1. Pharmacokinetics of the Monoclonal Antibody MHAA4549A Administered in Combination With Oseltamivir in Patients Hospitalized With Severe Influenza A Infection
- Author
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Jacqueline McBride, Melicent C. Peck, Priscilla Horn, Priya Kulkarni, Jeremy J. Lim, Jorge A. Tavel, Gaohong She, Rong Deng, Aide Castro, Elizabeth M. Newton, William D. Hanley, and Mauricio Maia
- Subjects
Oseltamivir ,medicine.medical_specialty ,MHAA4549A ,medicine.drug_class ,Administration, Oral ,Antibodies, Monoclonal, Humanized ,medicine.disease_cause ,Placebo ,Monoclonal antibody ,Antiviral Agents ,030226 pharmacology & pharmacy ,Gastroenterology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pharmacokinetics ,Nasopharynx ,Internal medicine ,Influenza, Human ,Influenza A virus ,medicine ,Humans ,Drug Interactions ,Pharmacology (medical) ,NON COVID ARTICLES ,Infusions, Intravenous ,Active metabolite ,Aged ,Pharmacology ,Inpatients ,business.industry ,Middle Aged ,Interim analysis ,Antibodies, Neutralizing ,Trachea ,medicine.anatomical_structure ,chemistry ,monoclonal antibody ,030220 oncology & carcinogenesis ,pharmacokinetics and drug metabolism ,Drug Therapy, Combination ,business ,Half-Life ,Respiratory tract - 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.
- Published
- 2020
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