Abstract:

Objective: To explore the changes of plasma concentration of bedaquiline during the treatment in patients with drug-resistant pulmonary tuberculosis and its association with QTc interval prolongation. Methods: All 119 patients with multidrug-resistant/rifampicin resistant pulmonary tuberculosis (MDR/RR-PTB) were enrolled prospectively according to the inclusion criteria in Beijing Chest Hospital from Feb. 2018 to Feb. 2020, provided with individualized bedaquiline-containing regimen by the expert group. Baseline information were collected before the first dose of bedaquiline and electrolyte (potassium, calcium and magnesium), blood routine, urine routine, hepatic and renal function, QTcF value and plasm drug concentration of bedaquiline were serially recorded at different time points post treatment initiation. Univariate and multivariate logistic regression analysis were performed to analyze the risk factors associated with QTc interval prolongation. Results: All 119 patients had completed full course of 72 week-treatment and were in period of post treatment follow-up. Out of them, 5 (4.2%) had QTcF >500ms within 24 weeks and bedaquiline was discontinued as per protocol; 114 patients completed full doses of bedaquiline, among which 53 took for 24 weeks and 61 took for 36 weeks. For the 114 patients who completed full administration of bedaquiline, their trough concentration was highest at the end of week 2 (1.753(1.365,2.412) μg/ml), significantly higher(Z=-9.222,P<0.001;Z=-7.798,P<0.001)than that at the end of week 4 (0.830(0.586,1.035) μg/ml) and week 24 (1.098(0.909,1.440) μg/ml) while it was higher at the end of week 24 than that at week 4 with significance(Z=-7.826,P<0.001). No matter patients with 24-week or 36-week bedaquiline exposure, the plasma concentration of it returned to the level at the end of week 4 (0.769(0.500,0.947) μg/ml and 0.824(0.642,1.023) μg/ml) respectively after bedaquiline was discontinued for 12 weeks. Furthermore, the plasma concentration of it was still close to the effective value (0.6 μg/ml) after bedaquiline was discontinued for 24 weeks. The trend for the QTcF value was basically consistent with that of bedaquiline plasma concentration which presented gradual increase with bedaquiline accumulated administration and hit the peak before and after its discontinuation, then decreased gradually. Eight cases (6.7%) had QTcF>500ms, 36 cases (30.3%) had QTcF>450ms and no serious ventricular arrhythmia was found in all patients during the above observation period. Multivariate analysis indicated that elder age (≥55 years), low body mass index (<18.5) and hypocalcemia (<2.3 mmol/L) were the risk factors for occurrence of QTc interval prolongation (OR (95%CI)=7.056 (1.841-27.043),3.850 (1.236-11.989), 2.786 (1.029-7.541)). Conclusion: Given the long half-life of bedaquiline, its effective plasma concentration could maintain until 24 weeks post its discontinuation. Moreover, extending bedaquiline exposure to 36 weeks presented safe and effective.During bedaquiline administration, the occurrence of QTc interval prolongation was relatively high but severity grade was mainly mild to moderate. ECG monitoring should be intensified for patients with elder age, low body mass index and hypocalcemia.

Key words: Bedaquiline, Tuberculosis,multidrug-resistant, Drug monitoring, Electrocardiograph, Factor analysis,statistical