Comparative single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride in young and elderly adults

Abstract

The single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride were compared in a randomized, two-period, crossover study involving six young (<35 years) and six elderly (.60 years) adults. Subjects ingested single 200-mg oral doses after an overnight fast, and serial plasma (0 to 96 h), nasal mucus (0 to 8 h), and urine (0 to 24 h) samples were collected for assay of drug concentration by electron capture gas chromatography. For both groups combined, rimantadine differed significantly from amantadine in peak plasma concentration (mean standard deviation, 0.25 ± 0.06 versus 0.65 0.22 ,ug/ml), plasma elimination half-life (36.5 15 versus 16.7 ± 7.7 h), and percentage of administered dose excreted unchanged in urine (0.6 0.8 versus 45.7 + 15.7%). No significant age-related differences were noted for rimantadine. Urinary excretion (0 to 24 h) of rimantadine and its hydroxylated metabolites averaged 19% of the administered dose. The maximum nasal mucus drug concentration was similar for both drugs (0.42 + 0.25 versus 0.45 0.32 ,ug/g), and the ratio of maximum nasal mucus to plasma concentration was over twofold higher after rimantadine than after amantadine. These findings may in part explain the clinical effectiveness of rimantadine in influenza A virus infections at dosages that have lower toxicity than those of amantadine.The adamantane compounds, amantadine hydrochloride and rimantadine hydrochloride, have well-documented prophylactic and therapeutic efficacy in influenza A virus infections (5, 21). Limited in vitro and animal model results suggest that rimantadine has greater influenza A virusinhibitory activity than amantadine (7,15,19). More importantly, clinical studies have found that at equivalent oral dosages of 200 mg (5) or 300 mg (8) per day rimantadine is associated with significantly fewer central nervous system side effects than amantadine. The differences in side effect rates observed between the two drugs appear to be related to differences in plasma concentrations (8). Whereas amantadine pharmacokinetics have received extensive study (1-4, 9, 17), the pharmacokinetics of oral rimantadine have not been delineated. Limited results in healthy adults indicate that rimantadine is associated with significantly lower plasma concentrations after single or multiple doses (8) and has a longer plasma half-life and lower urinary excretion than amantadine (20). In addition, the pharmacokinetics of these drugs have not been defined in the elderly, one of the target populations for the prevention of influenza A virus infections.The current study was conducted to determine the comparative single-dose pharmacokinetics of amantadine and rimantadine in both young and elderly adults. This study also incorported collection of nasal mucus samples to determine concentrations of these drugs in respiratory secretions after systemic administration.MATERIALS AND METHODS Study design. This study was a randomized, open-label, two-treatment, crossover study in which rimantadine and amantadine were ...

Multiple-dose pharmacokinetics of rimantadine in elderly adults

“…Only in time to Cmax did our study population differ from the younger adult population (2.5 and 1.9 h for the first and last doses, respectively, for our study population). The average time to Cmax of 4.0 h seen after a single 200-mg dose in elderly adults (9) is likewise longer than that observed in our study. In contrast to earlier studies, our study allowed volunteers to eat breakfast shortly after dosing.…”

“…However, this correlation has not been directly established. A previous study of rimantadine given at a single dose to volunteers suggested that rimantadine, unlike its relative, amantadine, may concentrate in respiratory secretions (9). In that short-term study (9) the ratio of concentration in nasal mucus to that in plasma peaked at 1.7 ± 1.1 (mean ± SD) at 8 h after administration.…”

“…This advantage may be attributable, in part, to the different pharmacokinetic profile of rimantadine. In an earlier study comparing the single-dose kinetics of amantadine and rimantadine in young (<35 years) and elderly (.60 years) subjects, rimantadine showed a significantly longer elimination half-life, lower peak concentration in plasma, and a larger volume of distribution compared with amantadine for both age groups (9). The same study (9) also predicted that the mean peak and trough rimantadine concentrations in plasma at steady-state would be 490 and 280 ng/ml, respectively, for elderly subjects.…”

“…Despite their chemical similarities, rimantadine differs from amantadine in having lower concentrations in plasma, longer elimination half-life in plasma, and more complex metabolic disposition (1-3, 9, 10, 19). Previous studies (1,9,19,20) have characterized the single-dose kinetics of rimantadine in children and in both young and elderly adults, and their findings suggest that rimantadine pharmacokinetics in elderly, ambulatory adults do not differ substantially from those in younger adults and that dosage adjustments are unnecessary for older adults. However, several long-term prophylaxis studies with elderly nursing-home patients showed that rimantadine at the conventional dosage (200 mg/ day) is associated both with much higher concentrations in plasma than predicted by the earlier single-dose pharmacokinetic studies and with an excess of adverse reactions (13; R. Dolin After fasting overnight, the subjects reported to the Clinical Research Center where they received a 100-mg rimantadine tablet with 240 ml of water immediately prior to a standard breakfast.…”

“…However, at the commonly used dosage of 200 mg/day, rimantadine causes significantly fewer adverse central nervous system (CNS) effects compared with amantadine (5,7,8,18). The lower risk of CNS toxicity associated with rimantadine is related in part to differences in the pharmacokinetics of the drugs (8,9). Despite their chemical similarities, rimantadine differs from amantadine in having lower concentrations in plasma, longer elimination half-life in plasma, and more complex metabolic disposition (1-3, 9, 10, 19).…”