Rimantadine clinical pharmacology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Clinical Pharmacology
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.