Pharmacodynamic evaluation of RWJ-270201, a novel neuraminidase inhibitor,in a lethal murine model of influenza predicts efficacy for once-daily dosing

We examined RWJ-270201 in a lethal model of influenza in BALB/c mice. The a im was to delineate the pharmacodynamically linked variable for the drug. C hallenge was performed with influenza virus A/Shong- dong/09/93 (H3N2). Tre atment was administered by gavage. Five doses (1 to 10 mg/kg of body weight ) and three schedules (every 24, 12, and 8 h) were evaluated with 10 mice p er group. There were 39 placebo-treated mice. Drug exposure was evaluated f or infected mice. Exposures were calculated after population modeling of al l the plasma concentration-time data simulataneously using the NPEM3 progra m. Evaluation of dose and schedule with Kaplan-Meier analysis and Cox propo rtional hazards modeling demonstrated that schedule offered no explanatory power relative to dose alone. Evaluation of peak concentration, trough conc entration, and area under the concentration-time curve (AUC) by the same me thods revealed that AUC was the dynamically linked variable. Again, schedul e offered no further explanatory power when included in the model with AUG. This indicates that AUC is the linked variable and that the anti-influenza effect of RWJ-270201 is independent of schedule. We conclude that once-dai ly dosing of RWJ-270201 should be evaluated in clinical trials of influenza therapy.