A Parallel Design Study to Assess the Bioequivalence of Generic and Branded Hydroxychloroquine Sulfate Tablets in Healthy Volunteers

Abstract

Hydroxychloroquine (HCQ) is a racemic 4-aminoquinoline derivative that was first introduced as an antimalarial, and subsequently applied to the treatment of autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. Information on the pharmacokinetics of HCQ in healthy volunteers, especially in a Chinese population is limited, and this study was conducted to provide support for a generic product to obtain marketing authorization in China.The aim of the present study was to compare the pharmacokinetics and assess bioequivalence of a new generic test and the branded reference hydroxychloroquine sulfate tablets in healthy volunteers.This was a parallel, open-label, randomized, single-dose, 1-period fasting study. 54 healthy subjects were randomly assigned (1:1) to receive 200 mg hydroxychloroquine sulfate tablets of the test or the reference formulation. 15 blood samples were collected and whole blood concentrations of HCQ were determined by a validated liquid chromatography-isotopic dilution mass spectrometry method. Log-transformed Cmax and AUC0-24 values were used to test for bioequivalence. The 2 formulations were considered bioequivalent if 90% confidence intervals (CIs) for the log-transformed ratios of Cmax and AUC0-24 were within the predetermined bioequivalence range of 80-125%. Tolerability was evaluated throughout the study by vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and interviews with the subjects about adverse events.54 healthy subjects were enrolled and completed the study (mean [SD] age, height, body weight, and BMI were 23.9 [2.4] years, 168.9 [5.0] cm, 61.3 [5.4] kg, and 21.5 [1.7] kg/m2), 27 subjects per group. No formulation or sequence effects were observed. The mean values of Cmax and AUC0-24 for the test and reference formulations of HCQ (197.6 and 199.0 ng/mL, 2460.1 and 2468.3 ng/mL/h) were not significantly different. The 90% CIs of the ratios of Cmax and AUC0-24 were 99.3% (98.1-102.1%), 99.7% (98.9-101.4%), respectively. 4 subjects (7.41%) experienced a total of 4 mild AEs (headache and microscopic hematuria, 1 each; and increase in plasma triglycerides, 2).The results of this study suggest that the test and reference hydroxychloroquine sulfate tablets are bioequivalent. Both formulations were generally well tolerated.

Pharmacokinetics, Bioequivalence, and Safety of 2 Formulations of Hydroxychloroquine Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions

“…A previous study reported a C max of 199.0 ng/mL, while in this trial the C max of the T preparation was 238.9 ng/mL 18 . The PK data of this trial were slightly higher than those of previous studies, indicating that our bioavailability of hydroxychloroquine T is better than the previous studies.…”

“…13 A previous parallel-designed fasting trial that was consistent with our research design, did not better evaluate the impact on food on the bioavailability of hydroxychloroquine in comparison with the study with a crossover study design 13 ; however, it (54 healthy subjects) had a smaller sample size than ours, and the sex ratio was unknown. 13,18 A previous study reported a C max of 199.0 ng/mL, while in this trial the C max of the T preparation was 238.9 ng/mL. 18 The PK data of this trial were slightly higher than those of previous studies, indicating that our bioavailability of hydroxychloroquine T is better than the previous studies.…”

“…13,18 A previous study reported a C max of 199.0 ng/mL, while in this trial the C max of the T preparation was 238.9 ng/mL. 18 The PK data of this trial were slightly higher than those of previous studies, indicating that our bioavailability of hydroxychloroquine T is better than the previous studies. Furthermore, the data difference in PK may be related to the drug delivery conditions, and the characteristics of the subjects, and the PK blood collection scheme.…”

“…Compared with the crossover study design, in the present trial, the study time was shortened and the uncontrollability of the washout period was avoided 13 . A previous parallel‐designed fasting trial that was consistent with our research design, did not better evaluate the impact on food on the bioavailability of hydroxychloroquine in comparison with the study with a crossover study design 13 ; however, it (54 healthy subjects) had a smaller sample size than ours, and the sex ratio was unknown 13,18 …”

Pharmacokinetics and Safety of Dapoxetine Hydrochloride in Healthy Chinese Men: Impact of Dose and High‐Fat Meal

“…Also, we estimated the point estimation of the geometric mean ratio (GMR) and its 90%CI (30 mg:60 mg dapoxetine). For 90%CI within the 80% to 125% range, the dapoxetine pharmacokinetics was considered dose proportional 11–14 . The Wilcoxon rank‐sum test was used to compare t max values between the treatment groups.…”