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Lack of ethnic differences in the pharmacokinetics and pharmacodynamics of inclacumab in healthy Japanese and Caucasian subjects

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Inclacumab, a novel monoclonal antibody against P-selectin, is in development for the treatment and prevention of atherosclerotic cardiovascular diseases. This study was conducted to investigate potential differences in the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single intravenous doses of inclacumab between Japanese and Caucasian healthy volunteers.

Method

Sixty-two subjects (31 Japanese and 31 Caucasian) were enrolled in a single-center, open-label, parallel, three dose groups (0.3, 3.0, and 20 mg/kg), single-dose study in Japanese and Caucasian healthy volunteers. Inclacumab concentrations, platelet–leukocyte aggregates (PLA), free/total soluble P-selectin (sP-selectin) ratio, and antibody formation were measured along with routine safety monitoring during the conduct of the study.

Results

The PK profiles of inclacumab in Caucasian and Japanese subjects were similar following single-dose intravenous infusion. The statistical analysis of peak (C max) and total exposure (AUClast) indicated that bioavailability was similar for both races when corrected for body weight. The geometric mean ratios for AUClast and C max in the Japanese versus Caucasian cohort were 101 and 111 %, respectively, in 0.3 mg/kg dose group, 108 and 107 %, respectively, in 3.0 mg/kg dose group, and 97 and 96 %, respectively, in 20 mg/kg dose group. No differences were observed in the level of PLA inhibition and mean free/total soluble P-selectin ratio between Japanese and Caucasian subjects. PK/PD relationship between the free/total sP-selectin ratio or PLA and plasma concentration of inclacumab appeared to be similar in both Japanese and Caucasian populations. The effect of race as a covariate was explored on both PK/PD models for PLA and free/total sP-selectin ratio and did not have a significant effect over the reduced model without race as a covariate.

Conclusions

Ethnicity had no clinically relevant influence on inclacumab pharmacokinetics or pharmacodynamics. No dose adjustment of inclacumab is required for differences in race.

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Acknowledgments

The authors would like to thank Dr. Amina Haggag, the principal investigator at Anaheim Clinical Trials (ACT) in California (USA), for her contribution to this study. The authors also thank Julia Braggs for the operational management of the study, Dr. Kevin Smart for his scientific input on the PKPD section, Corinne Petit-Frère for analyzing the PK and ADA samples, Martina Their for organizing the analysis of the soluble P-selectin samples, Bernhard Reis for scientific input on the PLA analysis, and Barbara O’Reilly for generation of study listings and tables.

Authors’ contributions

MM and ChS wrote the manuscript. MM, ChS, and GP designed and performed the research and analyzed the data.

Compliance with ethical standards

ᅟ

Conflicts of interest

This study was sponsored by Roche. All authors are employees of Roche.

Ethics approval

The study was conducted in full accordance with the principles of the Declaration of Helsinki and with the International Conference on Harmonization (ICH) E6 guideline for Good Clinical Practice (GCP) and local laws and regulations.

Consent to participate

All subjects gave written informed consent before participating in study-related procedures.

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Authors and Affiliations

  1. Roche Innovation Center Welwyn, Roche Products Ltd, Welwyn Garden City, UK

    Mary Morrison

  2. Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, CH-4070, Basel, Switzerland

    Guiseppe Palermo & Christophe Schmitt

Authors
  1. Mary Morrison
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  2. Guiseppe Palermo
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  3. Christophe Schmitt
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Corresponding author

Correspondence to Christophe Schmitt.

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Morrison, M., Palermo, G. & Schmitt, C. Lack of ethnic differences in the pharmacokinetics and pharmacodynamics of inclacumab in healthy Japanese and Caucasian subjects. Eur J Clin Pharmacol 71, 1365–1374 (2015). https://doi.org/10.1007/s00228-015-1938-4

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  • DOI: https://doi.org/10.1007/s00228-015-1938-4

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