Unexpectedly low drug exposures among Ugandan patients with TB and HIV receiving high-dose rifampicin.
Allan Kengo (1), Kamunkhwala Gausi (1), Ruth Nabisere (2), Joseph Musaazi (2), Allan Buzibye (2), Daniel Omali (2), Rob Aarnoutse (3), Mohammed Lamorde (2), Kelly E. Dooley (4), Derek James Sloan (5), Christine Sekaggya-Wiltshire (2), Paolo Denti (1).
(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa, (2) Infectious Disease Institute, College of Health Sciences, Makerere University, Kampala, Uganda, (3) Department of Pharmacy, Radboud university medical centre, Nijmegen, The Netherlands, (4) Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA, (5) Division of Infection and Global Health, School of Medicine, University of St. Andrews, United Kingdom.
Objectives: Rifampicin (RIF) is the key component of first-line regimens for drug‑susceptible tuberculosis (TB), with a concentration-dependent bactericidal effect (1). It undergoes saturable hepatic extraction and is a strong inducer of enzymes and transporters, including some involved in its own elimination (2). Increasing the current daily dose (10 mg/kg) may improve outcomes or reduce the treatment duration required for cure (3). The efficacy and safety of high-dose RIF has been demonstrated, mostly in the intensive phase (first 2 months) of TB treatment (3). However, its pharmacokinetics (PK) and drug‑interactions when coadministered with antiretroviral therapy (ART) have not been fully investigated. We aimed to characterize the PK of standard- and high-dose RIF in patients with TB/HIV taking efavirenz (EFV)- /dolutegravir (DTG)-based ART.
Methods:
Data were available from the SAEFRIF trial (NCT03982277) conducted in Kampala, Uganda. Participants with TB/HIV were randomized to receive either the standard 10 (10RHZE) or higher 35 mg/kg (35RHZE) RIF dose, together with standard doses of isoniazid, pyrazinamide, and ethambutol. In the 35RHZE arm, the fixed-dose combination ([FDC], Macleod’s/Svizera) was topped-up with RIF-only capsules (Cosmos). Two weeks into TB treatment, EFV-/DTG-based ART was started in the ART‑naïve participants while those already on therapy continued with their regimens. The DTG dose was doubled to 50 mg twice‑daily during TB therapy. After 6 weeks of TB treatment, PK samples were drawn at pre-dose, 1, 2, 4, and 8 h after an observed dose.
The data were interpreted with NONMEM (v7.5.0) and SAEM. Several structural models were considered, including a well-stirred liver-model with saturatable hepatic extraction, which has been successfully employed to describe RIF’s clearance nonlinearity (4,5). In this model, the typical liver volume (1 L) and hepatic blood flow (90 L/h) were fixed to those of a 70 kg male. Log-normally distributed between-subject variability, between-occasion variability, and combined additive and/or proportional residual error model, constituted the statistical model. Allometric scaling was applied to all clearance and volume parameters. Data below the lower limit of quantification (LLOQ) was imputed to LLOQ/2 and their additive error component increased by 50% LLOQ.
Results: 111 (62% male) participants were included in the final analysis, with median (interquartile range, [IQR]) age and weight of 36 (31-43) years and 53 (47-60) kg, respectively. 54 (49%) received 35RHZE, 63 (57%) were ART-experienced, and 55 (50%) were on EFV. The previously suggested RIF model with saturable hepatic extraction (4) adequately described the PK in the 10RHZE arm but overpredicted that in the 35RHZE arm. The overprediction was suitably corrected after estimating a 38% lower bioavailability for the top-up RIF-only capsules used in the 35RHZE arm compared to the FDC used in both arms. Allometric scaling using fat-free mass as body size desription best fit the data. The model estimated a typical maximum intrinsic clearance and Michaelis‑Menten constant of 133 (109‑165) L/h and 8.00 (5.32-10.9) mg/L, respectively. The model estimated a median (IQR) RIF AUC0‑24 of 32.3 (28.7-36.7) mg·h/L and 152.9 (137.6-175.2) mg·h/L for the 10RHZE and 35RHZE arms, respectively, which corresponds to a 4.7-fold increase in AUC between the 2 arms. Assuming the bioavailabilty of the top-up capsule to be the same as that of the FDC, a RIF AUC0‑24 of 230.4 (159.7-334.1) mg·h/L was predicted. This would be a 7.1-fold increase in AUC between 10RHZE and 35RHZE arms. No difference was found between the participants on DTG- and EFV‑based ART.
