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

A continuous effort has been given to find out a new drug that is effective against tuberculosis (TB) from both susceptible and resistant strains of Mycobacterium tuberculosis. Bedaquiline represents a recently approved anti-TB drug, which has a unique mechanism of action to fight against multi drug resistance (MDR). Some severe side effects and drug-drug interactions are associated with the treatment of bedaquiline. Moreover, World Health Organisation (WHO) has also been provided guidelines in the year of 2013 for the use of bedaquiline and encourages additional investigation into it. Hence, the pharmacokinetics of bedaquiline upon coadministration with the drug has to be explored in the preclinical model and for which a liquid chromatography tandem mass spectrometry (LC-MS/MS) based bioanalytical method for quantitation of bedaquiline will be useful. A simple, sensitive and rapid LC-MS/MS method was developed, validated and successfully applied to drug interactions of bedaquiline upon coadministration with cytochrome P450 3A4 (CYP3A4) inducers/inhibitors orally in Wistar rats. Results reveal that ciprofloxacin and fluconazole have marked effect to hinder the pharmacokinetics of bedaquiline but isoniazid, verapamil and carbamazepine have no significant effect on bedaquiline pharmacokinetics. Overall, this new bioanalytical method for estimation of bedaquiline in rat plasma was found to be helpful to assess the pharmacokinetics of bedaquiline and very much useful for evaluation of preclinical drug-drug interaction before considering costly and perilous clinical exploration.

Assessment of potential interaction between simvastatin and clarithromycin in healthy adult male subjects.

Cardiac patients with weak immune system are susceptible to bacterial infections. Their prescriptions frequently contain simvastatin and clarithromycin together. The objective of present project was to assess the potential interaction between simvastatin and clarithromycin by evaluating the clarithromycin effects on the pharmacokinetics of simvastatin in healthy adult male subjects. The study design comprised of two phases, used at interval of one week. In first phase simvastatin 20 mg alone was administered to each volunteer. In second phase, co-administration of simvastatin 20 mg with clarithromycin 250 mg was made under similar specified conditions. Blood samples were collected at specified time intervals. Simvastatin plasma concentrations were analyzed through High Performance Liquid Chromatography with UV detector at 238 nm wavelength. Using one compartment open model, MW/PHARM version 3.02 software program was used by F. Rombut for pharmacokinetic parameters calculation. Clarithromycin co-treatment resulted in 2.3 fold increase in maximum plasma concentration Cmax (from 2.47±0.34 ng.mL-1 to 5.66±1.18 ng.mL-1; p<0.05) and 3.9 fold increase in area under time versus concentration curve from 0 to 10 hours AUC0-10 (from 15.10±3.73 ng.hr.mL-1 to 58.49±15.73 ng.hr.mL-1; p<0.05) of simvastatin. These results suggest that co-prescription of simvastatin and clarithromycin should be avoided to minimize the adverse events resulting from high simvastatin concentration, without sacrificing therapeutic worth of simvastatin.

Assessment of inter-racial variability in CYP3A4 activity and inducibility among healthy adult males of Caucasian and South Asian ancestries.

PURPOSE: Cytochrome P450 (CYP) 3A4 is responsible for the metabolism of more than 30% of clinically used drugs. Inherent between subject variability in clearance of CYP3A4 substrates is substantial; by way of example, midazolam clearance varies by > 10-fold between individuals before considering the impact of extrinsic factors. Relatively little is known about inter-racial variability in the activity of this enzyme. METHODS: This study assessed inter-racial variability in midazolam exposure in a cohort (n = 30) of CYP3A genotyped, age-matched healthy males of Caucasian and South Asian ancestries. Midazolam exposure was assessed at baseline, following 7 days of rifampicin and following 3 days of clarithromycin. RESULTS: The geometric mean baseline midazolam area under the plasma concentration curve (AUC0-6) in Caucasians (1057 µg/L/min) was 27% greater than South Asians (768 µg/L/min). Similarly, the post-induction midazolam AUC0-6 in Caucasians (308 µg/L/min) was 50% greater than South Asians (154 µg/L/min), while the post-inhibition midazolam AUC0-6 in Caucasians (1834 µg/L/min) was 41% greater than South Asians (1079 µg/L/min). The difference in baseline AUC0-6 between Caucasians and South Asians was statistically significant (p ≤ 0.05), and a trend toward significance (p = 0.067) was observed for the post-induction AUC0-6 ratio, in both unadjusted and genotype adjusted analyses. CONCLUSIONS: Significantly higher midazolam clearance was observed in healthy age-matched males of South Asian compared to Caucasian ancestry that was not explained by differences in the frequency of CYP3A genotypes.