AUTHOR=Lin Sisi , Lou Yutao , Hao Rui , Shao Yiming , Yu Jin , Fang Lu , Bao Meihua , Yi Wu , Zhang Yiwen 

TITLE=A single-dose, randomized, open-label, four-period, crossover equivalence trial comparing the clinical similarity of the proposed biosimilar rupatadine fumarate to reference Wystamm® in healthy Chinese subjects

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1328142

DOI=10.3389/fphar.2024.1328142

ISSN=1663-9812

ABSTRACT=The aim of this study was to evaluate the bioequivalence of two formulations of rupatadine (10 mg tablets) under fasting and fed conditions in healthy Chinese subjects.Methods: A total of 72 subjects were randomly assigned to the fasting cohort (n = 36) or fed cohort (n = 36). Each cohort includes 4 single-dose observation periods and 7-day washout intervals.. Blood samples were collected at several timepoints for up to 72 h post-dose. Plasma concentration of rupatadine and the major active metabolites (desloratadine and 3-hydroxydesloratadine) were analyzed by a validated HPLC-MS/MS method. Non-compartmental analysis method was employed to determine the pharmacokinetic parameters. Based on the within-subject standard deviation of the reference formulation, a reference-scaled average bioequivalence or average bioequivalence method was used to evaluate the bioequivalence of the two formulations.In the fasting status, the reference-scaled average bioequivalence method was used to evaluate the bioequivalence of maximum observed rupatadine concentration (Cmax; subject standard deviation >0.294), while the average bioequivalence method was used to evaluate the bioequivalence of area under the rupatadine concentration-time curve from time 0 to the last detectable concentration (AUC0-t) and from time 0 to infinity (AUC0-∞ ). The geometric mean ratio (GMR) of the test/reference for Cmax was 95.91%, and the 95% upper confidence bound was 95.91%. For AUC0-t and AUC0-∞ comparisons, the GMR and 90% confidence interval (CI) were 98.76% (93.88%-103.90%) and 98.71% (93.93%-103.75%), respectively. In the fed status, the subject standard deviation values of Cmax, AUC0-t and AUC0-∞ were all < 0.294; therefore, the average bioequivalence method was used.The GMR and 90% CI for Cmax, AUC0-t, and AUC0-∞ were 101.19% (91.64%-111.74%), 98.80% (94.47%-103.33%), and 98.63% (94.42%-103.03%), respectively. The two-sided 90% CI of GMR for primary pharmacokinetic endpoints of desloratadine and 3-hydroxydesloratadine were also within 80%-125% for each cohort. These results met the bioequivalence criteria for highly variable drugs.All adverse events were mild and transient.: Rupatadine fumarate tablet showed a similar safety profile to reference Wystamm ® (J. Uriach y Compañía, S.A., Spain), and its pharmacokinetic bioequivalence was confirmed in healthy Chinese subjects under fasting and postprandial status. Clinical trial registration: [http://www.chinadrugtrials.org.cn/index.html], identifier [CTR20213217].