Prospective study of pharmacogenetics and pharmacokinetics of bedaquiline in patients with drug-resistant pulmonary tuberculosis

Background. Among the factors contributing to unsuccessful treatment outcomes in patients with drug-resistant pulmonary tuberculosis-particularly multidrug-resistant tuberculosis (MDR-TB)-considerable importance is attributed to interindividual variability in pharmacological response, which is largely determined by patients’ genetic characteristics. Recent advances in MDR-TB chemotherapy are closely associated with the introduction of bedaquiline. Bedaquiline is primarily metabolized by the cytochrome P450 enzyme CYP3A4; however, the impact of CYP3A4 gene polymorphisms on bedaquiline pharmacokinetics and treatment efficacy in patients with drug-resistant TB remains insufficiently studied. Personalized therapy based on a patient’s genetic profile represents a key strategy for optimizing dosing regimens, improving treatment efficacy, and reducing the risk of developing further drug resistance. Aims — to evaluate the influence of CYP3A4 polymorphic alleles (*1B/rs2740574 and *1G/rs2242480) on bedaquiline pharmacokinetic parameters and chemotherapy efficacy in patients with drug-resistant pulmonary tuberculosis, including those with MDR-TB. Methods. A prospective, observational cohort study was conducted involving 143 patients with pulmonary tuberculosis and confirmed drug-resistant Mycobacterium tuberculosis (including MDR, pre-XDR, and XDR-TB) treated at the Central TB Research Institute (CTRIT), Russia, between 2022 and 2024 (66 women and 77 men). Three observation groups were formed based on genotype: Group 1 — wild-type CYP3A4*1 (n = 99); Group 2 — *1B (rs2740574) carriers (n = 10); Group 3 — *1G (rs2242480) carriers (n = 34). Genotyping was performed using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP). Bedaquiline was administered as part of individualized chemotherapy regimens at a dose of 400 mg once daily for 2 weeks, followed by 200 mg three times weekly for up to 6 months. Bedaquiline pharmacokinetic parameters were assessed in 30 patients using high-performance liquid chromatography. Treatment efficacy was evaluated based on sputum culture conversion by month 6. Statistical analysis employed nonparametric Kruskal–Wallis and Mann–Whitney tests for group comparisons. Results. Patients carrying the CYP3A4 *1G (rs2242480) allele showed significantly higher bedaquiline exposure compared to wild-type individuals: AUC₀_–₂₄ (49.06 vs. 41.99 µg·h/mL; p < 0.05), C_max (3.13 vs. 2.21 µg/mL; p < 0.05), and AUC₀_–₂₄/MIC ratio (196.24 vs. 167.94; p < 0.05), suggesting reduced metabolic clearance. In contrast, the *1B variant was associated with lower AUC₀_–₂₄. Although culture conversion rates at 6 months did not differ significantly (p = 0.87), a trend toward higher efficacy was observed in *1G carriers (95.8%) versus wild-type patients (84.5%). Conclusion. The CYP3A4 *1G (rs2242480) polymorphism is associated with decreased bedaquiline metabolism, leading to increased systemic drug exposure and a potential improvement in treatment response. These findings highlight the role of CYP3A4 genetics in bedaquiline pharmacokinetics and support the integration of CYP3A4 genotyping into personalized MDR-TB treatment strategies. The *1G allele may serve as a promising pharmacogenetic biomarker for optimizing bedaquiline dosing in drug-resistant tuberculosis.