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

Abstract

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.Influenza virus infections caused by both A and B strains continue to be a cause of morbidity and mortality, particularly for patients who are elderly or otherwise immunocompromised (2, 9).The viral neuraminidase is a logical target for antiviral chemotherapy, as it is readily accessible and is a necessary site for ongoing spread of viral infection. In addition, this enzyme is appealing as a target for chemotherapy because it would be expected to affect clinical outcome, even after infection initiation, because of its ability to interrupt viral spread. Further, it differs from older agents like amantadine and rimantadine in having a lower probability of viral emergence of resistance (7).RWJ-270201 is a new, potent member of the neuraminidase inhibitor class of influenza antivirals. Other members of this class currently available to the physician have been well reviewed (1). Previous studies with mice have demonstrated a pharmacokinetic profile that produced sufficient exposure to conclude that this agent would be useful for the therapy of influenza infection (data on file, R. W. Johnson Pharmaceutical Research Institute, Raritan, N.J.).Experience with other classes of anti-infectives has demonstrated that animal model experiments that delineate which pharmacodynamic variable (peak concentration/50% inhibitory concentration [IC 50 The ability to delineate which aspect of the concentrationtime curve affects outcome is extremely valuable, as it allows the choice of the proper dosing schedule and facilitates the setting of a therapeutic goal. For these reasons, we decided to investigate RWJ-270201 in a lethal murine model of influenza infection and attempt to delineate the pharmacodynamic variable most closely linked to outcome. MATERIALS AND METHODS Virus....

Phenotypic Drug Susceptibility Assay for Influenza Virus Neuraminidase Inhibitors

“…Peramivir has in vitro and in vivo activities equal to or greater than those of zanamivir and oseltamivir carboxylate against a number of influenza type A and B viruses (2,4,5,10,18,(46)(47)(48)(49). The compound is bioavailable after oral treatment and can be given once a day (1,10,18,51). In addition to the NA inhibitors, cyanovir-N, an inhibitor of the influenza virus HA, is also under development (41).…”

“…The pyrrolidinebased compound A-315675, the pyrazinecarboximide-based compound T-750, and the cyclopentane peramivir (RWJ-270201) are under study for their activities against influenza type A and B viruses (1,12,26,27,38). Peramivir has in vitro and in vivo activities equal to or greater than those of zanamivir and oseltamivir carboxylate against a number of influenza type A and B viruses (2,4,5,10,18,(46)(47)(48)(49). The compound is bioavailable after oral treatment and can be given once a day (1,10,18,51).…”

Prediction of the Pharmacodynamically Linked Variable of Oseltamivir Carboxylate for Influenza A Virus Using an In Vitro Hollow-Fiber Infection Model System

“…For this and other reasons, clinical validation for these findings should be sought. It should be noted, however, that the pharmacodynamically linked variable in an animal model for the neuraminidase inhibitor peramivir was also the AUC/EC 50 ratio (17).…”

RWJ-270201 (BCX-1812): a novel neuraminidase inhibitor for influenza

“…In the murine e¤cacy studies described above, RWJ-270201 was administered according to the same schedule used for oseltamivir, namely twice-daily dosing. However, the pharmacodynamic evaluation of RWJ-270201 in the murine in£uenza model predicted the e¡ec-tiveness of once-daily dosing (Drusano et al 2001). In order to understand the pharmacodynamic relationships between the dose and schedule of administration in mice better, BALB/c mice were challenged with in£uenza A/ Shangdong/09/93 (H3N2) and then were treated with ¢ve doses of placebo or RWJ-270201 (1^10 mg kg 71 d 71 ) administered every 8, 12 or 24 h. Treated animals were monitored for day of death compared with untreated, infected mice.…”