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Pharmacokinetics of the Monoclonal Antibody MHAA4549A Administered in Combination With Oseltamivir in Patients Hospitalized With Severe Influenza A Infection.

ABSTRACT: MHAA4549A is a human anti-influenza A monoclonal antibody developed to treat influenza A. We report MHAA4549A serum, nasopharyngeal, and tracheal aspirate pharmacokinetics from a phase 2b study in hospitalized patients with severe influenza A. Patients were randomized 1:1:1 into 3 groups receiving single intravenous doses of 3600 mg (n = 55) or 8400 mg (n = 47) MHAA4549A or placebo (n = 56). Patients also received oral oseltamivir twice daily for ?5 days. Serum, nasopharyngeal, and tracheal aspirate pharmacokinetic samples were collected on days 1-60 from MHAA4549A-treated groups. Day 5 plasma samples from all groups were collected for assessing the pharmacokinetics of oseltamivir and its active metabolite, oseltamivir carboxylate. Noncompartmental pharmacokinetic analysis was performed using Phoenix WinNonlin. Data were collected during a preplanned interim analysis that became final when the trial terminated because of a lack of efficacy. Serum MHAA4549A concentrations were dose-proportional and biphasic. Mean MHAA4549A clearance was 288-350 mL/day, and mean half-life was 17.8-19.0 days. Nasopharyngeal MHAA4549A concentrations were non-dose-proportional. We detected MHAA4549A in tracheal aspirate samples, but intersubject variability was high. MHAA4549A serum and nasopharyngeal exposures were confirmed in all MHAA4549A-treated patients. Serum MHAA4549A had faster clearance and a shorter half-life in influenza A-infected patients compared with healthy subjects. MHAA4549A detection in tracheal aspirate samples indicated exposure in the lower respiratory tract. Oseltamivir and oseltamivir carboxylate exposures were similar between MHAA4549A-treated and placebo groups, suggesting a lack of MHAA4549A interference with oseltamivir pharmacokinetics.

SUBMITTER: Deng R

PROVIDER: S-EPMC7586956 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Pharmacokinetics of the Monoclonal Antibody MHAA4549A Administered in Combination With Oseltamivir in Patients Hospitalized With Severe Influenza A Infection.

Deng Rong R She Gaohong G Maia Mauricio M Lim Jeremy J JJ Peck Melicent C MC McBride Jacqueline M JM Kulkarni Priya P Horn Priscilla P Castro Aide A Newton Elizabeth E Tavel Jorge A JA Hanley William D WD

Journal of clinical pharmacology 20200704 11

MHAA4549A is a human anti-influenza A monoclonal antibody developed to treat influenza A. We report MHAA4549A serum, nasopharyngeal, and tracheal aspirate pharmacokinetics from a phase 2b study in hospitalized patients with severe influenza A. Patients were randomized 1:1:1 into 3 groups receiving single intravenous doses of 3600 mg (n = 55) or 8400 mg (n = 47) MHAA4549A or placebo (n = 56). Patients also received oral oseltamivir twice daily for ≥5 days. Serum, nasopharyngeal, and tracheal aspi ...[more]

PMID: 32621543

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Project description:For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i.v.) doses of placebo, 3,600 mg MHAA4549A, or 8,400 mg MHAA4549A each combined with oral oseltamivir (+OTV) in patients hospitalized with severe influenza A virus infection. Patients, enrolled across 68 clinical sites in 18 countries, were randomized 1:1:1. The primary outcome was the median time to normalization of respiratory function, defined as the time to removal of supplemental oxygen support to maintain a stable oxygen saturation (SpO2) of ≥95%. Safety, pharmacokinetics, and effects on influenza viral load were also assessed. One hundred sixty-six patients were randomized and analyzed during a preplanned interim analysis. Compared to placebo+OTV, MHAA4549A+OTV did not significantly reduce the time to normalization of respiratory function (placebo+OTV, 4.28 days; 3,600 mg MHAA4549A+OTV, 2.78 days; 8,400 mg MHAA4549A+OTV, 2.65 days), nor did it improve other secondary clinical outcomes. Adverse event frequency was balanced across cohorts. MHAA4549A+OTV did not further reduce viral load versus placebo+OTV. In hospitalized patients with influenza A virus infection, MHAA4549A did not improve clinical outcomes over OTV alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A virus infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02293863.).

Dataset Information

Pharmacokinetics of the Monoclonal Antibody MHAA4549A Administered in Combination With Oseltamivir in Patients Hospitalized With Severe Influenza A Infection.

Publications

Pharmacokinetics of the Monoclonal Antibody MHAA4549A Administered in Combination With Oseltamivir in Patients Hospitalized With Severe Influenza A Infection.

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