Journal of Bioequivalence & Bioavailability

Abstract

Evaluation of Bioequivalence and Cardio-Hepatic Safety of a Single Dose of Fixed Dose Combination of Artemether and Lumefantrine

Suhas Sahebrao Khandave, Santosh Shrikrishna Joshi, Satish Vitthal Sawant and Shahoo Vasant Onkar

Background and objective: The existing fixed-dose combination, Coartem® (artemether 20 mg and lumefantrine 80 mg) requires 4 tablets per dose and a total of 24 tablets for the six-dose regimen for the treatment of uncomplicated P. falciparum malaria compromising the patient compliance. Also, the cardiotoxicity due to lumefantrine because of its structural similarity with halofantrine remains a matter of debate in therapeutics. To enhance the patient compliance, the fixed-dose combination of artemether/lumefantrine (80/480 mg) is formulated by Sequel Pharmachem Pvt. Ltd. India. In the present study, this fixed dose combination (test product) was evaluated for its bioequivalence to the reference product, Coartem® 20/120 mg (artemether 20 mg and lumefantrine 120 mg) of Novartis Pharma Ltd. with assessment of cardio-hepatic safety. Methods: A randomized, open label, two-treatment, two-period, two-sequence, single-dose, crossover bioequivalence study with comparative safety evaluation was conducted on 72 healthy Indian human subjects under a fed condition. Quantification of artemether, dihydroartemisinin, and lumefantrine was done by a validated LC-MS/ MS method. For bioequivalence, AUC0-240, AUC0-inf and Cmax for artemether and lumefantrine were considered. Safety assessment was done by monitoring vital signs, QTc interval, serum ALT and AST values before and after treatment. Max QTc, baseline-corrected QTcmax, AST and ALT values were considered for statistical comparison between the two treatments. Drug plasma concentrations estimated at identical time points with the ECG recordings were correlated with ECG parameters. Results: The test product was bioequivalent to the reference product as per the standard bioequivalence criteria. There was no clinically significant difference between the two treatments for all the safety parameters. No significant observation suggestive of cardiotoxicity and hepatotoxicity was noted in this study. Conclusion: The test product can be used as a therapeutic option with likely better patient compliance in the treatment of uncomplicated P. falciparum malaria.