In – Vivo Bioavailability comparison between generic and innovator brands: The case of Artemether-Lumefantrine tablet formulation
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Date
MAY, 2016.
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Abstract
With the introduction of the artemisinin-based combination therapies (ACTs) due to issues with treatment failure with monotherapies, the treatment outcomes of malaria have been improved significantly. Globally, from 2001 to 2015 there has been huge reduction in the incidence of malaria cases and deaths. This has been mainly attributed to prevention strategies and treatment interventions with effective and potent ACTs. These control measures have been estimated to have forestalled about more than 650 million cases in the last 15 years. Locally, the main ACT of choice for the treatment of uncomplicated malaria has been Artemether-Lumefantrine with a good number of less costly generic brands being good options for clients who cannot afford the relatively expensive innovator brand; Coartem®.
In the Sub-Saharan region of Africa, where generic substitution is encouraged and several studies have reported the presence of substandard ACTs on the various retail markets; this study sought to compare the in-vivo bioavailabilities of a locally manufactured generic artemether-lumefantrine tablet formulation to that of the innovator brand.
Methodology: A pilot survey was carried out to identify and sample the most available locally manufactured Artemether-lumefantrine generic tablet formulation on the market together with the innovator brand. The authenticity and genuineness of the samples were confirmed with colorimetric and melting point tests. The pharmaceutical equivalence of the innovator and generic brands was determined using compendial tests such as uniformity of weight, friability, percentage content and disintegration tests. In addition, in-vitro dissolution profiles were determined using the USP-2 apparatus. The release profiles were compared based on their fit factors.A reverse phase HPLC/UV detection method was developed for the in-vivo bioavailability study. The in-vivo bioavailability study on the two tablet formulations was in the form of single dose, two-period, cross-over design involving 20 healthy rabbits. The pharmacokinetic parameters AUC0-72, AUC0-ꝏ, and Cmax for both brands derived from the study were analysed statistically to check if the Food and Drugs Authority bioequivalence criterion has been satisfied.
Results: Both the generic and innovator brands of Artemether-lumefantrine that were sampled passed the test and satisfied the requirements for identification, uniformity of weight, friability, disintegration and percentage content. The artemether component of both brands complied with the pharmacopoeia specification for dissolution testing while the lumefantrine did not. An accurate RP-HPLC/UV detection method was developed, validated and use to quantify the lumefantrine levels in the plasma in the bioequivalence study.
After subjecting the pharmacokinetic parameters to the FDA bioequivalence criterion, average bioequivalence was demonstrated with the geometric mean ratios and corresponding 90% confidence intervals falling within the acceptable limits of 0.80 – 1.25.
Conclusion: Based on the similarity demonstrated between the two brands, evidence have been shown to support substitution in favour of the generic brand; as it would likely produce similar plasma drug levels and by inference similar therapeutic response as the innovator.A reverse phase HPLC/UV detection method was developed for the in-vivo bioavailability study. The in-vivo bioavailability study on the two tablet formulations was in the form of single dose, two-period, cross-over design involving 20 healthy rabbits. The pharmacokinetic parameters AUC0-72, AUC0-ꝏ, and Cmax for both brands derived from the study were analysed statistically to check if the Food and Drugs Authority bioequivalence criterion has been satisfied.
Results: Both the generic and innovator brands of Artemether-lumefantrine that were sampled passed the test and satisfied the requirements for identification, uniformity of weight, friability, disintegration and percentage content. The artemether component of both brands complied with the pharmacopoeia specification for dissolution testing while the lumefantrine did not. An accurate RP-HPLC/UV detection method was developed, validated and use to quantify the lumefantrine levels in the plasma in the bioequivalence study.
After subjecting the pharmacokinetic parameters to the FDA bioequivalence criterion, average bioequivalence was demonstrated with the geometric mean ratios and corresponding 90% confidence intervals falling within the acceptable limits of 0.80 – 1.25.
Conclusion: Based on the similarity demonstrated between the two brands, evidence have been shown to support substitution in favour of the generic brand; as it would likely produce similar plasma drug levels and by inference similar therapeutic response as the innovator.
Description
Thesis submitted to the School of Graduate Studies in partial fulfilment of the requirements for the Award of Master of Philosophy in Pharmaceutics