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Clinical Pharmacokinetics

, Volume 57, Issue 3, pp 367–377 | Cite as

Pharmacokinetics of MHAA4549A, an Anti-Influenza A Monoclonal Antibody, in Healthy Subjects Challenged with Influenza A Virus in a Phase IIa Randomized Trial

  • Rong Deng
  • Ai Ping Lee
  • Mauricio Maia
  • Jeremy J. Lim
  • Tracy Burgess
  • Priscilla Horn
  • Michael A. Derby
  • Elizabeth Newton
  • Jorge A. Tavel
  • William D. Hanley
Original Research Article

Abstract

Background and Objectives

MHAA4549A, a human anti-influenza immunoglobulin (Ig) G1 monoclonal antibody, is being developed to treat patients hospitalized for influenza A infection. This study examined the pharmacokinetics (PKs) of MHAA4549A in a phase IIa, randomized, double-blind, dose-ranging trial in healthy volunteers challenged with influenza A virus.

Methods

Serum PK data were collected from 60 subjects in three single-dose groups (400, 1200, or 3600 mg) who received MHAA4549A intravenously 24–36 h after inoculation with the influenza A virus. Nasopharyngeal swab MHAA4549A concentration data were collected on days 1–8, and all subjects, including the placebo group, received 75 mg oseltamivir twice daily from days 7 to 11. Plasma samples were collected 4 h postdose on day 8 for oseltamivir and its active metabolite oseltamivir carboxylate (OC) (all subjects, n = 100), including subjects treated with oseltamivir alone and placebo. Noncompartmental analysis was performed for both nasal and serum PKs.

Results

MHAA4549A showed dose-proportional serum PKs with a long terminal half-life (approximately 21.9–24.6 days) and slow clearance (approximately 152–240 mL/day); however, nasopharyngeal swab PKs were not dose proportional. No differences in mean plasma concentrations of oseltamivir and OC at 4 h postdose on day 8 were observed between the MHAA4549A treatment and placebo groups. No subjects who received MHAA4549A developed anti-drug antibodies.

Conclusion

MHAA4549A serum PKs were consistent with that of a human IgG1antibody without known endogenous targets. MHAA4549A showed nonlinear PKs in nasopharyngeal swab samples, which will guide future dose selection to achieve the high drug concentrations needed at the site of action for efficacy. These data demonstrate no PK interactions between MHAA4549A and oseltamivir, and support flat dosing.

Trial Registration

ClinicalTrials.gov identifier, NCT01980966.

Notes

Compliance with Ethical Standards

Conflict of interest

Michael A. Derby is a former employee of, and Rong Deng, Ai Ping Lee, Mauricio Maia, Jeremy J. Lim, Tracy Burgess, Priscilla Horn, Elizabeth Newton, Jorge A. Tavel, and William D. Hanley are current employees of Genentech, Inc., a subsidiary of the Roche Group. All authors own Roche stock.

Ethics approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Funding

This study was funded by Genentech, Inc. Anshin BioSolutions and Deborah Solymar (Genentech, Inc.) provided assistance with manuscript editing and writing and were funded by Genentech, Inc.

Informed consent

Informed consent was obtained from all individual participants included in this study.

Supplementary material

40262_2017_564_MOESM1_ESM.pdf (264 kb)
Supplementary material 1 (PDF 263 kb)

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Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  • Rong Deng
    • 1
  • Ai Ping Lee
    • 1
  • Mauricio Maia
    • 1
  • Jeremy J. Lim
    • 1
  • Tracy Burgess
    • 1
  • Priscilla Horn
    • 1
  • Michael A. Derby
    • 1
  • Elizabeth Newton
    • 1
  • Jorge A. Tavel
    • 1
  • William D. Hanley
    • 1
  1. 1.Genentech, Inc.South San FranciscoUSA

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