Nardotto Glauco Henrique Balthazar, Svenson Elin M, Bollela Valdes Roberto, Rocha Adriana, Slavov Svetoslav Nanev, Ximenez João Paulo Bianchi, Della Pasqua Oscar, Lanchote Vera Lucia
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto 14040-903, Brazil.
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
Pharmaceutics. 2024 Jul 23;16(8):970. doi: 10.3390/pharmaceutics16080970.
The present study aims to characterise the pharmacokinetics of rifampicin (RIF) in tuberculosis (TB) patients with and without HIV co-infection, considering the formation of 25-O-desacetyl-rifampicin (desRIF). It is hypothesised that the metabolite formation, HIV co-infection and drug formulation may further explain the interindividual variation in the exposure to RIF. Pharmacokinetic, clinical, and demographic data from TB patients with (TB-HIV+ group; = 18) or without HIV (TB-HIV- group; = 15) who were receiving RIF as part of a four-drug fixed-dose combination (FDC) regimen (RIF, isoniazid, pyrazinamide, and ethambutol) were analysed, along with the published literature data on the relative bioavailability of different formulations. A population pharmacokinetic model, including the formation of desRIF, was developed and compared to a model based solely on the parent drug. HIV co-infection does not alter the plasma exposure to RIF and the desRIF formation does not contribute to the observed variability in the RIF disposition. The relative bioavailability and RIF plasma exposure were significantly lower than previously reported for the standard regimen with FDC tablets. Furthermore, participants weighting less than 50 kg do not reach the same RIF plasma exposure as compared to those weighting >50 kg. In conclusion, as no covariate was identified other than body weight on CL/F and Vd/F, low systemic exposure to RIF is likely to be caused by the low bioavailability of the formulation.
本研究旨在描述利福平（RIF）在合并或未合并人类免疫缺陷病毒（HIV）感染的结核病（TB）患者中的药代动力学特征，同时考虑25 - O - 去乙酰基利福平（desRIF）的形成。研究假设代谢物形成、HIV合并感染和药物剂型可能进一步解释RIF暴露的个体间差异。分析了接受包含RIF的四联固定剂量复方制剂（FDC，即RIF、异烟肼、吡嗪酰胺和乙胺丁醇）治疗的合并HIV感染的TB患者（TB - HIV +组；n = 18）和未合并HIV感染的TB患者（TB - HIV -组；n = 15）的药代动力学、临床和人口统计学数据，以及不同剂型相对生物利用度的已发表文献数据。建立了一个包括desRIF形成的群体药代动力学模型，并与仅基于母体药物的模型进行比较。HIV合并感染不会改变RIF的血浆暴露，desRIF的形成也不会导致观察到的RIF处置变异性。相对生物利用度和RIF血浆暴露显著低于先前报道的FDC片剂标准方案。此外，体重小于50 kg的参与者与体重>50 kg的参与者相比，未达到相同的RIF血浆暴露水平。总之，由于除体重外未发现影响CL/F和Vd/F的其他协变量，RIF全身暴露低可能是由于制剂生物利用度低所致。