Conclusions: A previously published model fit our data and identified lower bioavailability of a single‑drug RIF formulation used to achieve the high dose. This finding is in line with previous reports of poor bioavailability of some RIF formulations (6,7). Whereas our standard dose RIF AUC0-24 was comparable to previous reports (4,8), we observed a lower fold increase in that of high-dose cohort than would have been predicted, though the increase was still supra-proportional (8–11). Upon adjusting for the lower bioavailability of the top-up formulation, our models predicted an increase in exposure consistent with the observed data. In conclusion, lower bioavailability of top up RIF formulations may affect exposures achieved in high-dose cohorts.
References:
[1] te Brake LHM, de Jager V, Narunsky K, Vanker N, Svensson EM, Phillips PPJ, et al. Increased bactericidal activity but dose-limiting intolerability at 50 mg·kg −1 rifampicin. European Respiratory Journal [Internet]. 2021 Jul 4;58(1):2000955. Available from: http://erj.ersjournals.com/lookup/doi/10.1183/13993003.00955-2020
[2] Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivistö KT. Pharmacokinetic interactions with rifampicin : clinical relevance. Clin Pharmacokinet [Internet]. 2003;42(9):819–50. Available from: http://link.springer.com/10.2165/00003088-200342090-00003.
[3] Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis [Internet]. 2017 Jan 1;17(1):39–49. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1473309916302742.
[4] Chirehwa MT, Rustomjee R, Mthiyane T, Onyebujoh P, Smith P, McIlleron H, 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]. 2016 Jan [cited 2021 Jul 8];60(1):487–94.
[5] Garcia-Prats AJ, Svensson EM, Winckler J, Draper HR, Fairlie L, van der Laan LE, et al. Pharmacokinetics and safety of high-dose rifampicin in children with TB: the Opti-Rif trial. Journal of Antimicrobial Chemotherapy [Internet]. 2021 Nov 12 [cited 2022 Jan 19];76(12):3237–46. Available from: https://academic.oup.com/jac/article/76/12/3237/6371307.
[6] Sekaggya-Wiltshire C, Chirehwa M, Musaazi J, Von Braun A, Buzibye A, Muller D, et al. Low Antituberculosis Drug Concentrations in HIV-Tuberculosis-Coinfected Adults with Low Body Weight: Is It Time To Update Dosing Guidelines? .2019.
[7] Mcilleron H, Wash P, Burger A, Folb P, Smith P. Widespread distribution of a single drug rifampicin formulation of inferior bioavailability in South Africa. Vol. 6, INT J TUBERC LUNG DIS. 2002.
[8] Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis [Internet]. 2017;17(1):39–49. Available from: http://dx.doi.org/10.1016/S1473-3099(16)30274-2.
[9] Cresswell F v, Meya DB, Kagimu E, Grint D, te Brake L, Kasibante J, et al. High-Dose Oral and Intravenous Rifampicin for the Treatment of Tuberculous Meningitis in Predominantly Human Immunodeficiency Virus (HIV)-Positive Ugandan Adults: A Phase II Open-Label Randomized Controlled Trial. Clinical Infectious Diseases [Internet]. 2021 Sep 7;73(5):876–84. Available from: https://academic.oup.com/cid/article/73/5/876/6159697.
[10] Boeree MJ, Diacon AH, Dawson R, Narunsky K, du Bois J, Venter A, et al. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis. Am J Respir Crit Care Med. 2015 May 1;191(9):1058–65.
[11] Wasserman S, Davis A, Stek C, Chirehwa M, Botha S, Daroowala R, et al. Plasma pharmacokinetics of high-dose oral versus intravenous rifampicin in patients with tuberculous meningitis: a randomized controlled trial. Antimicrob Agents Chemother. 2021;65(8).
