Safety and efficacy of intranasal pirodavir (R77975) in experimental rhinovirus infection

Abstract

Pirodavir (R77975) is a capsid-binding, antipicornaviral agent with in vitro activity against most rhinovirus (RV) serotypes. We conducted four double-blind, controlled trials to assess the efficacy of intranasal pirodavir in experimentally induced RV infection of susceptible volunteers. Intranasal pirodavir (2 mg per dose) or the hydroxypropyl-13-cyclodextxin vehicle as a placebo was given by metered pump spray. In three prophylaxis trials, subjects were inoculated with RV within 10 min of the second and third doses. When sprays were given six times per day for a total of 25 doses, infection, detected by either virus shedding or seroconversion, developed in 100%o of the 13 placebo-treated subjects and 58% of the 12 pirodavir-treated subjects (P = 0.015). Clinical colds developed in 54% of placebo-treated subjects and 8% of pirodavir-treated subjects during drug administration (efficacy = 85%, P = 0.03), although late-developing colds developed in several subjects in both groups. Significant reductions in morning symptom scores and in the frequency of abnormal middle-ear pressures were also found in the pirodavir group. In contrast, in two prophylaxis studies using three doses daily, no significant antiviral or clinical benefits were observed. When frequent sprays were initiated at 24 h after RV challenge, significant reductions in virus shedding but no clinical benefits were found. Intranasal pirodavir was generally well tolerated but was associated with an excess rate of transient unpleasant taste. The findings indicated that frequent intranasal sprays of pirodavir were effective in preventing experimentally induced RV illness.

An Orally Available 3-Ethoxybenzisoxazole Capsid Binder with Clinical Activity against Human Rhinovirus

“…14 While effective in experimental challenge studies when administered very frequently intranasally, 15,16 the ester functionality of pirodavir 2 has been shown to undergo facile hydrolysis in vivo to the carboxylic acid, which is inactive, 17 and this ease of hydrolysis renders the molecule unsuitable for oral administration.…”

Antipicornavirus Drugs: Current Status

“…Pirodavir was found to bind to the capsid protein in the same hydrophobic pocket as the WlN compounds and other related inhibitors (Chapman et al, 1991;Shepard et al, 1993). When administered intranasally six times a day for 5 days to patients with naturally occurring colds, an effect on virus shedding was observed; however, no clinical benefit resulted (Hayden et al, , 1993. Presumably, the lack of a clinical effect was the result of the rapid hydrolysis of the ester to the corresponding acid, which was inactive.…”

“…Several virus-specific compounds have been clinically evaluated 402 against both rhinovirus (Turner & Hayden, 1992;Hayden et al, 1992Hayden et al, , 1993 and enterovirus infections (Schiff et al, (Turner et al, 1989;Monto et al, 1989) and bradykinin antagonists (Higgins et al, 1990) have been unsuccessful. This review will focus on the current status in this area of antiviral chemotherapy and will include the results of clinical trials where available, as well as recently discovered compounds which are active against this family of viruses.…”

Antiviral Therapy for Enteroviruses and Rhinoviruses

“…Certain compounds demonstrate both anti-EV and anti-RV activity (Otto et al, 1985;Pevear, 1999), others are more selective to one picornavirus genus or the other (Buontempo et al, 1997;Cox et al, 1996). Trials of the 'R' series of capsid-binding compounds have been limited to intranasal administration to patients with RV colds (Al-Nakib et al, 1989;Barrow et al, 1990;Hayden et al, 1992). Pirodavir (R77975) and R61837 were efficacious in experimentally-induced RV colds when these drugs were administered intranasally before or after infection, but prior to onset of symptoms (Barrow et al, 1990;Hayden et al, 1992); pirodavir required six times daily dosing, with efficacy loss at three daily doses (Hayden et al, 1992).…”

“…Trials of the 'R' series of capsid-binding compounds have been limited to intranasal administration to patients with RV colds (Al-Nakib et al, 1989;Barrow et al, 1990;Hayden et al, 1992). Pirodavir (R77975) and R61837 were efficacious in experimentally-induced RV colds when these drugs were administered intranasally before or after infection, but prior to onset of symptoms (Barrow et al, 1990;Hayden et al, 1992); pirodavir required six times daily dosing, with efficacy loss at three daily doses (Hayden et al, 1992). Another series of capsid-binding compounds, the phenoxyl imidazoles, are broad spectrum inhibitors of the EVs and demonstrate therapeutic oral efficacy in animal models (Buontempo et al, 1997;Cox et al, 1996).…”