Background
Rifampicin is the cornerstone drug for drug-susceptible tuberculosis (TB) (1). Recent findings suggest that increasing doses above the current 10mg/kg/day may improve outcomes in critically-ill patients (2,3). The objective of this analysis was to investigate the pharmacokinetics (PK) of high-dose rifampicin in patients with HIV-associated disseminated TB.
Methods
Data were collected from the ongoing New-Strat TB trial in Cape Town (NCT04951986). Participants with HIV-associated disseminated TB were randomised to standard TB treatment (10 mg/kg/day) or high-dose rifampicin (35 mg/kg/day) plus levofloxacin (3). PK sampling occurred on day 2 of TB treatment, with sparse samples at pre-dose, 2, and 8-hours post-dose, and intensive samples at pre-dose, 1, 2, 4, 6, 8, and 24-hours post-dose. Plasma rifampicin concentrations were quantified using LC-MS/MS.
Data were analysed using nonlinear mixed effects modelling in NONMEM (v7.5.1). Several models were evaluated including a previous rifampicin model incorporating a well-stirred liver model with saturable hepatic extraction (4).
Results
Plasma samples were collected from 56 participants. The participants had a median (interquartile range [IQR]) age of 37 (31-46) years, weight of 52 (44-63) kg, and fat-free mass (FFM) of 41 (34-45) kg. Around 35% (20) of study participants were on high-dose rifampicin and 65% (36) were on standard-dose regimen. Total body weight and FFM were evaluated as body size descriptors. The published model by Chirehwa et al.,(4) adequately described the PK profiles of our study participants and the previously reported dose-exposure nonlinearity. Our model estimated lower maximum intrinsic clearance compared to published models (5,6).
Conclusion
A published model successfully characterised rifampicin PK in critically-ill patients with HIV-associated disseminated TB receiving standard or high-dose rifampicin. The PK were comparable to previous reports (5,6) in adults with pulmonary uncomplicated TB. These findings support continued investigation of high-dose rifampicin and will inform future analyses to optimize treatment.
References
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- Nabisere R, Musaazi J, Denti P, Aber F, Lamorde M, Dooley KE, et al. Pharmacokinetics, SAfety/tolerability, and EFficacy of high-dose RIFampicin in tuberculosis-HIV co-infected patients on efavirenz- or dolutegravir-based antiretroviral therapy: study protocol for an open-label, phase II clinical trial (SAEFRIF). Trials [Internet]. 2020;21(1):181. Available from: https://doi.org/10.1186/s13063-020-4132-7
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- T CM, Roxana R, Thuli M, Philip O, Peter S, Helen M, et al. Model-Based Evaluation of Higher Doses of Rifampin Using a Semimechanistic Model Incorporating Autoinduction and Saturation of Hepatic Extraction. Antimicrob Agents Chemother [Internet]. 2015 Dec 31;60(1):487–94. Available from: https://doi.org/10.1128/aac.01830-15
- Allan K, Kamunkhwala G, Ruth N, Joseph M, Allan B, Denis O, et al. Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin. Antimicrob Agents Chemother [Internet]. 2023 Oct 18;67(11):e00431-23. Available from: https://doi.org/10.1128/aac.00431-23
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