Bioequivalence of Sarpogrelate in Healthy Chinese Subjects Under Fasting and Fed Conditions: A 4‐Way Replicate Crossover Investigation by a Reference‐Scaled Average Bioequivalence Approach

Abstract

Sarpogrelate is widely used to treat peripheral vascular disorders. However, it has been demonstrated to have a poor pharmacokinetic (PK) profile and marked within‐subject variability. Here, the bioequivalence of 2 formulations of sarpogrelate (100‐mg tablets) was assessed by using the reference‐scaled average bioequivalence (RSABE) method, and the PK parameters were quantified in healthy Chinese subjects under fasting (n = 38) and fed (n = 35) conditions. In this open and randomized 4‐way replicate study, a single dose of sarpogrelate was administered followed by a 3‐day washout period. The sarpogrelate concentration in blood samples was measured by liquid chromatography‐tandem mass spectrometry within 6 hours (fasting) or 10 hours (fed) of drug administration, and the PK parameters were determined by a noncompartmental model. The bioequivalence of the 2 formulations under both conditions was assessed using the ratios of ln(peak concentration [Cmax]) and ln(area under the concentration‐time curve [AUC]) within the limits based on the RSABE method. The 90% CIs for the ratios of lnCmax, lnAUC0‐t, and lnAUC0‐∞ were 0.8531–1.1100, 0.9616–1.0737, and 0.9550–1.0684, respectively, under fasting conditions and 0.8918–1.1076, 0.9818–1.0694, and 0.9818–1.0686, respectively, under fed conditions, which were within the RSABE acceptance limits. Food intake decreased the systemic exposure and the Cmax of sarpogrelate by 0.9‐fold and 0.5‐fold, respectively.

Bioequivalence Study Comparing Fixed-Dose Combination of Clopidogrel and Aspirin with Coadministration of Individual Formulations in Chinese Subjects Under Fed Conditions: A Phase I, Open-Label, Randomized, Crossover Study

“…As per international guidelines, including those from the Food and Drug Administration (FDA) and NMPA, the most suitable approach to evaluate bioequivalence of such highly variable drugs is RSABE, which takes into account the intra-subject variability and is comparable with the reference product in replicate trial design [19,21,23]. Various trials have assessed the bioequivalence of highly variable drugs using the RSABE method [24][25][26][27][28][29].…”

“…As per international guidelines, including those from the Food and Drug Administration (FDA) and NMPA, the most suitable approach to evaluate bioequivalence of such highly variable drugs is RSABE, which takes into account the intra-subject variability and is comparable with the reference product in replicate trial design [ 19 , 21 , 23 ]. Various trials have assessed the bioequivalence of highly variable drugs using the RSABE method [ 24 – 29 ]. The RSABE method of analysis employs the use of a three-period, three-sequence, crossover or a four-period, two-sequence, crossover study design for evaluating bioequivalence of highly variable drugs [ 30 ].…”

Pharmacokinetics and Bioequivalence of Clopidogrel Hydrogen Sulfate Tablets in Fed and Fasted Conditions: An Open‐Label, Randomized, Semireplicated Crossover Study in Healthy Chinese Volunteers

“…Reference‐scaled average bioequivalence (RSABE) approaches for highly variable drugs were based on linearly scaling the BE limits according to the within‐subject variability of the reference formulation 15 . Reference‐scaled or average bioequivalence (RSABE or ABE, respectively) was used for BE evaluation depending on the SD corresponding to within‐subject variability of the reference product (S WR ) 16 . The FDA recommends that S WR should be set to 0.294 as a cutoff value.…”

“…15 Reference-scaled or average bioequivalence (RSABE or ABE, respectively) was used for BE evaluation depending on the SD corresponding to within-subject variability of the reference product (S WR ). 16 The FDA recommends that S WR should be set to 0.294 as a cutoff value. If S WR ࣙ 0.294, the RSABE approach can be used.…”