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Antimicrobial Agents and Chemotherapy, July 2001, p. 2115-2118, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2115-2118.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Pharmacodynamic Evaluation of RWJ-270201, a Novel Neuraminidase Inhibitor, in a Lethal Murine Model of Influenza Predicts Efficacy for Once-Daily Dosing

G. L. Drusano,^1,* S. L. Preston,¹ D. Smee,² K. Bush,³ K. Bailey,² and R. W. Sidwell²

Division of Clinical Pharmacology, Clinical Research Initiative, Albany Medical College, Albany, New York,¹ Utah State University, Logan, Utah,² and The R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey³

Received 21 November 2000/Returned for modification 1 April 2001/Accepted 24 April 2001

We examined RWJ-270201 in a lethal model of influenza in BALB/c mice. The aim was to delineate the pharmacodynamically linked variable for the drug. Challenge was performed with influenza virus A/Shongdong/09/93 (H3N2). Treatment 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 per group. There were 39 placebo-treated mice. Drug exposure was evaluated for infected mice. Exposures were calculated after population modeling of all the plasma concentration-time data simulataneously using the NPEM3 program. Evaluation of dose and schedule with Kaplan-Meier analysis and Cox proportional hazards modeling demonstrated that schedule offered no explanatory power relative to dose alone. Evaluation of peak concentration, trough concentration, and area under the concentration-time curve (AUC) by the same methods revealed that AUC was the dynamically linked variable. Again, schedule offered no further explanatory power when included in the model with AUC. 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-daily dosing of RWJ-270201 should be evaluated in clinical trials of influenza therapy.

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^* Corresponding author. Mailing address: Division of Clinical Pharmacology, Clinical Research Institute, Albany Medical College, Albany, NY 12208. Phone: (518) 262-6330. Fax: (518) 262-6333. E-mail: GLDRUSANO{at}AOL.COM

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Antimicrobial Agents and Chemotherapy, July 2001, p. 2115-2118, Vol. 45, No. 7
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.7.2115-2118.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

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