Comparison of bioavailability between the most available generic tablet formulation containing artemether and lumefantrine on the Tanzanian market and the innovator’s product

Abstract

BackgroundExistence of anti-malarial generic drugs with low bioavailability marketed on sub-Saharan Africa raises a concern on patients achieving therapeutic concentrations after intake of such products. This work compared bioavailability of one generic tablet formulation with innovator’s product. Both were fixed dose combination tablet formulations containing artemether and lumefantrine.MethodologyThe study was conducted in Dar Es Salaam, Tanzania, in which a survey of the most abundant generic containing artemether-lumefantrine tablet formulation was carried out in retail pharmacies. The most widely available generic (Artefan®, Ajanta Pharma Ltd, Maharashtra, India) was sampled for bioavailability comparison with Coartem® (Novartis Pharma, Basel, Switzerland) - the innovator’s product. A randomized, two-treatment cross-over study was conducted in 18 healthy Tanzanian black male volunteers. Each volunteer received Artefan® (test) and Coartem® (as reference) formulation separated by 42 days of drug-free washout period. Serial blood samples were collected up to 168 hours after oral administration of a single dose of each treatment. Quantitation of lumefantrine plasma levels was done using HPLC with UV detection. Bioequivalence of the two products was assessed in accordance with the US Food and Drug Authority (FDA) guidelines.ResultsThe most widely available generic in pharmacies was Artefan® from India. All eighteen enrolled volunteers completed the study and both test and reference tablet formulations were well tolerated. It was possible to quantify lumefantrine alone, therefore, the pharmacokinetic parameters reported herein are for lumefantrine. The geometric mean ratios for Cmax, AUC0-t and AUC0-∞ were 84% in all cases and within FDA recommended bioequivalence limits of 80% – 125%, but the 90% confidence intervals were outside FDA recommended limits (CI 49–143%, 53 - 137%, 52 - 135% respectively). There were no statistical significant differences between the two formulations with regard to PK parameters (P > 0.05).ConclusionsAlthough the ratios of AUCs and Cmax were within the acceptable FDA range, bioequivalence between Artefan® and Coartem® tablet formulations was not demonstrated due to failure to comply with the FDA 90% confidence interval criteria. Based on the observed total drug exposure (AUCs), Artefan® is likely to produce a similar therapeutic response as Coartem®.

Usefulness of day 7 lumefantrine plasma concentration as a predictor of malaria treatment outcome in under-fives children treated with artemether-lumefantrine in Tanzania

“…During the introduction of ALu in Tanzania in the year 2006, Coartem ® , which is a product from the innovator company Novartis, was prequalified to be used in the country. Due to poor availability and high cost of innovator's product, since 2013 generic ACT medicines were approved by the government to be used in the management of uncomplicated malaria [16]. In 2012, a community pharmacy-based study was conducted in Tanzania and found that Artefan ® , a generic anti-malarial drug-containing ALu was the most widely distributed brand compared to other ACT medicines [16].…”

“…Due to poor availability and high cost of innovator's product, since 2013 generic ACT medicines were approved by the government to be used in the management of uncomplicated malaria [16]. In 2012, a community pharmacy-based study was conducted in Tanzania and found that Artefan ® , a generic anti-malarial drug-containing ALu was the most widely distributed brand compared to other ACT medicines [16]. However, substandard and fake anti-malarial generic products were previously reported to be available in the drug outlets in South East Asia [17] and sub-Saharan African countries including Tanzania [18][19][20][21][22][23][24].…”

“…Recently, a survey conducted by the ACT watch Group in Tanzania indicated that the availability of qualityassured ACT medicines was a major concern in most of the drug outlets [25]. Because of the high-level of availability of generic anti-malarial Artefan ® in the public health facilities, at the Medical Stores Department (MSD) and in private pharmacies in Tanzania, its bioequivalence with innovator product Coartem ® was evaluated in 2012 [16]. Based on the Food and Drug Authority (FDA) criteria of bioequivalence, data did not confirm bioequivalence [16].…”

“…Because of the high-level of availability of generic anti-malarial Artefan ® in the public health facilities, at the Medical Stores Department (MSD) and in private pharmacies in Tanzania, its bioequivalence with innovator product Coartem ® was evaluated in 2012 [16]. Based on the Food and Drug Authority (FDA) criteria of bioequivalence, data did not confirm bioequivalence [16]. Failure of the generic product to fulfill all FDA stipulated criteria for bioequivalence would mean Artefan ® was not suitable for use in the management of malaria in clinical settings.…”

Compliance of private pharmacies in Uganda with controlled prescription drugs regulations: a mixed-methods study

“…In Uganda, a study of 170 registered drug shops found that 93.5% prescribed antibiotics over-the-counter [34]. In Tanzania a simulated client study of 85 accredited drug dispensing outlets (ADDOs) reported that 79% dispensed antibiotics without prescriptions [43] while in Hanoi, Vietnam, 83% of the pharmacies dispensed antibiotics without a prescription [41].…”