Koele Simon E, Heinrich Norbert, De Jager Veronique R, Dreisbach Julia, Phillips Patrick P J, Gross-Demel Petra, Dawson Rodney, Narunsky Kim, Wildner Leticia M, Mchugh Timothy D, Te Brake Lindsey H M, Diacon Andreas H, Aarnoutse Rob E, Hoelscher Michael, Svensson Elin M
Department of Pharmacy, Radboud Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, The Netherlands.
Institute of Infectious Diseases and Tropical Medicine, LMU University Hospital, LMU, Munich, Germany.
J Antimicrob Chemother. 2025 May 2;80(5):1315-1323. doi: 10.1093/jac/dkaf076.
BTZ-043 is a first-in-class benzothiazinone for the treatment of TB with demonstrated early bactericidal activity. BTZ-043 is metabolized into two major metabolites: M1 and M2. The aim of this study was to characterize the pharmacokinetics (PK) and early exposure-response (pharmacokinetic/pharmacodynamic, PK/PD) relationship for BTZ-043.
A population PK/PD model for BTZ-043 and its metabolites was developed using data from a sequential Phase 1b/2a, randomized, controlled clinical trial in participants with pulmonary TB. BTZ-043 was administered in daily doses ranging from 250 to 1750 mg over 14 days. The decrease in bacterial load was determined by culture of sputum samples to quantify cfu on solid medium, and time to positivity in liquid medium.
In total, 77 participants received the experimental treatment. PK were best described by two-compartment disposition models for BTZ-043 and M2, and a one-compartment disposition model for M1. When given without food, the bioavailability was 54% (95% CI: 43%-65%) lower than with food. The decrease in bacterial load was described by a bilinear model with estimated node at 48 h. Participants in the highest dose group in Stage 2 (1000 mg) had a 2-fold faster decrease in mycobacterial load during the initial 2 days compared with participants in the lowest dose group (250 mg), driven by an Emax relationship to the BTZ-043total exposure (BTZ-043 + M2).
We characterized the population PK/PD of BTZ-043 in trial participants with pulmonary TB. An exposure-response relationship was only apparent for the first 2 days on treatment, indicating the need for further dose-finding studies.
BTZ-043是一种用于治疗结核病的新型苯并噻嗪酮，已证明具有早期杀菌活性。BTZ-043代谢为两种主要代谢物：M1和M2。本研究的目的是描述BTZ-043的药代动力学（PK）和早期暴露-反应（药代动力学/药效学，PK/PD）关系。
利用一项针对肺结核患者的1b/2a期序贯、随机、对照临床试验的数据，建立了BTZ-043及其代谢物的群体PK/PD模型。BTZ-043在14天内每日给药剂量范围为250至1750毫克。通过对痰液样本进行培养以量化固体培养基上的菌落形成单位（cfu）以及液体培养基中的阳性时间来确定细菌载量的降低。
共有77名参与者接受了实验性治疗。BTZ-043和M2的药代动力学最好用二室处置模型描述，M1的药代动力学最好用一室处置模型描述。空腹给药时，生物利用度比进食时低54%（95%CI：43%-65%）。细菌载量的降低用双线性模型描述，估计节点在48小时。在第2阶段最高剂量组（1000毫克）的参与者在最初2天内分枝杆菌载量的下降速度比最低剂量组（250毫克）的参与者快2倍，这是由与BTZ-043总暴露量（BTZ-043 + M2）的Emax关系驱动的。
我们描述了肺结核试验参与者中BTZ-043的群体PK/PD。暴露-反应关系仅在治疗的前2天明显，表明需要进一步进行剂量探索研究。
