Relationship between Plasma and Intracellular Concentrations of Bedaquiline and Its M2 Metabolite in South African Patients with Rifampin-Resistant Tuberculosis

• Type of Material: Article
• Authors: Precious Ngwalero, University of Cape Town; James CM Brust, Albert Einstein College of Medicine; Stijn W van Beek, Radboud University Nijmegen; Sean Wasserman, University of Cape Town; Gary Maartens, University of Cape Town; Graeme Meintjes, University of Cape Town; Anton Joubert, University of Cape Town; Jennifer Norman, University of Cape Town; Sandra Castel, University of Cape Town; Neel Gandhi, Emory University; Paolo Denti, University of Cape Town; Helen McIlleron, University of Cape Town; Elin M Svensson, Radboud University Nijmegen; Lubbe Wiesner, University of Cape Town
• Language: English
• Date: 2021-10-01
• Publisher: AMER SOC MICROBIOLOGY
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Ngwalero et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1128/AAC.02399-20
• Title of Journal or Parent Work: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
• Volume: 65
• Issue: 11
• Start Page: e0239920
• End Page: e0239920
• Grant/Funding Information: J.C.M.B. is supported by the U.S. National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH; grant no. R01AI114304, R01AI145679, K24AI155045, P30AI124414, and UL1TR001073). N.R.G. is supported by the U.S. NIAID/NIH (grant no. K24AI114444, U19AI111211, and P30AI051519). The University of Cape Town Clinical Pharmacokinetics Laboratory is supported in part by the AIDS Clinical Trials Group (ACTG) and by NIAID (grant no. UM1AI068634, UM1AI068636, and UM1AI106701), as well as by the Infant Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT; grant no. U01 AI068632); H.M. is supported by the Wellcome Trust (grant no. 206379/Z/17/Z). G. Meintjes was supported by the Wellcome Trust (grant no. 098316, 214321/Z/18/Z, and 203135/Z/16/Z) and the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (grant no. 64787). S.W. is supported by the European & Developing Countries Clinical Trials Partnership (grant no. CDF1018), Wellcome Trust (grant no. 203135/Z/16/Z), and National Institutes of Health (grant no. K43TW011421 [principal investigator, S. Wasserman]).
• Keywords: bedaquiline; MODEL; NEVIRAPINE; metabolite; intracellular; Life Sciences & Biomedicine; LOPINAVIR/RITONAVIR; Science & Technology; TMC207; SAQUINAVIR; EFAVIRENZ; Pharmacology & Pharmacy; DRUG CONCENTRATIONS; drug-resistant tuberculosis; POPULATION PHARMACOKINETICS; TRANSPORTERS; pharmacokinetics; Microbiology; HIV
• Research Categories: Health Sciences, Public Health; Health Sciences, Medicine and Surgery

Abstract

Bedaquiline is recommended for the treatment of all patients with rifampin-resistant tuberculosis (RR-TB). Bedaquiline accumulates within cells, but its intracellular pharmacokinetics have not been characterized, which may have implications for dose optimization. We developed a novel assay using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure the intracellular concentrations of bedaquiline and its primary metabolite M2 in patients with RR-TB in South Africa. Twenty-one participants were enrolled and underwent sparse sampling of plasma and peripheral blood mononuclear cells (PBMCs) at months 1, 2, and 6 of treatment and at 3 and 6 months after bedaquiline treatment completion. Intensive sampling was performed at month 2. We used noncompartmental analysis to describe plasma and intracellular exposures and a population pharmacokinetic model to explore the relationship between plasma and intracellular pharmacokinetics and the effects of key covariates. Bedaquiline concentrations from month 1 to month 6 of treatment ranged from 94.7 to 2,540 ng/ml in plasma and 16.2 to 5,478 ng/ml in PBMCs, and concentrations of M2 over the 6-month treatment period ranged from 34.3 to 496 ng/ml in plasma and 109.2 to 16,764 ng/ml in PBMCs. Plasma concentrations of bedaquiline were higher than those of M2, but intracellular concentrations of M2 were considerably higher than those of bedaquiline. In the pharmacokinetic modeling, we estimated a linear increase in the intracellular-plasma accumulation ratio for bedaquiline and M2, reaching maximum effect after 2 months of treatment. The typical intracellular-plasma ratios 1 and 2 months after start of treatment were 0.61 (95% confidence interval [CI]: 0.42 to 0.92) and 1.10 (95% CI: 0.74 to 1.63) for bedaquiline and 12.4 (95% CI: 8.8 to 17.8) and 22.2 (95% CI: 15.6 to 32.3) for M2. The intracellular-plasma ratios for both bedaquiline and M2 were decreased by 54% (95% CI: 24 to 72%) in HIV-positive patients compared to HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. M2 accumulated at higher concentrations intracellularly than bedaquiline, supporting in vitro evidence that M2 is the main inducer of phospholipidosis.