Population pharmacokinetics and model-based dosing evaluation of bedaquiline in multidrug-resistant tuberculosis patients

Abstract

Aims: Bedaquiline is now recommended to all patients in the treatment of multidrug-resistant tuberculosis (MDR-TB) using standard dosing regimens. As the ability to measure blood drug concentrations is very limited, little is known about drug exposure and treatment outcome. Thus, this study aimed to model the population pharmacokinetics as well as to evaluate the currently recommended dosage.Methodology: A bedaquiline population pharmacokinetic (PK) model was developed based on samples collected from the development cohort before and 1, 2, 3, 4, 5, 6, 8, 12, 18, and 24 h after drug intake on week 2 and week 4 of treatment. In a prospective validation cohort of patients with MDR-TB, treated with bedaquiline-containing standardized regimen, drug exposure was assessed using the developed population PK model and thresholds were identified by relating to 2-month and 6-month sputum culture conversion and final treatment outcome using classification and regression tree analysis. In an exploratory analysis by the probability of target attainment (PTA) analysis, we evaluated the recommended dosage at different MIC levels by Middlebrook 7H11 agar dilution (7H11).Results: Bedaquiline pharmacokinetic data from 55 patients with MDR-TB were best described by a three-compartment model with dual zero-order input. Body weight was a covariate of the clearance and the central volume of distribution, albumin was a covariate of the clearance. In the validation cohort, we enrolled 159 patients with MDR-TB. The 7H11 MIC mode (range) of bedaquiline was 0.06 mg (0.008–0.25 mg/L). The study participants with AUC0-24h/MIC above 175.5 had a higher probability of culture conversion after 2-month treatment (adjusted relative risk, aRR:16.4; 95%CI: 5.3–50.4). Similarly, those with AUC0-24h/MIC above 118.2 had a higher probability of culture conversion after 6-month treatment (aRR:20.1; 95%CI: 2.9–139.4), and those with AUC0-24h/MIC above 74.6 had a higher probability of successful treatment outcome (aRR:9.7; 95%CI: 1.5–64.8). Based on the identified thresholds, simulations showed that the WHO recommended dosage (400 mg once daily for 14 days followed by 200 mg thrice weekly) resulted in PTA >90% for the majority of isolates (94%; MICs ≤0.125 mg/L).Conclusion: We established a population PK model for bedaquiline in patients with MDR-TB in China. Based on the thresholds and MIC distribution derived in a clinical study, the recommended dosage of bedaquiline is sufficient for the treatment of MDR-TB.

Molecular mechanisms of resistance and treatment efficacy of clofazimine and bedaquiline against Mycobacterium tuberculosis

“…Surprisingly, drug susceptibility is a significant factor influencing the sputum culture conversion, as earlier stated ( 8 ). Of note, a current study by Shao et al ( 146 ) demonstrated that the 24-h area under the curve (AUC 0-24h /MIC) higher than 175.5 showed an increased probability of sputum culture conversion following a two-month therapy. In addition, after 6 months of treatment, those with AUC 0-24h /MIC values higher than 118.2 demonstrated a higher likelihood of sputum culture conversion and AUC0-24 h/MIC higher than 74.6 showed a higher probability of a favorable outcome after treatment.…”

Bedaquiline Resistance after Effective Treatment of Multidrug-Resistant Tuberculosis, Namibia

“…Shao et al showed in their population pharmocokinetic model that the current WHO recommended dosing of bedaquiline achieves a probability >90% of target attainment ( 10 ). However, Tanneau et al proposed an exposure‒response relationship for bedaquiline, whereas the half-life of bacterial clearance was longer in pre–extensively drug-resistant (XDR) and XDR TB than in MDR TB.…”

“…None of those factors were present in the case we describe. Shao et al showed in their population pharmocokinetic model that the current WHO recommended dosing of bedaquiline achieves a probability >90% of target attainment (10) for bedaquiline, whereas the half-life of bacterial clearance was longer in pre-extensively drug-resistant (XDR) and XDR TB than in MDR TB. One might speculate that dose adjustments to bedaquiline favorably influence treatment outcomes (11), as has been done so far in individual cases applying therapeutic drug monitoring (12).…”