一线抗结核药物治疗结核病患者的治疗药物监测最佳采样策略。
Optimal Sampling Strategies for Therapeutic Drug Monitoring of First-Line Tuberculosis Drugs in Patients with Tuberculosis.
机构信息
Department of Internal Medicine, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia.
Department of Pulmonary Diseases and Tuberculosis, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
出版信息
Clin Pharmacokinet. 2019 Nov;58(11):1445-1454. doi: 10.1007/s40262-019-00763-3.
BACKGROUND
The 24-h area under the concentration-time curve (AUC)/minimal inhibitory concentration ratio is the best predictive pharmacokinetic/pharmacodynamic (PK/PD) parameter of the efficacy of first-line anti-tuberculosis (TB) drugs. An optimal sampling strategy (OSS) is useful for accurately estimating AUC; however, OSS has not been developed in the fed state or in the early phase of treatment for first-line anti-TB drugs.
METHODS
An OSS for the prediction of AUC of isoniazid, rifampicin, ethambutol and pyrazinamide was developed for TB patients starting treatment. A prospective, randomized, crossover trial was performed during the first 3 days of treatment in which first-line anti-TB drugs were administered either intravenously or in fasting or fed conditions. The PK data were used to develop OSS with best subset selection multiple linear regression. The OSS was internally validated using a jackknife analysis and externally validated with other patients from different ethnicities and in a steady state of treatment.
RESULTS
OSS using time points of 2, 4 and 8 h post-dose performed best. Bias was < 5% and imprecision was < 15% for all drugs except ethambutol in the fed condition. External validation showed that OSS cannot be used for rifampicin in steady state conditions.
CONCLUSION
OSS at 2, 4 and 8 h post-dose enabled an accurate and precise prediction of AUC values of first-line anti-TB drugs in this population.
TRIAL REGISTRATION
ClinicalTrials.gov (NCT02121314).
背景
24 小时浓度-时间曲线下面积（AUC）/最低抑菌浓度比值是预测一线抗结核（TB）药物疗效的最佳药代动力学/药效学（PK/PD）参数。优化采样策略（OSS）有助于准确估计 AUC；然而，在一线抗 TB 药物的进食状态或治疗早期尚未开发 OSS。
方法
本研究旨在为开始治疗的 TB 患者开发预测异烟肼、利福平、乙胺丁醇和吡嗪酰胺 AUC 的 OSS。在治疗的前 3 天进行了一项前瞻性、随机、交叉试验，在此期间，一线抗 TB 药物要么静脉注射，要么在空腹或进食条件下给药。使用 PK 数据，采用最佳子集选择多元线性回归法开发 OSS。通过 Jackknife 分析对内进行验证，并使用来自不同种族和治疗稳定状态的其他患者进行外部验证。
结果
给药后 2、4 和 8 小时的 OSS 表现最佳。在进食条件下，除乙胺丁醇外，所有药物的偏倚均<5%，不精密度均<15%。外部验证表明，OSS 不能用于稳态条件下的利福平。
结论
在该人群中，给药后 2、4 和 8 小时的 OSS 能够准确、精密地预测一线抗 TB 药物的 AUC 值。
试验注册
ClinicalTrials.gov（NCT02121314）。
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