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Investigating the relationship between plasma and intracellular concentrations of bedaquiline and its metabolite N-desmethyl bedaquiline (M2) in drug resistant-TB patients with and without HIV infection in South Africa
Both bedaquiline (approved by the FDA for use in pulmonary MDR-TB) and its metabolite, M2, exhibit intracellular antimycobacterial activity against tuberculosis. Understanding their intracellular pharmacokinetics is useful in elucidating the drug exposure-efficacy and exposure-toxicity relationships...
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| Format: | Thesis |
| Language: | English English |
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Department of Medicine
2026
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| Summary: | Both bedaquiline (approved by the FDA for use in pulmonary MDR-TB) and its metabolite, M2, exhibit intracellular antimycobacterial activity against tuberculosis. Understanding their intracellular pharmacokinetics is useful in elucidating the drug exposure-efficacy and exposure-toxicity relationships. LC-MS/MS assays were developed to quantify total bedaquiline and M2 in human plasma and peripheral blood mononuclear cells (PBMCs) and their unbound fractions in human plasma. Bedaquiline and M2 were extracted from both matrices by precipitation and solid phase extraction and quantified by LC-MS/MS. Unbound fractions of both analytes were isolated from the plasma by ultracentrifugation and quantified by a slightly adjusted method. The methods were validated over plasma ranges of 20.0–5000 ng/mL and 10.0–500 ng/mL and intracellular ranges of 2.5–200 pg/million cells and 12.5–1000 pg/million cells for bedaquiline and M2, respectively, and over a range of 0.100–5.00 ng/mL for both unbound fractions. Bedaquiline and M2 were measured in plasma and PBMC samples, prepared from blood samples collected by sparse and intensive sampling in the PROBeX clinical study in which 21 participants received bedaquiline-containing regimens for the treatment of RR-TB. A non- compartmental analysis described plasma and intracellular drug exposures, and a population pharmacokinetic model explored the relationship between total plasma and intracellular drug pharmacokinetics. Total plasma concentrations were higher for bedaquiline than for M2, whereas intracellular concentrations were higher for M2 than for bedaquiline, supporting in vitro evidence that M2 is the main inducer of phospholipidosis within the cells. The intracellular-plasma accumulation ratio for bedaquiline and M2 increased linearly, peaking after 2 months of treatment. Intracellular-plasma ratios for both bedaquiline and M2 were lower in HIV-positive than in HIV-negative patients. Bedaquiline and M2 were detectable in PBMCs 6 months after treatment discontinuation. Unbound concentrations of bedaquiline and M2 were higher than those reported in the literature. This finding requires further investigation. This first-time investigation into intracellular bedaquiline and M2 concentrations gives insight into bedaquiline pharmacokinetics, particularly in the context of RR-TB treatment. Our method for quantifying unbound bedaquiline and M2 in human plasma provides a foundation for further research into similar highly protein-bound and lipophilic drugs. |
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