title: A drug-disease model describing the effect of oseltamivir neuraminidase inhibition on influenza virus progression.
abstract: A population drug-disease model was developed to describe the time course of influenza virus with and without oseltamivir treatment and to investigate opportunities for antiviral combination therapy. Data included viral titers from 208 subjects, across 4 studies, receiving placebo and oseltamivir at 20 to 200 mg twice daily for 5 days. A 3-compartment mathematical model, comprising target cells infected at rate β, free virus produced at rate p and cleared at rate c, and infected cells cleared at rate δ, was implemented in NONMEM with an inhibitory Hill function on virus production (p), accounting for the oseltamivir effect. In congruence with clinical data, the model predicts that the standard 75-mg regimen initiated 2 days after infection decreased viral shedding duration by 1.5 days versus placebo; the 150-mg regimen decreased shedding by an additional average 0.25 day. The model also predicts that initiation of oseltamivir sooner postinfection, specifically at day 0.5 or 1, results in proportionally greater decreases in viral shedding duration of 5 and 3.5 days, respectively. Furthermore, the model suggests that combining oseltamivir (acting to subdue virus production rate) with an antiviral whose activity decreases viral infectivity (β) results in a moderate additive effect dependent on therapy initiation time. In contrast, the combination of oseltamivir with an antiviral whose activity increases viral clearance (c) shows significant additive effects independent of therapy initiation time. The utility of the model for investigating the pharmacodynamic effects of novel antivirals alone or in combination on emergent influenza virus strains warrants further investigation.
authors.affiliation: Department of Clinical Pharmacology, Roche Pharmaceutical Research and Early Development, New York City, New York, USA mohamed.kamal@roche.com.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Kamal
authors.affiliation: Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Ronald
authors.initials: R
authors.lastname: Gieschke
authors.affiliation: Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Annabelle
authors.initials: A
authors.lastname: Lemenuel-Diot
authors.affiliation: Department of Physics, Ryerson University, Toronto, Ontario, Canada.
authors.forename: Catherine A A
authors.initials: CA
authors.lastname: Beauchemin
authors.affiliation: d3 Medicine LLC, Parsippany, New Jersey, USA University at Buffalo, School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York, USA.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Smith
authors.affiliation: d3 Medicine LLC, Parsippany, New Jersey, USA Monash Institute of Pharmaceutical Sciences, Melbourne, Australia.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Rayner
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D008954:Models, Biological; D009439:Neuraminidase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology*; D053139:Oseltamivir / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D053139:Oseltamivir; D009439:Neuraminidase