Alghamdi Wael A, Al-Shaer Mohammad H, Kipiani Maia, Barbakadze Ketevan, Mikiashvili Lali, Kempker Russell R, Peloquin Charles A
Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, Saudi Arabia.
Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA.
J Antimicrob Chemother. 2021 Mar 12;76(4):1019-1024. doi: 10.1093/jac/dkaa550.
Pharmacokinetic data are needed for newly implemented anti-tuberculosis drugs to help optimize their use.
To help fill existing knowledge gaps, we evaluated the pharmacokinetic parameters of novel and repurposed anti-tuberculosis drugs among patients with drug-resistant pulmonary tuberculosis.
A prospective cohort study among patients ≥16 years with confirmed pulmonary drug-resistant TB was conducted in Tbilisi, Georgia. Patients receiving bedaquiline, delamanid and/or clofazimine were included. Blood samples were collected 4-6 weeks after drug initiation, and serum concentrations were measured using validated liquid chromatography tandem mass spectrometry assays. A non-compartmental analysis was performed, and the association of exposure parameters with covariates was explored.
Among 99 patients, the average age and weight were 40 years and 65 kg, respectively. The median Cmin was 0.68 mg/L for bedaquiline, 0.17 mg/L for delamanid, and 0.52 mg/L for clofazimine. The median AUC0-24 was 30.6 mg·h/L for bedaquiline, 16.1 mg·h/L for clofazimine, and the AUC0-12 was 2.9 mg·h/L for delamanid. Among the significant covariates associated with drug exposure parameters were weight and sex for bedaquiline, alcohol use for delamanid, and weight for clofazimine.
We found a strong association of weight with bedaquiline and clofazimine exposure parameters, suggesting the need for weight-based dosing for those agents.
新应用的抗结核药物需要药代动力学数据以助于优化其使用。
为填补现有知识空白，我们评估了耐多药肺结核患者中新型及重新利用的抗结核药物的药代动力学参数。
在格鲁吉亚第比利斯对年龄≥16岁的确诊耐多药肺结核患者进行了一项前瞻性队列研究。纳入接受贝达喹啉、地拉曼尼和/或氯法齐明治疗的患者。在开始用药4 - 6周后采集血样，使用经过验证的液相色谱串联质谱分析法测定血清浓度。进行非房室分析，并探讨暴露参数与协变量之间的关联。
99例患者中，平均年龄和体重分别为40岁和65千克。贝达喹啉的Cmin中位数为0.68毫克/升，地拉曼尼为0.17毫克/升，氯法齐明为0.52毫克/升。贝达喹啉的AUC0 - 24中位数为30.6毫克·小时/升，氯法齐明为16.1毫克·小时/升，地拉曼尼的AUC0 - 12为2.9毫克·小时/升。与药物暴露参数相关的显著协变量中，贝达喹啉为体重和性别，地拉曼尼为饮酒情况，氯法齐明为体重。
我们发现体重与贝达喹啉和氯法齐明的暴露参数密切相关，这表明这些药物需要根据体重给药。
