title: Pharmacokinetics and Bioequivalence Study of Hydroxychloroquine Sulfate Tablets in Chinese Healthy Volunteers by LC-MS/MS.
abstract: BACKGROUND
  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: Cmax, Tmax, AUC0-t, AUC0-∝, and t1/2. The bioequivalence between the test and reference products was assessed based on the following parameters: Cmax, AUC0-60d, and AUC0-∝using the ANOVA method. If the 90% CI for AUC0-twas within 80-125% and for Cmaxwas 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 Cmaxfor HCQ is 103.8-142.3%; the AUC0-60 is 100-114.2% and AUC0-∝100-115.5%. Both met the criteria according to the SFDA's guidelines for bioequivalence. The relative bioavailability was 109.5% (according to AUC0-60d) and 110.7% (according to AUC0-∝). 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.
authors.affiliation: Department of Clinical Pharmacology Laboratory, Nanjing First Hospital, Nanjing Medical University, 210006, Nanjing, Jiang Su, China. fanhongwei178@sina.com.
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Fan
authors.affiliation: Department of Clinical Pharmacology Laboratory, Nanjing First Hospital, Nanjing Medical University, 210006, Nanjing, Jiang Su, China.
authors.forename: Zhi-Xiang
authors.initials: ZX
authors.lastname: Ma
authors.affiliation: XenoBiotic Laboratories China, 210038, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: XenoBiotic Laboratories China, 210038, Nanjing, China.
authors.forename: Xing-Ye
authors.initials: XY
authors.lastname: Yang
authors.affiliation: Department of Clinical Pharmacology Laboratory, Nanjing First Hospital, Nanjing Medical University, 210006, Nanjing, Jiang Su, China.
authors.forename: Jun-Lin
authors.initials: JL
authors.lastname: Cheng
authors.affiliation: The 2nd Affliated Hospital of Nanjing Medical University, 210011, Nanjing, China. Yingbinli65@sina.com.
authors.forename: Ying-Bin
authors.initials: YB
authors.lastname: Li
keywords: Bioequivalence; Hydroxychloroquine (HCQ); Pharmacokinetics