Background and Objective

Delamanid is a nitroimidazole, a novel class of drug for treating tuberculosis, and is primarily metabolized by albumin into the metabolite DM-6705. The aims of this analysis were to develop a population pharmacokinetic (PK) model to characterize the concentration-time course of delamanid and DM-6705 in adults with drug-resistant tuberculosis and to explore a potential drug–drug interaction with bedaquiline when coadministered.

Methods

Delamanid and DM-6705 concentrations after oral administration, from 52 participants (of whom 26 took bedaquiline concurrently and 20 were HIV-1 positive) enrolled in the DELIBERATE trial were analyzed using nonlinear mixed-effects modeling.

Results

Delamanid PK were described by a one-compartment disposition model with transit compartment absorption (mean absorption time of 1.45 h [95% confidence interval 0.501–2.20]) and linear elimination, while the PK of DM-6705 metabolite were described by a one-compartment disposition model with delamanid clearance as input and linear elimination. Predicted terminal half-life values for delamanid and DM-6705 were 15.1 h and 7.8 days, respectively. The impact of plasma albumin concentrations on delamanid metabolism was not significant. Bedaquiline coadministration did not affect delamanid PK. Other than allometric scaling with body weight, no patients’ demographics were significant (including HIV).

Conclusions

This is the first joint PK model of delamanid and its DM-6705 metabolite. As such, it can be utilized in future exposure–response or exposure–safety analyses. Importantly, albumin concentrations, bedaquiline coadministration, and HIV co-infection (dolutegravir coadministration) did not have an effect on delamanid and DM-6705 PK.

中文翻译：

---

单独接受德拉马尼或与贝达喹啉联合用药的耐药结核病患者中德拉马尼及其主要代谢物 DM-6705 的群体药代动力学

背景和目的

Delamanid 是一种硝基咪唑，是一类治疗结核病的新型药物，主要由白蛋白代谢为代谢物 DM-6705。本分析的目的是开发群体药代动力学 (PK) 模型，以表征成人耐药结核病患者中 delamanid 和 DM-6705 的浓度-时间过程，并探讨共同给药时与贝达喹啉的潜在药物相互作用。

方法

使用非线性混合效应模型对参加 DELIBERATE 试验的 52 名参与者（其中 26 名同时服用贝达喹啉，20 名 HIV-1 阳性）口服给药后的德拉马尼和 DM-6705 浓度进行了分析。

结果

Delamanid PK 通过具有转运隔室吸收（平均吸收时间为 1.45 小时 [95% 置信区间 0.501–2.20]）和线性消除的单室处置模型来描述，而 DM-6705 代谢物的 PK 通过单室描述来描述。以 delamanid 间隙作为输入和线性消除的隔室配置模型。delamanid 和 DM-6705 的预测终末半衰期值分别为 15.1 小时和 7.8 天。血浆白蛋白浓度对德拉马尼代谢的影响不显着。贝达喹啉联合用药不影响德拉马尼 PK。除了与体重相关的异速生长外，没有患者的人口统计数据具有显着性（包括艾滋病毒）。

结论

这是delamanid及其DM-6705代谢物的第一个联合PK模型。因此，它可以用于未来的暴露-反应或暴露-安全性分析。重要的是，白蛋白浓度、贝达喹啉联合用药和 HIV 合并感染（多替拉韦联合用药）对德拉马尼和 DM-6705 PK 没有影响。