Safety and pharmacokinetics of rimantadine small-particle aerosol

Abstract

The safety and pharmacokinetics of rimantadine administered by small-particle aerosol were assessed in healthy adults and adults with acute influenza virus infection. Aerosolized rimantadine delivered at a concentration of 40 ,Ig/liter of air was associated with nasal burning and irritation in normal volunteers. A concentration of 20 ,ug/liter of air was well tolerated for up to 12 h by normal volunteers and was not associated with any changes in pulmonary function, as measured by routine spirometry, plethysmography, or diffusion capacity of carbon monoxide. Mean peak levels of drug in serum were approximately 10-fold lower after 12 h of aerosol administration than they were after oral administration of 200 mg (29.7 versus 255 ng/ml, respectively), while mean nasal wash levels were approximately 100-fold higher (6,650 versus 66.6 ng/ml, respectively). Elimination half-lives were similar after both aerosol and oral administration (24.1 and 25.2 h, respectively), and rimantadine urinary excretion was <1% per 24 h in both groups. Twenty micrograms of aerosolized rimantadine per liter of air given 12 h daily for 3 days to nine adults with acute influenza virus infection was well tolerated. Levels in plasma after 12 h of aerosol inhalation were similar to those in normal volunteers, but were higher at the end of the third treatment than they were at the end of the first treatment (88.3 versus 47.9 ng/ml, respectively). Thus, rimantadine delivered via small-particle aerosol at a dose of 20 jig/liter of air was well tolerated in normal volunteers and in those with acute influenza and was associated with high local concentrations.Small-particle aerosol (SPA) delivery of antiviral agents was evaluated for the treatment of viral respiratory tract infections. This method of drug administration usually results in higher concentrations of drug at the site of infection than systemic administration does, may decrease or ameliorate systemic toxicities seen after systemic administration, and has been more effective than the systemic administration of antiviral agents in murine (31) and ferret (9) animal models of acute influenza virus infection. SPA delivery of antiviral agents has also been effective in the treatment of human respiratory viral diseases (13,14,17,22,24,28).Rimantadine has better antiviral activity against some influenza A virus strains than amantadine does (5), is better tolerated when taken orally (8), and is effective as a prophylactic (8, 35) and therapeutic (20,26,30,34,35) agent in influenza A virus infections. Hayden et al. (22) have previously reported the use of rimantadine delivered by ultrasonic nebulizer in subjects given an attenuated influenza A virus; except for minor complaints, the drug was well tolerated. No pharmacokinetic data were reported.Although the combination of amantadine or rimantadine with ribavirin has been shown to have additive or synergistic activity in vitro (6, 21) and when administered systemically in a murine model of acute influenzal pneumonia (11, 33), only the combination o...

In Vitro and In Vivo Activities of Aminoadamantane and Aminoalkylcyclohexane Derivatives against Trypanosoma brucei

“…Pharmacokinetic data are not available for most of the compounds used in the study described in this report, but both amantadine and rimantadine have been well studied. Steady-state levels in serum of 0.5 to 1.0 g ml Ϫ1 (2.5 to 5.0 M) and above and serum half-lives of between 24 and 36 h have been widely reported (1,2,9,14,26). In addition, the drugs readily gain access to the central nervous system (22).…”

Efficacy of Ion-Channel Inhibitors Amantadine, Memantine and Rimantadine for the Treatment of SARS-CoV-2 In Vitro

“…Moreover, adamantane derivatives appear to largely distribute to the lungs, with lung tissue concentrations above Cmax ( Table S4 ). Finally, inhibitor concentrations in the respiratory tract might be further increased by the improvement of formulations allowing topical administration by inhalation [ 23 ]. Therefore, while cell culture systems provide a useful tool for determining antiviral effect and the potency of compounds in a time- and cost-effective manner, future in vivo studies would be useful to determine the clinical potential of ion-channel inhibitors for the treatment of COVID-19.…”