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

Abstract

Purpose: 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) and fed cohort (n = 36). Each cohort includes four single-dose observation periods and 7-day washout intervals. Blood samples were collected at several timepoints for up to 72 h post-dose. The plasma concentration of rupatadine and the major active metabolites (desloratadine and 3-hydroxydesloratadine) were analyzed by a validated HPLC-MS/MS method. The 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.

Results: For the fasting status, the reference-scaled average bioequivalence method was used to evaluate the bioequivalence of the maximum observed rupatadine concentration (C_max; subject standard deviation > 0.294), while the average bioequivalence method was used to evaluate the bioequivalence of the area under the rupatadine concentration-time curve from time 0 to the last detectable concentration (AUC_0-t) and from time 0 to infinity (AUC_0-∞). The geometric mean ratio (GMR) of the test/reference for C_max was 95.91%, and the upper bound of the 95% confidence interval was 95.91%. For AUC_0-t and AUC_0-∞ comparisons, the GMR and 90% confidence interval (CI) were 98.76% (93.88%-103.90%) and 98.71% (93.93%-103.75%), respectively. For the fed status, the subject standard deviation values of C_max, AUC_0-t, and AUC_0-∞ were all <0.294; therefore, the average bioequivalence method was used. The GMR and 90% CI for C_max, AUC_0-t, and AUC_0-∞ 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 the GMR for primary pharmacokinetic endpoints of desloratadine and 3-hydroxydesloratadine was also within 80%-125% for each cohort. These results met the bioequivalence criteria for highly variable drugs. All adverse events (AEs) were mild and transient.

Conclusion: The test drug rupatadine fumarate showed a similar safety profile to the reference drug Wystamm^® (J. Uriach y Compañía, S.A., Spain), and its pharmacokinetic bioequivalence was confirmed in healthy Chinese subjects based on fasting and postprandial status.

Clinical trial registration: http://www.chinadrugtrials.org.cn/index.html, identifier CTR20213217.

Keywords: bioequivalence; pharmacokinetics; reference-scaled average bioequivalence; rupatadine fumarate; safety.

FIGURE 1

Flow chart of the study. Abbreviations: T, test; R, rupatadine; N, number of subjects. Notes: reference indicates Wystamm^®; A and B represent groups of the fasting status; and C and D represent groups of the postprandial status.

FIGURE 2

Plasma concentration–time curves. The mean (±SD) plasma concentration–time curves of rupatadine (A), desloratadine (B), and 3-hydroxydesloratadine (C) after a single oral administration of 10 mg rupatadine fumarate or Wystamm^® under the fasting status. The mean (±SD) plasma concentration–time curves of rupatadine (D), desloratadine (E), and 3-hydroxydesloratadine (F) after a single oral administration of 10 mg rupatadine fumarate or Wystamm^® under the postprandial status. Abbreviations: SD, standard deviation.

FIGURE 3

90% CIs of AUC_0-t, C_max, and AUC_0-∞ for rupatadine fumarate and Wystamm^® under the fasting status (A) and postprandial status (B). Abbreviations: AUC_0-t, area under the rupatadine concentration–time curve from time 0 to the last detectable concentration; AUC_0-∞, area under the rupatadine concentration–time curve from time 0 to infinity; CI, confidence interval; and C_max, maximum observed rupatadine concentration.