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.

Impact of Disease States on the Oral Pharmacokinetics of EIDD-1931 (an Active Form of Molnupiravir) in Rats for Implication in the Dose Adjustment

“…Serum levels of urea and creatinine are known to rise during renal impairment. 21 We also observed substantial augmentation of their levels by 3.5-and 4.4-fold, respectively, compared to normal rats (Figure 2A,B). Additionally, altered histopathological features of the kidney, like inflammatory cell infiltration and desquamation of tubular epithelial cells, verified the fact of kidney injury introduction (Figure 2C,D).…”

“…The kidney injury was induced in 10 rats by treating cisplatin (7 mg/kg) via the intraperitoneal route. , Normal saline was used as a vehicle to prepare the cisplatin dose. After 72 h, a blood sample was obtained from all the animals to measure serum creatinine and urea levels.…”

“…Diabetes was induced in 10 rats by treating streptozotocin (50 mg/kg) intraperitoneally, and after a gap of 15 min, nicotinamide (110 mg/kg) was administered through the same route. 21 The vehicle was sodium citrate buffer (0.1 M, pH 4.5) and normal saline to prepare the dose of streptozotocin and nicotinamide, respectively. After 7 days, a blood sample was obtained from all animals to assess serum glucose levels.…”

Pharmacokinetic Assessment of Rottlerin from Mallotus philippensis Using a Highly Sensitive Liquid Chromatography–Tandem Mass Spectrometry-Based Bioanalytical Method

“…Blood (∼120 μL) was withdrawn at each time point from the retro-orbital plexus. Then, the sample was centrifuged at 8000 rpm for 10 min to take out 50 μL of plasma and kept at −80 °C until analysis. , On the day of analysis, the plasma samples were thawed, processed, and analyzed as mentioned above for rottlerin.…”

Tuberculosis and comorbidities: treatment challenges in patients with comorbid diabetes mellitus and depression

“… 73 Animal models in rats have shown that bedaquiline blood concentrations are altered in the presence of DM, making a dose adjustment necessary to avoid therapeutic failure. 73 , 74 However, recent evidence from 2021 that compares bedaquiline treatment in TB patients vs TB-DM patients has shown that administering the same dose for both groups results in similar TB outcomes. 75 Similar studies need to be conducted for pretomanid.…”