On the bioavailability of oral chondroitin sulfate formulations: proposed criteria for bioequivalence studies.
Bioibérica, Scientific Medical Department, Plaza Francesc Macià 7, 08029 Barcelona, Spain. jverges@bioiberica.com
Chondroitin sulfate (CS) is a symptomatic slow-acting drug for osteoarthritis (SYSADOA). It should be noted, however, that there is a CS formulation approved as a drug in Europe, with evidenced efficacy and safety demonstrated by clinical trials in osteoarthritic patients. This formulation should therefore be considered as the reference product. This CS is manufactured by Bioibérica (Spain), commercialized in Europe by IBSA (Switzerland) and Bioibérica, and in the United States by Nutramax. Hence, all other CS formulations must demonstrate their bioequivalence with the reference product. Pharmacokinetic studies have shown that oral exogenous CS is absorbed as several metabolites, and the active moiety has not yet been identified. It is thus difficult to establish bioequivalence from plasma concentration against time curves. However, the FDA permits bioequivalence studies comparing the time course of the pharmacological response with two formulations of the same compound. It has been reported that the time course of CS response can be fitted to a modified Hill equation, as follows: E-E0=[(Emax x Ty )/(T50y+Ty)]. Where E is the effect at time T, E0 is the basal effect, Emax is the maximal effect, T50 is the time required to achieve 50% of the maximal effect and y is the sigmoid slope factor. Hence, it is proposed that a generic CS can be compared to the reference product using the Emax, T50, and y values derived by non-linear regression fitting to the modified Hill equation. The reference/test formulation ratio with the 90% confidence intervals (CI) can thus be estimated. If CI for each parameter ratio lies within 0.8-1.2, both CS formulations can be considered as bioequivalent. In the absence of such bioequivalence studies, physicians and patients are advised to use the reference product to obtain the maximal benefit in terms of efficacy and safety.
PMID: 15633611 [PubMed - indexed for MEDLINE]