Summary:
Bioequivalence studies are fundamental for the approval of generic medicinal products by Health Authorities and they are performed to ensure similarity in terms of safety and efficacy of the tested products. Two formulations of the same active substance can be considered bioequivalent if they are pharmaceutically equivalent and their bioavailabilities (rate and extent of absorption) after administration of the same molar dose lie within acceptable predefined limits.
The determination of bioequivalence includes the assessment of the main pharmacokinetic parameters, AUC (area under the curve concentration of drug in the blood versus time) and Cmax (maximum drug concentration in the blood). In cases where rapid release is claimed to be clinically relevant and of importance for onset of action the parameter AUCTmaxR (initial area up to the time of maximum drug concentration of the reference product) may also be assessed.
In addition, there are cases as in certain modified release formulations, where for treatment efficacy reasons a controlled duration of drug effect is required. However, different rates of release for formulations with biphasic release mechanism, such as modified release formulations of methylphenidate, may lead to a different shape of concentration - time curves and therapeutically non-equivalent formulations. Methylphenidate is a stimulant of the central nervous system, and is the most commonly used medication for Attention Deficit Hyperactivity Disorder (ADHD), which is a neurobehavioral disorder with onset during childhood. If left untreated, ADHD remains in adulthood and is associated with poor academic achievement and low occupational status. Methylphenidate exists in a number of different brands, often in the form of biphasic modified release formulations. Both the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have reviewed bioequivalence guidelines for this type of formulations, introducing additional parameters of bioequivalence, i.e. partial areas (pAUCs) for different cut-off time points, focusing on the characterization of all phases.
It has been also proposed in the literature that the bioequivalence of two formulations of the same active substance could be determined by assessing the similarity of the corresponding drug concentration in plasma vs. time curves after per os administration,by Direct Curve Comparison Indices (DCCIs). In a study investigating the theoretical sensitivity of DCCIs to reflect differences in pharmacokinetic profiles, it was found that an index (e.g. f1, ξ1 or ξ2) calculated up to two time points (Tmax, time of maximum drug concentration of the reference formulation and tlast, time of last sampling) provided in all cases, an effective tool for pharmacokinetic profile comparisons.
The present study examines the sensitivity of DCCIs f1 ξ1 and ξ2 to reflect differences in drug plasma concentration vs. time curves for test and reference formulations with biphasic release, using extensive simulations. Specifically, an assessment of the bioequivalence criteria for biphasic release formulations of methylphenidate using partial DCCIs is considered. Estimation of f1,t1-t2, ξ1,t1-t2and ξ2,t1-t2 is performed assuming as cut-off time points, the time points defined in the revised guidelines of FDA and EMA for pAUCs for this type of modified release formulations. In all cases, an evaluation of the contribution of each index in the relevant bioequivalence criterion is performed.
Moreover, a comparative evaluation of the bioequivalence criterion based on “partial” DCCIs, f1,t1-t2, ξ1,t1-t2 and ξ2,t1-t2, with the bioequivalence criterion estimated in a previous study using the classic parameters, Cmax, and pAUCs, according to the FDA guidance for biphasic release formulations of methylphenidate and the EMA guideline for multiphasic release formulations is performed. For this purpose, two biphasic release formulations of methylphenidate hydrochloride are used as model products: Ritalin LA® (reference formulation I) and Concerta® (reference formulation II).
Ιn the majority of the cases studied, the bioequivalence criterion based on the index f1,t1-t2 appear less permissive than the criteria based on the other two indices. Furthermore, by comparing the results obtained for the simulations of the two model formulations, it seems that the indices appear more sensitive to changes in parameters of the pharmacokinetic model in the case of simulations of formulation II than for the simulations of formulation I. Also, the bioequivalence criterion based on the combination of partial DCCIs calculated using the cut-off time points recommended in the FDA guidance for pAUCs, in most of the cases, is less permissive than the criterion based on the cut-off time points proposed in the EMA guideline.
The evaluation of the bioequivalence criteria based on DCCIs in comparison to the criteria based on the classic pharmacokinetic parameters revealed the following interesting conclusions: The criteria based on DCCIs were in all cases more strict than the criteria defined only by pAUCs. Moreover, in none of the 36 different simulation cases studied, did the FDA or EMA criteria appear to be overall more strict than the criteria based on DCCIs. In several cases, indices and classic pharmacokinetic parameters exhibit different sensitivity depending on the parameters of the pharmacokinetic drug release model, which vary in each simulation. This implies areas showing acceptance of bioequivalence based on indices, but rejection based on the FDA or the EMA criteria, and vice versa. The rejection of bioequivalence using the criteria based on classic pharmacokinetic parameters, is due to Cmax for the FDA and Cmax,1 and Cmax,2 for the EMA and not to pAUCs. In these cases, when partial indices were calculated from time 3 h or 4 h until Tmax2R, i.e. until the time of maximum concentration during the second (slower) phase of absorption, then all indices showed rejection of bioequivalence and therefore "tightening" of the criterion. This is in agreement with the results of a study performed for formulations with one release phase, where the combination of the indices calculated until two cut-off time points, i.e. until TmaxR and tlast, led to a very sensitive bioequivalence criterion, which was equally or more sensitive than the classic criteria based on parameters Cmax, AUC and AUCTmaxR. Thus, also in the case of biphasic release formulations, selection of the appropriate cut-off time point is crucial for the sensitivity of the bioequivalence criterion.
Finally, for the majority of simulations studied, bioequivalence acceptance areas based on DCCIs were smaller and included in the respective acceptance areas based on the bioequivalence criteria defined by FDA or EMA. Partial indices calculated for the period of 3 h - 7 h, appear to contribute significantly to the "tightening" of the bioequivalence criterion, while partial indices calculated for the period of 7 h - 12 h, in very few cases seem to tighten the bioequivalence criterion.
Keywords:
Bioequivalence studies, bioequivalence criteria, direct curve comparison indices, difference factor f1, Rescigno index ξi, modified release formulations, biphasic release formulations, ADHD, methylphenidate, methylphenidate generic formulations, Ritalin LA®, Concerta®
