined by validated liquid chromatography-mass spectrometry methods. Nonlinear mixed-effects models were applied to describe the population PK of those drugs using MonolixSuite2016R1 (Lixoft, France). Bayesian estimation was performed, the correlation coefficient, bias, and precision between the observed and predicted areas under the concentration-time curve (AUCs) were calculated, and Bland-Altman plots were analyzed. The population PK of RIF and PZA was described by a one-compartment model and that for INH and EMB by a two-compartment model. Plasma maximum concentration () and AUC targets were based on published results for children from India. The lowest target values for pediatric TB patients were attainable at the WHO-recommended dosage schedule for RIF and INH, except for -acetyltransferase 2 non-slow acetylators (rapid and intermediate acetylators) in the lower-weight bands. However, higher published adult targets were not attainable for RIF and INH. The targets were not achieved for PZA and EMB. (This study has been registered at ClinicalTrials.gov under identifier NCT01687504.).
优化儿童抗结核（anti-TB）药物剂量尚未确定。2010 年，世界卫生组织（WHO）推荐修订儿童一线抗结核药物剂量。迄今为止，研究 WHO 修订剂量是否充足的药代动力学（PK）研究结果相互矛盾。我们使用其中一项研究的数据进行群体 PK 建模，以确定最佳剂量范围。加纳儿童在推荐的利福平（RIF）、异烟肼（INH）、吡嗪酰胺（PZA）和乙胺丁醇（EMB）治疗下，至少接受 4 周的治疗，采集血样，在给药前和给药后 1、2、4 和 8 小时采集。药物浓度通过验证的液相色谱-质谱法测定。使用 MonolixSuite2016R1（法国 Lixoft）应用非线性混合效应模型描述这些药物的群体 PK。进行贝叶斯估计，计算观测和预测浓度-时间曲线下面积（AUCs）之间的相关系数、偏差和精度，并分析 Bland-Altman 图。RIF 和 PZA 的群体 PK 由单室模型描述，INH 和 EMB 的群体 PK 由双室模型描述。血浆最大浓度（）和 AUC 目标基于印度儿童的已发表结果。除了体重较轻的快速和中间乙酰化者（乙酰基转移酶 2 非慢乙酰化者）外，RIF 和 INH 的 WHO 推荐剂量方案可达到儿科结核病患者的最低目标值。然而，对于 RIF 和 INH，无法达到较高的已发表成人目标值。PZA 和 EMB 的目标值未达到。（本研究已在 ClinicalTrials.gov 注册，标识符为 NCT01687504。）。
