Effect of Disease State on the Pharmacokinetics of Bedaquiline in Renal-Impaired and Diabetic Rats

Abstract

Bedaquiline (TMC-207) is a key anti-tubercular drug to fight against multidrug resistance tuberculosis. Little information is available till date on the impact of any disease state toward its pharmacokinetic behavior. The present research work aimed to investigate the effect of renal impairment and diabetes mellitus on the oral pharmacokinetics of bedaquiline in the rat model. Renal impairment and diabetes mellitus were induced in the Wistar rat model separately using cisplatin and streptozotocin, respectively, and thereafter, an oral pharmacokinetic study of bedaquiline was carried out in the individual disease models as well as in the normal rat model. Pharmacokinetic parameters of bedaquiline were not altered markedly in cisplatin-induced renal-impaired rats compared to normal rats except an area under the curve (AUC) for plasma concentration of bedaquiline in the experimental time frame (AUC_0-t ) reduced to 3477 ± 228 from 4984 ± 1174 ng h/mL, respectively. Maximum plasma concentrations of bedaquiline (259 ± 77 ng/mL), AUC_0-t (3112 ± 1046 ng h/mL), and AUC_0-∞ (3673 ± 1493 ng h/mL) were significantly reduced along with an increase in the clearance of bedaquiline (3.1 ± 1.1 L/h/kg) in the case of streptozotocin-induced diabetic rats compared to respective pharmacokinetic parameters of bedaquiline (482 ± 170 ng/mL, 4984 ± 1174 ng h/mL, and 6137 ± 1542 ng h/mL) in the normal rats. Preclinical findings suggest that dose adjustment of bedaquiline is required in the diabetes mellitus condition to prevent the therapeutic failure of bedaquiline treatment, but clinical exploration is needed to establish the fact. It is the first report for the consequence of renal impairment and diabetes mellitus on the pharmacokinetics of bedaquiline in the preclinical model.

Figure 1

Summary of work plan for the present research work.

Figure 2

Main biochemical parameters of the rats for carrying out oral pharmacokinetic studies of bedaquiline: (A) serum creatinine level of normal rats and renal-impaired rats; (B) serum urea level of normal rats and renal-impaired rats; (C) blood glucose level of normal rats and diabetic rats. Data are presented as mean ± standard deviation (SD) (n = 10). Data were compared between normal rats vs renal impaired rats or normal rats vs diabetic rats. Data were found to be statistically significant (***) at the p < 0.001 level.

Figure 3

Mean plasma concentration vs time profile of bedaquiline after its oral administration at 10 mg/kg in normal rats, renal-impaired rats, and diabetic rats. Data are presented as mean ± SD (n = 5).

Figure 4

Representative SRM chromatograms with transition pairs of m/z 555.2 > 58.4 and m/z 295.9 > 214.0 for blank plasma sample (A,B), plasma sample spiked at LLOQ of bedaquiline with IS (C,D), plasma sample spiked at ULOQ with IS (E,F), bedaquiline level at 8 and 24 h in the pharmacokinetic study sample of normal rats (G,H), bedaquiline level at 8 and 24 h in the pharmacokinetic study sample of renal-impaired rats (I,J), and bedaquiline level at 8 and 24 h in the pharmacokinetic study sample of diabetic rats (K,L).

Figure 4

Representative SRM chromatograms with transition pairs of m/z 555.2 > 58.4 and m/z 295.9 > 214.0 for blank plasma sample (A,B), plasma sample spiked at LLOQ of bedaquiline with IS (C,D), plasma sample spiked at ULOQ with IS (E,F), bedaquiline level at 8 and 24 h in the pharmacokinetic study sample of normal rats (G,H), bedaquiline level at 8 and 24 h in the pharmacokinetic study sample of renal-impaired rats (I,J), and bedaquiline level at 8 and 24 h in the pharmacokinetic study sample of diabetic rats (K,L).