Population pharmacokinetic modeling of rifampicin at standard and high doses in adults with tuberculous meningitis

Noha Abdelgawad (1), Sean Wasserman (2, 3), Kamunkhwala Gausi (1), Angharad Davis (2), Cari Stek (2), Lubbe Wiesner (1), Robert J. Wilkinson (2), Paolo Denti (1)

(1) Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa, (2) Wellcome Centre for Infectious Diseases Research in Africa, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa, (3) Division of Infectious Diseases and HIV Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa

Objectives:

Tuberculous meningitis (TBM) is the most fatal form of tuberculosis (TB) that is involves inflammation of the meninges. People with HIV are at particularly high risk, with a 50% mortality rate despite treatment [1]. The standard treatment regimen for TBM is based on that of pulmonary TB, which does not consider the ability of drugs to penetrate the blood-brain barrier, possibly resulting in suboptimal drug exposures at the site of disease. Rifampicin is the main drug used in TB treatment at doses of 10 mg/kg [1]. Rifampicin is mainly metabolized by liver esterases and excreted in the bile. At higher doses, saturable elimination of rifampicin is observed due to saturation of the biliary transport mechanisms [2]. Rifampicin, with repeated dosing, induces its own clearance - thought to be mediated via Pregnane X Receptor-mediated mechanisms that induces the esterases - with clearance expected to double after 2 weeks [3].

Several clinical studies have reported improved efficacy for higher daily doses of 35 mg/kg of rifampicin [4,5] and this dose is currently being evaluated in several clinical trials for TBM. Pharmacokinetics (PK) of high-dose rifampicin is not well characterised in TBM patients where different clinical phenotype and severity may alter physiology, with implications for dosing. We aimed to describe the plasma PK of standard- (10 mg/kg) versus high-dose (35 mg/kg) daily rifampicin in adults with TBM and HIV.

Methods:

This PK study was nested in the Phase 2 LASER-TBM trial, which enrolled adults with HIV & TBM in South Africa to evaluate the safety of intensified anti-TB therapy and aspirin for TBM. Participants were enrolled within 5 days of starting standard TB regimen (rifampicin 10 mg/kg, isoniazid, pyrazinamide, ethambutol) and were randomized into one of three groups: a control arm that received standard TB regimen and two experimental arms that received additional rifampicin on top of the standard dose (total oral dose 35 mg/kg) plus linezolid, with or without aspirin. Participants in both experimental arms underwent a second randomization to receive rifampicin either orally (35 mg/kg) or as an intravenous (IV) infusion (20 mg/kg) for the first 3 days.

Intensive plasma sampling was performed on day 3 of enrolment at pre-dose, and at 0.5, 1, 2, 3, 6, 8-10, and 24 hours post-dose. Sparse plasma sampling was drawn on day 28, at pre-dose, 2, and 4 hours post-dose. Rifampicin plasma concentrations were measured by LC-MS/MS. The data was modelled in NONMEM^® 7.5 using FOCE-I. Different structural models were tested, including 1- and 2-compartment disposition models, with linear elimination or saturable hepatic extraction. For this latter model, unbound rifampicin fraction was fixed to 20%, while the hepatic blood flow and volume of distribution of the liver were fixed to 90 L/h and 1 L, respectively [3]. Allometric scaling of all disposition parameters was tested by either body weight or fat-free mass (FFM).

Results:

Model development was performed using 415 rifampicin plasma concentrations from 49 participants with median (min – max) age 38 (25–56) years, weight 60 (30–96) kg, and fat-free mass (FFM) 46 (23-60) kg. Rifampicin PK was best described as a 2-compartment model with first-order absorption and lag time and elimination using saturable hepatic extraction. Autoinduction was described using an exponential increase with time on treatment based on estimates obtained by Chirehwa et al. [3].

Oral bioavailability (F_oral) was estimated to be around 80%. The typical values of intrinsic clearance (CL_int) at steady-state, central volume of distribution (V), intercompartmental clearance, and peripheral volume of distribution were 281 L/h, 39 L, 7 L/h, and 25 L, respectively, which were best allometrically scaled by FFM. The model included between-subject variability in CL_int, and V, between-visit variability in CL_int, and between-occasion variability in F_oral, absorption rate constant, and lag time.

Conclusion:

A previously proposed model of rifampicin in pulmonary TB [3] was successfully adapted to describe the PK in TBM patients receiving standard-dose, high-dose or IV. The PK are similar to previous reports in pulmonary TB [6]. We were able to characterize bi-compartmental disposition, thanks to the inclusion of both IV and oral, which has been previously described in children by Sevensson et al. [6]. Our estimate of F_oral is similar to that by Loos et al. [7]. Further research is needed to elucidate if high-dose rifampicin would result in higher levels at the site of disease, for which this model can be used for.

References:

1. Thwaites GE, Bang ND, Dung NH, Quy HT, Oanh DTT, Thoa NTC, et al. The influence of HIV infection on clinical presentation, response to treatment, and outcome in adults with Tuberculous meningitis. J Infect Dis [Internet]. J Infect Dis; 2005 [cited 2022 Apr 4];192:2134–41. Available from: https://pubmed.ncbi.nlm.nih.gov/16288379/
2. Acocella G. Pharmacokinetics and Metabolism of Rifampin in Humans. Clin Infect Dis [Internet]. 1983;5:S428–32. Available from: http://academic.oup.com/cid/article/5/Supplement_3/S428/275576/Pharmacokinetics-and-Metabolism-of-Rifampin-in
3. 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.[Erratum appears in Antimicrob Agents Chemother. 2016 May;60(5):3262; PMID: 27107106]. Antimicrob Agents Chemother. 2015;60:487–94.
4. 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]. Lancet Publishing Group; 2017 [cited 2022 Oct 15];17:39–49. Available from: http://www.thelancet.com/article/S1473309916302742/fulltext
5. 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 [Internet]. American Thoracic Society; 2015 [cited 2022 Oct 16];191:1058–65. Available from: www.clinicaltrials.gov
6. Svensson EM, DIan S, Te Brake L, Ganiem AR, Yunivita V, Van Laarhoven A, et al. Model-Based Meta-analysis of Rifampicin Exposure and Mortality in Indonesian Tuberculous Meningitis Trials. Clin Infect Dis. 2020;71:1817–23.
7. Loos U, Musch E, Jensen JC, Mikus G, Schwabe HK, Eichelbaum M. Pharmacokinetics of oral and intravenous rifampicin during chronic administration. Klin Wochenschr [Internet]. Springer-Verlag; 1985 [cited 2021 Apr 27];63:1205–11. Available from: https://link.springer.com/article/10.1007/BF01733779

Reference: PAGE 31 (2023) Abstr 10653 [www.page-meeting.org/?abstract=10653]

Poster: Drug/Disease Modelling - Infection

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