Comparative Pharmacokinetics, Bioequivalence and Safety Study of Two Recombinant Human Chorionic Gonadotropin Injections in Healthy Chinese Subjects

Abstract

Objective

To evaluate the pharmacokinetics (PK), bioequivalence and safety profile of the recombinant human chorionic gonadotropin (r-hCG) injection formulation LZM003 (test drug) comparing with that of Ovidrel^® (reference drug) in healthy Chinese subjects.

Methods

This is a randomized, single-blind, single-dose, two-arm and two-period crossover Phase I study. Subjects were randomized evenly to a single dose of LZM003 or reference drug injected subcutaneously, with a 10-day or longer between-treatment washout period. PK parameters, anti-drug antibodies (ADAs), and adverse events (AEs) were assessed. The primary PK endpoints were area under the curve (AUC) of the concentration–time curve from zero to last quantifiable concentration (AUC_0-t), AUC from zero to infinity (AUC_0-∞), and peak concentration (C_max). Bioequivalence was determined by assessing whether the 90% confidence intervals (CIs) for the geometric mean ratio (GMR) of LZM003 to reference drug fell within predefined margins of 80% −125%.

Results

Forty-eight subjects (24 males and 24 females) were enrolled and one subject withdrew for personal reasons. Mean values of primary PK parameters were similar (p > 0.05) between LZM003 and the reference drug. The 90% CIs for primary PK endpoints’ GMR of LZM003 to reference drug ranged between 0.9144 and 1.1845, which were within bioequivalence margins of 80−125%. Incidence of AEs was similar (p > 0.05) between the two groups. Neither LZM003 nor reference drug produced anti-drug antibody (ADA) in healthy subjects.

Conclusion

LZM003 and reference drug were bioequivalent. The PK and safety assessments were similar (p > 0.05) between the two formulations in healthy Chinese subjects.

Trial Registration Number

ChiCTR-IIR-16010158 (http://www.chictr.org.cn).

Trial Registration Date

December 15, 2016.

Keywords:

• bioequivalence
• human chorionic gonadotropin
• Chinese subject
• pharmacokinetics

Abbreviations

ADA, anti-drug antibody; ADA-AS, Anti-drug antibody analysis set; AE, adverse event; ANOVA, analysis of variance; ART, assisted reproductive techniques; AUC_0-∞, area under the curve between 0 and infinity; AUC_0-t, serum concentration until the last concentration observed; BEAS, bioequivalence analysis set; BMI, body mass index; CHO, Chinese hamster ovary; CI, confidence interval; CL, total body clearance; C_max, peak of concentration; CTCAE, Common Terminology Criteria for Adverse Events; E2, estradiol; EC, Ethics Committee; ECG, electrocardiography; ECL, electrochemiluminescent; ELISA, enzyme-linked immunosorbent assay; F, relative bioavailability; FAS, full analysis set; FSH, follicle stimulating hormone; GCP, good clinical practice; GMR, geometric mean ratio; GMR, geometric mean ratio; hCG, human chorionic gonadotropin; hMG, human menopausal gonadotropin; HQC, high quality control; ICF, informed consent forms; ISR, incurred sample re-analysis; LH, luteinizing hormone; LLOQ, lower limit of quantitation; LQC, low quality control; MedDRA, Medical Dictionary for Regulatory Activities; MQC, middle quality control; NAb, neutralizing antibody s; P, progesterone; PHS, pooled human serum; PK, pharmacokinetics; PKAS, pharmacokinetic analysis set; PLA, People’s Liberation Army; PRL, prolactin; PT, Preferred Term; QC, quality control; r-hCG, recombinant hCG; SD, standard deviation; SOC, System Organ Class; SS, safety set; STD, standard curve; t_1/2, terminal elimination half-life; TEAE, treatment-emergent adverse event; T_max, time to C_max; TOST, two one-sided t-tests; u-hCG, urinary hCG; ULOQ, upper limit of quantitation; V_d, apparent volume of distribution; λ_z, rate constant of apparent terminal elimination.

Data Sharing Statement

We used electronic case record form (eCRF) to collect individual identified participant data (IPD) in this trial. We are not ready to share deidentified participant data until National Medical Products Administration (NMPA) is approved for LZM003. However, the protocol of this trial is available by searching the registration number ChiCTR-IIR-16010158 at http://www.chictr.org.cn.

Disclosure

The authors report no conflicts of interest in this work.