Pharmacokinetics, pharmacodynamics, safety, and tolerability of single-dose denosumab in healthy Chinese volunteers: A randomized, single-blind, placebo-controlled study

Abstract

Background: Denosumab is a fully human monoclonal antibody against receptor activator of nuclear factor kappa-B ligand, a cytokine essential for the formation, function and survival of osteoclasts. This study assessed the pharmacokinetics, pharmacodynamics, safety and tolerability of single-dose denosumab (60 and 120 mg) in healthy Chinese volunteers.

Methods: This randomized (3:3:2), single-blind, placebo-controlled study enrolled healthy Chinese volunteers to receive single subcutaneous injection of denosumab 60 mg, 120 mg, or placebo. Study consisted of screening period (up to 21 days), treatment and assessment period (19 weeks), and an end-of-study visit (at week 26). Denosumab pharmacokinetics and pharmacodynamics parameters were estimated using non-compartmental analysis. Safety and tolerability were assessed throughout the study.

Results: A total of 63 volunteers received the study treatment and 62 (98.4%) completed the study. Denosumab serum concentrations peaked at around Day 10 with dose-proportional increase from 60 mg to 120 mg. The mean terminal half-life of denosumab 60 mg and 120 mg was 15 days and 26 days, respectively. The serum C-terminal cross-linking telopeptide of type I collagen concentration-time profiles were similar (>80% decrease within 5 days) between denosumab 60 mg and 120 mg groups. The most commonly reported adverse event (AE) was decreased blood calcium levels (denosumab 60 mg, n = 13; denosumab 120 mg, n = 13; placebo, n = 1); however only one volunteer had calcium level below the abnormality value of potential clinical importance and none of the volunteers developed symptoms of hypocalcemia. The majority of AEs were of mild to moderate intensity. There were no deaths, serious AEs, or withdrawal from study due to AEs. No clinically significant findings in vital signs or electrocardiogram were observed.

Conclusions: Both denosumab 60 mg and 120 mg were well tolerated with no new safety concerns identified in healthy Chinese volunteers with similar pharmacokinetics and pharmacodynamics profiles to that of Caucasians.

Trial registration: ClinicalTrial.gov NCT02135640.

Conflict of interest statement

We have the following interests. Funding for this study was provided by GlaxoSmithKline (China) R&D Company Limited, Shanghai, China. Wenjing Zhu, Antonio Nino and Fan Zhang are employees of GSK and Antonio Nino owns GSK stock options. Hongxin Zhao was an employee of GSK during the conduct of study and during the manuscript development. Currently, he is affiliated with Shanghai Roche Pharmaceuticals Ltd. Qian Chen, Chaoying Hu, Yanmei Liu, Rong Song and Yun Liu were investigators for the study and have nothing to disclose. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Fig 1. Study design and volunteers disposition.

aOne volunteer withdrew consent before administration of study treatment. bVolunteers from placebo group were not included for PK assessment. cOne volunteer who received denosumab 60 mg withdrew from study (investigator discretion; study day 147). PK, pharmacokinetic; PD, pharmacodynamic; Wk, week.

Fig 2. Mean serum concentration-time plot of denosumab following single subcutaneous administration at doses of 60 mg and 120 mg.

Error bar represents standard deviation.

Fig 3. Change from baseline in median serum CTX1.

Error bar represents range. CTX1, C-terminal cross-linking telopeptide of type I collagen.