Allan Kengo 1,2, Christopher Cousins 3,4, Celina Suresh 3, Elizabeth Challenger 5, Rovina Ruslami 6, Anchalee Avihingsanon 7, Emmanuel Gutierrez 8, Jitendra Kumar Saini 9, Nan Kai Na 3, Rob Aarnoutse 10, Saye Khoo 5, Christine Sekaggya-Wiltshire 1, Nick I Paton 3, Elin M. Svensson 10,11
1 Infectious disease institute, Makerere University (Kampala, Uganda), 2 Gulu University (Gulu, Uganda), 3 Infectious Diseases Translational Research Programme and Yong Loo Lin School of Medicine, National University of Singapore (, Singapore), 4 City St George’s University of London (London, United Kingdom), 5 Centre for Experimental Therapeutics (TherEx), Institute of Systems Molecular and Integrative Biology University of Liverpool (Liverpool, United Kingdom), 6 Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran (Bandung, Indonesia), 7 HIV-NAT, Thai Red Cross AIDS and Infectious Disease Research Centre and Center of Excellence in Tuberculosis, Faculty of Medicine, Chulalongkorn University (Bangkok, Thailand), 8 De La Salle Medical and Health Sciences Institute (Cavite, Philippines), 9 National Institute of Tuberculosis and Respiratory Diseases (New Delhi, India), 10 Department of Pharmacy, Pharmacology and Toxicology, Radboud University Medical Center (Nijmegen, Netherlands), 11 Department of Pharmacy, Uppsala University (Uppsala, Sweden)
Background and objective:
Pyrazinamide is an essential component of the first-line combination treatment for drug-susceptible tuberculosis (TB), taken by approximately 8 million people globally each year, and is also recommended in some regimens for treatment of drug-resistant tuberculosis. Following oral administration, pyrazinamide is rapidly absorbed, with peak plasma concentrations typically achieved within two hours. The drug is widely distributed, undergoes hepatic metabolism, and is primarily eliminated renally, largely as metabolites (1).
First-line TB treatment also contains rifampicin, a potent inducer of drug-metabolizing enzymes and transporters (2). Previous studies have suggested a possible drug-drug interaction (DDI) between these drugs based on observation of increased pyrazinamide clearance during initial treatment, but the extent and clinical relevance have not been well characterized. There is current research interest in modifying standard TB treatment to improve efficacy or tolerability. To this end, some trials are increasing the dose of rifampicin or replacing rifampicin with bedaquiline. In the context of such novel regimens, there is a greater need to understand the impact of the putative rifampicin-pyrazinamide DDI: higher doses of rifampicin might lead to sub-therapeutic pyrazinamide levels, or removing rifampicin might lead to increased pyrazinamide levels and greater toxicity.
The TRUNCATE-TB trial investigated regimens based on standard treatment with these modifications. This nested pharmacokinetic (PK) modelling study provides an opportunity to characterize the DDI between pyrazinamide and rifampicin at standard versus higher doses and the effect of removing rifampicin completely from the regimen.
Methods:
TRUNCATE-TB (NCT03474198) was an adaptive, open-label, non-inferiority, multi-site trial where adult participants with rifampicin-susceptible TB were randomly assigned to receive standard treatment or treatment using the TRUNCATE-strategy (comprising an initial period of 8 weeks treatment; with follow up and retreatment of treatment failure or relapse). The 8-week regimens used included two with higher rifampicin dose (20-35mg/kg versus 10mg/kg in the standard regimen) and one in which rifampicin was replaced with bedaquiline. Pyrazinamide was consistently administered at a standard dose across the four study arms, including the standard treatment arm.
Sparse PK blood sampling was conducted in all trial participants at week 4 (pre-dose and 2 h post dose), and week 8 (pre-dose and 4 h post dose). A subgroup of 95 participants underwent intensive PK sampling at week 8 (pre-dose, 1, 2, 3, 4, 5, 6, 8 and 12 h). At all PK visits, blood samples were centrifuged and plasma frozen, then shipped in batches to the Bioanalytical Facility in Liverpool, UK. Drug quantitation was conducted using a fully validated liquid chromatography-mass spectrometry method with a lower limit of quantification of 0.1 mg/L. Pyrazinamide PK data was analyzed by population pharmacokinetics (PopPK) modeling using NONMEM software.
Results:
A total of 2383 (34% intense) samples from 575 participants were included in the analysis. Participants were from Indonesia (45%), Philippines (32%), Thailand (7.3%), Uganda (13.4%), and India (2.4%). Their median (IQR) age and weight were 32 years (23 – 43) and 50 kg (44 – 58), respectively. Overall, 176 (30.6%) participants received a bedaquiline-regimen, 172 (29.9%) received standard dose rifampicin, and 97 (16.9%) and 130 (22.6%) received high dose rifampicin-containing regimens at 20 mg/kg and 35 mg/kg, respectively.
A previously published 1-compartment model with transit compartment absorption and first-order elimination, incorporating allometric scaling of clearance and volume (3), was applied with modifications and it adequately described the data. On standard dose rifampicin, PZA clearance and volume were 3.84 mg/L, and 39.5 L, respectively. On higher dose rifampicin (20-35mg/kg combined), PZA clearance increased to 4.29 mg/L. In the regimen where rifampicin was replaced with bedaquiline, PZA clearance was lower at 3.0 mg/L. The model estimated median pyrazinamide 24-hour area under the concentration–time curve (AUC0-24, IQR) was 311 mg·h/L (272–347) with standard-dose rifampicin, and 271 mg·h/L (234–310) with higher-dose rifampicin and 331 mg·h/L (288–375) without rifampicin.
Discussion and conclusion:
Higher doses of rifampicin increased pyrazinamide clearance compared to the standard dose, but the effect on AUC was modest and dose modification appears not to be required. Replacing rifampicin with bedaquiline decreased pyrazinamide clearance and modestly increased its AUC. Although these changes were small, some degree of caution may still be warranted when using rifampicin-sparing, pyrazinamide containing regimens in clinical practice or research.
References:
1. Lacroix C, Phan Hoang T, Nouveau J, Guyonnaud C, Laine G, Duwoos H, et al. Pharmacokinetics of pyrazinamide and its metabolites in healthy subjects. Eur J Clin Pharmacot. 1989. Report.
2. Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin : clinical relevance. Clin Pharmacokinet. 2003;42(9):819–50. doi:10.2165/00003088-200342090-00003 PubMed PMID: 12882588.
3. Wijk M, Gausi K, Malatesta S, Weber SE, Court R, Myers B, et al. The impact of alcohol and illicit substance use on the pharmacokinetics of first-line TB drugs. Journal of Antimicrobial Chemotherapy. 2024 Aug 1;79(8):2022–30. doi:10.1093/jac/dkae206 PubMed PMID: 38985541.
Reference: PAGE 34 (2026) Abstr 12281 [www.page-meeting.org/?abstract=12281]
Poster: Drug/Disease Modelling - Infection