Department of Pharmacy, Uppsala University, Uppsala, Sweden.
TB Alliance, New York, NY, USA.
Clin Pharmacokinet. 2022 Nov;61(11):1585-1593. doi: 10.1007/s40262-022-01163-w. Epub 2022 Sep 30.
The dispersible tablet formulation (DTF) of pretomanid has been developed to facilitate future use in children. This work aimed to assess the pharmacokinetics (PK) and relative bioavailability of the DTF compared to the marketed formulation (MF) and the potential influence of dose.
Pretomanid DTF was investigated in a single-dose, randomized, four-period, cross-over study, with 7 days of washout between doses. Forty-eight healthy volunteers were enrolled and randomized into one of two panels to receive doses either in the fasted state or after a high-fat meal. Each volunteer received doses of 10, 50, and 200 mg DTF, and 200 mg MF pretomanid. Blood samples for pharmacokinetic assessment were drawn following a rich schedule up to 96 h after each single dose. The study data from the panel receiving the high-fat meal were analyzed using a nonlinear mixed-effects modeling approach, and all data were characterized with noncompartmental methods.
A one-compartment model with first-order elimination and absorption through a transit compartment captured the mean and variability of the observed pretomanid concentrations with acceptable precision. No significant difference in bioavailability was found between formulations. The mean absorption time for the DTF was typically 137% (86-171%) of that for the MF. The bioavailability was found to be dose dependent with a small positive and larger negative correlation under fed and fasted conditions, respectively.
Using data from a relative bioavailability study in healthy adult volunteers, a mathematical model has been developed to inform dose selection for the investigation of pretomanid in children using the new dispersible tablet formulation. Under fed conditions and at the currently marketed adult dose of 200 mg, the formulation type was found to influence the absorption rate, but not the bioavailability. The bioavailability of the DTF was slightly positively correlated with doses when administered with food.
ClinicalTrials.gov Identifier: NCT04309656, first posted on 16 March 2020.
为方便未来在儿童中使用，已开发出吡嗪酰胺分散片（DTF）制剂。本研究旨在评估 DTF 与市售制剂（MF）相比的药代动力学（PK）和相对生物利用度，以及剂量的潜在影响。
采用单剂量、随机、四周期交叉研究，两次给药间洗脱期为 7 天。共纳入 48 名健康志愿者，按空腹或高脂肪餐后两种方案分为两个组接受给药。每个志愿者接受 10、50 和 200mg DTF 以及 200mg MF 吡嗪酰胺单剂量治疗。在单次给药后，采用密集时间表采血进行药代动力学评估，至 96 小时。采用非线性混合效应模型分析接受高脂肪餐志愿者的研究数据，所有数据均采用非房室模型法进行特征描述。
采用一室模型加一级消除和通过转运室吸收可较好地描述观察到的吡嗪酰胺浓度的均值和变异性，且精度可接受。两种制剂间生物利用度无显著差异。DTF 的平均吸收时间通常为 MF 的 137%（86-171%）。在进食和空腹条件下，生物利用度与剂量呈正相关和负相关，且相关程度较小和较大。
在健康成年志愿者的相对生物利用度研究中获得的数据基础上，建立了一个数学模型，为使用新的分散片制剂在儿童中研究吡嗪酰胺提供了剂量选择信息。在进食条件下，按目前上市的成人剂量 200mg 给药时，制剂类型被发现会影响吸收速率，但不影响生物利用度。当与食物一起给药时，DTF 的生物利用度与剂量呈轻微正相关。
ClinicalTrials.gov 标识符：NCT04309656，首次于 2020 年 3 月 16 日发布。
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