Abstract
INTRODUCTION: Hydroxychloroquine (HCQ), 4-aminoquinoline, is an antimalarial drug and has become a basic therapy for rheumatic disease treatment. It can stabilize the condition of SLE patients and reduce the chances of patient relapse through its immunosuppressive function and antiinflammatory effects. This drug was absorbed completely and rapidly by oral administration, but has a prolonged half-life for elimination. The objective of this study was to evaluate the pharmacokinetic parameters and relative bioequivalence of a new generic (test) formulation with the branded (reference) formulation of HCQ in healthy Chinese male volunteers. This study was designed to acquire regulatory approval for the test formulation. METHODS: This study was conducted with a randomized, single-dose, two-period, and crossover design. The male subjects were randomly assigned to two groups at a 1:1 ratio to receive 0.2 g hydroxychloroquine sulfate tablets (0.1 g/piece) of the two formulations after a 3-month washout period then administered the alternate formulation. Study drugs were administered after overnight fasting (over 10 h). Plasma concentrations of hydroxychloroquine were measured by a validated LC-MS/MS method. The following pharmacokinetic properties were determined by a noncompartmental pharmacokinetic method: C (max), T (max), AUC(0-t) , AUC(0-∝), and t (1/2). The bioequivalence between the test and reference products was assessed based on the following parameters: C (max), AUC0-60d, and AUC(0-∝) using the ANOVA method. If the 90% CI for AUC(0-t) was within 80-125% and for C (max) was within 70-143% of the statistical interval proposed by the SFDA, the two formulations were assumed bioequivalent. Concerning the main pharmacokinetic charateristics of hydroxychloroquine, a long half-life drug, the pharmacokinetic parameters of 0-72 h were determined according to the FDA. Furthermore, a comparison was made between the parameters at 0-60 days and 0-72 h to evaluate whether a truncated AUC method can be applied to estimate the relative bioavailability of HCQ. Tolerability was assessed by monitoring vital signs and laboratory tests and by questioning subjects about adverse events. RESULTS: The 90% CI of C (max) for HCQ is 103.8-142.3%; the AUC0-60 is 100-114.2% and AUC(0-∝) 100-115.5%. Both met the criteria according to the SFDA's guidelines for bioequivalence. The relative bioavailability was 109.5% (according to AUC(0-60d)) and 110.7% (according to AUC(0-∝)). No serious or unexpected adverse events were observed. CONCLUSIONS: In this study, the pharmacokinetic studies and results were conducted so that the test and reference formulations of HCQ met the Chinese criteria for assuming bioequivalence. Both formulations were well tolerated in the population studies.