tetano
Editor, Senior Moderator
Clin Pharmacokinet. 2017 Jun 21. doi: 10.1007/s40262-017-0564-y. [Epub ahead of print]
[h=1]Pharmacokinetics of MHAA4549A, an Anti-Influenza A Monoclonal Antibody, in Healthy Subjects Challenged with Influenza A Virus in a Phase IIa Randomized Trial.[/h] Deng R[SUP]1[/SUP], Lee AP[SUP]2[/SUP], Maia M[SUP]2[/SUP], Lim JJ[SUP]2[/SUP], Burgess T[SUP]2[/SUP], Horn P[SUP]2[/SUP], Derby MA[SUP]2[/SUP], Newton E[SUP]2[/SUP], Tavel JA[SUP]2[/SUP], Hanley WD[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND AND OBJECTIVES:[/h] 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.
[h=4]METHODS:[/h] 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.
[h=4]RESULTS:[/h] 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.
[h=4]CONCLUSION:[/h] 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.
[h=4]TRIAL REGISTRATION:[/h] ClinicalTrials.gov identifier, NCT01980966.
PMID: 28639229 DOI: 10.1007/s40262-017-0564-y
[h=1]Pharmacokinetics of MHAA4549A, an Anti-Influenza A Monoclonal Antibody, in Healthy Subjects Challenged with Influenza A Virus in a Phase IIa Randomized Trial.[/h] Deng R[SUP]1[/SUP], Lee AP[SUP]2[/SUP], Maia M[SUP]2[/SUP], Lim JJ[SUP]2[/SUP], Burgess T[SUP]2[/SUP], Horn P[SUP]2[/SUP], Derby MA[SUP]2[/SUP], Newton E[SUP]2[/SUP], Tavel JA[SUP]2[/SUP], Hanley WD[SUP]2[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] [h=4]BACKGROUND AND OBJECTIVES:[/h] 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.
[h=4]METHODS:[/h] 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.
[h=4]RESULTS:[/h] 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.
[h=4]CONCLUSION:[/h] 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.
[h=4]TRIAL REGISTRATION:[/h] ClinicalTrials.gov identifier, NCT01980966.
PMID: 28639229 DOI: 10.1007/s40262-017-0564-y