Assessment of preclinical drug interactions of bedaquiline by a highly sensitive LC-ESI-MS/MS based bioanalytical method

Kotwal, Pankul; Magotra, Asmita; Dogra, Ashish; Sharma, Shrestha; Gour, Abhishek; Bhatt, Shipra; Wazir, Priya; Singh, Parvinder Pal; Singh, Gurdarshan; Nandi, Utpal

doi:10.1016/j.jchromb.2019.02.022

Cited by 14 publications

(16 citation statements)

References 25 publications

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“…Plasma samples (10 μL each) were processed by the addition of IS (2 μL of 100 μg/mL) followed by 188 μL of the solvent mixture containing acetonitrile: methanol (84:16, v/v) for plasma protein precipitation. 16 Then, samples were vortex mixed for 2 min and centrifuged at 18,626 g for 10 min. The organic layer was separated and transferred to the vial for analysis by LC–tandem MS (LC–MS/MS).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Methodsmentioning

confidence: 99%

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

et al. 2021

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“…This increased plasma exposure of bedaquiline along with decreased clearance was tested considering clarithromycin is a CYP3A inhibitor, in view of literature evidence available for other CYP3A inhibitors (erythromycin, ciprofloxacin, fluconazole, ketoconazole, and lopinavir/ritonavir). 24,37,38 The mean plasma concentration of clarithromycin (in combination with bedaquiline) reached a peak at 3 hours after dosing, followed by a gradual decrease until 12 hours after dosing, and steady-state was achieved in the study; the PK profile of clarithromycin is already well established. 39 Owing to its long half-life and highly lipophilic nature, bedaquiline is known to prolong the QT interval (mainly driven by metabolite M2); additionally, hepatotoxicity is one of its known adverse drug reactions.…”

Section: Discussionmentioning

confidence: 99%

“…Further, simulated C trough of bedaquiline with clarithromycin coadministration was found to be higher at weeks 24 and 48 as compared to its monotherapy, suggesting that an adjustment of the bedaquiline dose, especially in the maintenance period, would be warranted to avoid the potential increase of safety risk for patients with pulmonary nontuberculous mycobacteria having a longer treatment duration (ie, 48 weeks) compared to MDR‐TB (ie, 24 weeks) according to their standard of care 3,4,33 . This was considered due to inhibition of bedaquiline clearance by clarithromycin, in view of literature evidence available for other CYP3A inhibitors 24,37,38,48 . Thus, to achieve a similar bedaquiline exposure with pulmonary nontuberculous mycobacteria treatment as that of the currently used regimen in MDR‐TB, a combination of bedaquiline (400 mg once daily for 2 weeks, followed by 200 mg twice a week for 46 weeks, regimen A) and clarithromycin was found to be an optimal dosing regimen that can be further evaluated in the treatment of pulmonary nontuberculous mycobacteria; safety and efficacy of this regimen will be confirmed in a future study.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Bedaquiline‐Clarithromycin for Dose Selection Against Pulmonary Nontuberculous Mycobacteria Based on a Phase 1, Randomized, Pharmacokinetic Study

Kurosawa¹,

Rossenu

Biewenga

et al. 2021

The Journal of Clinical Pharma

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Based on the in vitro profile of bedaquiline against mycobacterial species, it is being investigated for clinical efficacy against pulmonary nontuberculous mycobacteria (PNTM). Being a cytochrome P450 3A substrate, pharmacokinetic interactions of bedaquiline are anticipated with clarithromycin (a cytochrome P450 3A inhibitor), which is routinely used in pulmonary nontuberculous mycobacteria treatment. This phase 1, randomized, crossover study assessed the impact of steady-state clarithromycin (500 mg every 12 hours for 14 days) on the pharmacokinetics of bedaquiline and its metabolite (M2) after single-dose bedaquiline (100 mg; n = 16). Using these data, population pharmacokinetic modeling and simulation analyses were performed to determine the effect of clarithromycin on steady-state bedaquiline exposure. Although no effect was observed on maximum plasma concentration of bedaquiline and time to achieve maximum plasma concentration, its mean plasma exposure increased by 14% after 10 days of clarithromycin coadministration, with slower formation of M2. Simulations showed that bedaquiline plasma trough concentration at steady state was higher (up to 41% until week 48) with clarithromycin coadministration as compared to its monotherapy (400 mg once daily for 2 weeks, followed by 200 mg 3 times a week for 46 weeks; reference regimen). The overall exposure of a simulated bedaquiline regimen (400 mg once dialy for 2 weeks, followed by 200 mg twice a week for 46 weeks) with clarithromycin was comparable (<15% difference) to the monotherapy. Overall, combination of bedaquiline (400 mg once daily for 2 weeks, followed by 200 mg twice a week for 46 weeks) with clarithromycin seems a suitable regimen to be explored for efficacy and safety against pulmonary nontuberculous mycobacteria.

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“…Freeze/thaw and long-term stability of bedaquiline samples were established by LC-MS/ MS method and bedaquiline was reported stable for long term and freeze/thaw stability in plasma [14]. Few studies reported methods to improve absorption of bedaquiline and pharmacokinetics of bedaquiline in rat plasma, the results showed that bedaquiline is safe without interaction or degradation in plasma [15,16]; therefore, it was thought of interest to study the effect of pH and temperature on degradation of bedaquiline in hydrolytic solutions by degradation kinetics study. Degradation kinetic study of bedaquiline showed that the pH and ionic strength of acid/alkali had profound effect on rate constant.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of physicochemical stability and degradation kinetics of bedaquiline in hydrolytic solutions of different pH

Rajput

Vanavi

2021

Futur J Pharm Sci

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Background Tuberculosis is an infection that has high mortality rate in human as well as in animals if it remains unattained for long time. Scientists are always desirous to discover new molecules against Mycobacterium tuberculosis; one of them is bedaquiline which was recently approved to treat multidrug resistance TB. During the clinical study of new molecule stability and impurity are the key aspects to develop formulation. Stability issues in bulk drug are dangerous to drug safety and needs careful attention in formulation development. Bedaquiline stability study was completed with reversed-phase high-performance liquid chromatography (HPLC) and utilized in degradation kinetic study of bedaquiline in aqueous condition under different pH, temperature, and concentrations of degradant. Results Linearity was obtained in 50.0-250.0μg/ml, correlation coefficient, and regression line equation were 0.998 and Y=18528x + 7E+06 respectively. Intraday, inter day precision, and repeatability RSD were less than 2.0%. Average recovery in accuracy study was more than 98.0% showed that good recovery was obtained. Degradation kinetics parameters like activation energy (Ea), half-life (t50), rate constant (k), and shelf life (t90) were calculated under different condition for bedaquiline. Entropy and enthalpy of reaction was studied to gather knowledge about energy of system. Conclusion The result explained that bedaquiline degradation was pH-dependant, as increase in concentration of degradant and temperature, there was increase in degradation rate of bedaquiline. Bedaquiline was stable in neutral aqueous condition and at lower temperatures, shows that drug is hydrophobic in nature. Kinetic data showed that bedaquiline followed first order kinetics in acidic and alkaline pH.

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Assessment of preclinical drug interactions of bedaquiline by a highly sensitive LC-ESI-MS/MS based bioanalytical method

Cited by 14 publications

References 25 publications

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

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

Population Pharmacokinetic Analysis of Bedaquiline‐Clarithromycin for Dose Selection Against Pulmonary Nontuberculous Mycobacteria Based on a Phase 1, Randomized, Pharmacokinetic Study

Evaluation of physicochemical stability and degradation kinetics of bedaquiline in hydrolytic solutions of different pH

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