Rimantadine clinical pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Clinical Pharmacology
MECHANISM OF ACTION: The mechanism of action of rimantadine is not fully understood. Rimantadine appears to exert its inhibitory effect early in the viral replicative cycle, possibly inhibiting the uncoating of the virus. Genetic studies suggest that a virus protein specified by the virion M2 gene plays an important role in the susceptibility of influenza A virus to inhibition by rimantadine.
MICROBIOLOGY: Rimantadine is inhibitory to the in vitro replication of influenza A virus isolates from each of the three antigenic subtypes, i.e., H1N1, H2N2 and H3N2, that have been isolated from man. Rimantadine has little or no activity against influenza B virus (Ref. 1,2). Rimantadine does not appear to interfere with the immunogenicity of inactivated influenza A vaccine.
A quantitative relationship between the in vitro susceptibility of influenza A virus to rimantadine and clinical response to therapy has not been established.
Susceptibility test results, expressed as the concentration of the drug required to inhibit virus replication by 50% or more in a cell culture system, vary greatly (from 4 ng/mL to 20 μg/mL) depending upon the assay protocol used, size of the virus inoculum, isolates of the influenza A virus strains tested, and the cell types used (Ref. 2).
Rimantadine-resistant strains of influenza A virus have emerged among freshly isolated epidemic strains in closed settings where rimantadine has been used. Resistant viruses have been shown to be transmissible and to cause typical influenza illness. (Ref. 3)
PHARMACOKINETICS: Although the pharmacokinetic profile of Flumadine has been described, no pharmacodynamic data establishing a correlation between plasma concentration and its antiviral effect are available.
The tablet and syrup formulations of Flumadine are equally absorbed after oral administration. The mean ± SD peak plasma concentration after a single 100 mg dose of Flumadine was 74 ± 22 ng/mL (range: 45 to 138 ng/mL). The time to peak concentration was 6 ± 1 hours in healthy adults (age 20 to 44 years). The single dose elimination half-life in this population was 25.4 ± 6.3 hours (range: 13 to 65 hours). The single dose elimination half-life in a group of healthy 71 to 79 year-old subjects was 32 ± 16 hours (range: 20 to 65 hours).
After the administration of rimantadine 100 mg twice daily to healthy volunteers (age 18 to 70 years) for 10 days, area under the curve (AUC) values were approximately 30% greater than predicted from a single dose. Plasma trough levels at steady state ranged between 118 and 468 ng/mL. In these patients no age-related differences in pharmacokinetics were detected. However, in a comparison of three groups of healthy older subjects (age 50-60, 61-70 and 71-79 years), the 71 to 79 year-old group had average AUC values, peak concentrations and elimination half-life values at steady state that were 20 to 30% higher than the other two groups. Steady-state concentrations in elderly nursing home patients (age 68 to 102 years) were 2- to 4-fold higher than those seen in healthy young and elderly adults.
The pharmacokinetic profile of rimantadine in children has not been established. In a group (n=10) of children 4 to 8 years old who were given a single dose (6.6 mg/kg) of Flumadine syrup, plasma concentrations of rimantadine ranged from 446 to 988 ng/mL at 5 to 6 hours and from 170 to 424 ng/mL at 24 hours. In some children drug was detected in plasma 72 hours after the last dose.
Following oral administration, rimantadine is extensively metabolized in the liver with less than 25% of the dose excreted in the urine as unchanged drug. Three hydroxylated metabolites have been found in plasma. These metabolites, an additional conjugated metabolite and parent drug account for 74 ± 10% (n=4) of a single 200 mg dose of rimantadine excreted in urine over 72 hours.
In a group (n=14) of patients with chronic liver disease, the majority of whom were stabilized cirrhotics, the pharmacokinetics of rimantadine were not appreciably altered following a single 200 mg oral dose compared to 6 healthy subjects who were sex, age and weight matched to 6 of the patients with liver disease. After administration of a single
200 mg dose to patients (n=10) with severe hepatic dysfunction, AUC was approximately 3-fold larger, elimination half-life was approximately 2-fold longer and apparent clearance was about 50% lower when compared to historic data from healthy subjects.
Studies of the effects of renal insufficiency on the pharmacokinetics of rimantadine have given inconsistent results. Following administration of a single 200 mg oral dose of rimantadine to 8 patients with a creatinine clearance (CLcr) of 31-50 mL/min and 6 patients with a CLcr of 11-30 mL/min, the apparent clearance was 37% and 16% lower, respectively, and plasma metabolite concentrations were higher when compared to weight-, age-, and sex-matched healthy subjects (n=9, CLcr > 50 mL/min). After a single 200 mg oral dose of rimantadine was given to 8 hemodialysis patients (CLcr 0-10 mL/min), there was a 1.6-fold increase in the elimination half-life and a 40% decrease in apparent clearance compared to age-matched healthy subjects. Hemodialysis did not contribute to the clearance of rimantadine. The in vitro human plasma protein binding of rimantadine is about 40% over typical plasma concentrations. Albumin is the major binding protein.[1]
References
Adapted from the FDA Package Insert.