Safety of prolonged administration of rimantadine hydrochloride in the prophylaxis of influenza A virus infections in nursing homes

To assess the possible effect of aging on rimantadine hydrochloride pharmacokinetics, single-and multiple-dose kinetics were determined in 18 healthy adults with ages between 51 and 79 years. Subjects ingested single 100-mg oral doses of rimantadine after an overnight fast, followed after 5 days by a dosage of 100 mg twice a day for 9.5 days. No differences were observed among the age-stratffied groups in measured or derived pharmacokinetic parameters. Peak concentrations in plasma (mean ± standard deviation) following the single-and multiple-dose regimens, respectively, were 89 ± 25 and 417 ± 129 ng/ml for subjects who were 50 to 60 years of age (group 1), 92 ± 24 and 401 ± 84 ng/ml for those 61 to 70 years of age (group 2), and 10014 and 538 ± 51 for those 71 to 79 years of age (group 3). The elimination half-life in plasma following multiple doses averaged 33.5 h for group 1, 32.5 h for group 2, and 38.6 h for group 3. Steady-state concentrations in nasal mucus developed by day 5 of dosing (1.5-fold higher than concentrations in plasma), and rimantadine remained detectable in secretions for 5 days after the last dose in 65% of subjects. Stepwise regression analysis suggested that changes in maximum concentration in plasma and area under the concentration-time curve at steady state may be related to creatinine clearance. The results indicate that no important differences in rimantadine multiple-dose pharmacokinetics exist among healthy elderly adults with ages between 51 and 79 years.Rimantadine (ot-methyl-1-adamantanemethylamine hydrochloride) shares similar antiviral activity in vitro and clinical efficacy in influenza A virus infections with its analog amantadine (5, 15-18, 22, 23). 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). 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 imm...

Section: Discussionmentioning

confidence: 75%

“…One female (subject 12) developed an acute purulent bronchitis on day 16 of the study that was associated with premature ventricular contractions. She was treated with oral antimicrobial agents.…”

Section: Resultsmentioning

confidence: 99%

Multiple-dose pharmacokinetics of rimantadine in elderly adults

Tominack

Wills

Gustavson

et al. 1988

“…However, there is evidence that the therapeutic index for rimantadine is wide. Patriarca et al (8) reported no correlations between adverse experiences and rimantadine concentrations in serum which ranged from 634 to 2,600 ng/ml 3 to 4 h after the last dose of a 100-mg-twice-daily 10-day regimen. Similarly, there were no correlations between rimantadine concentrations in serum in excess of 1,000 ng/ml and adverse events in studies conducted by the Rochester group (R. Betts and R. Dolin, personal communication).…”

Section: Resultsmentioning

confidence: 99%

Effect of cimetidine on the disposition of rimantadine in healthy subjects

Holazo

Choma

Brown

et al. 1989

Twenty-three healthy male and female subjects received single 100-mg oral doses of rimantadine hydrochloride on two occasions in an open-label, sequential design with a 6-day washout between doses. The first dose of rimantadine was administered alone, and the second dose was administered concomitantly with cimetidine (300 mg four times a day for 6 days). Blood and urine samples were collected, and rimantadine concentrations were determined by a gas-chromatographic-mass-spectrometric method. There were no changes in the rate of absorption and the renal clearance of rimantadine when it was administered with cimetidine. Both parametric and nonparametric tests showed significant differences in the area under the concentration-time curve, apparent total clearance, and elimination rate constant between the treatments (P < 0.01). The apparent total clearance was reduced by 18%, resulting in higher values for the area under the concentration-time curve in the presence of cimetidine. However, the wide therapeutic index of rimantadine renders these changes of little, if any, clinical consequence.Rimantadine (oc-methyl-l-adamantanemethylamine hydrochloride), an analog of amantadine with equipotent antiviral activity (5, 6), is being evaluated for prophylaxis and treatment against influenza A viral infections (1, 2, 8-10, 13, 17). Rimantadine is extensively metabolized by the liver, and renal excretion of the parent drug and its metabolites is the major pathway of elimination (4, 14-16). Drugs which affect the hepatic microsomal enzyme systems have the potential for altering the metabolism of rimantadine, since the major pathway is hydroxylation. The histamine H2 receptor antagonist cimetidine is known to have an inhibitory effect on hepatic oxidative drug-metabolizing enzymes (12). Since rimantadine may be prescribed for patients taking cimetidine, the potential metabolic interaction between these two drugs provided the rationale for investigating the effect of cimetidine on the disposition of rimantadine. The aim of the present study was to compare the disposition of rimantadine after single 100-mg oral doses of rimantadine hydrochloride before and during cimetidine treatment in healthy subjects. MATERIALS AND METHODSTwenty-three healthy subjects (20 male and 3 female), ranging in age from 22 to 45 years and ranging in weight from 57 to 89 kg, participated in this study after giving their written, informed consent. Only females of non-child-bearing potential were admitted into the study. The subjects were in good general health as determined by base-line history, physical examination, hematologic examination, urinalysis, and determination of serum chemistries. The use of alcohol and over-the

“…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).…”

Section: Discussionmentioning

confidence: 99%

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

Kelly

Quack

Miles

2001

We reported recently that the bloodstream form of the African trypanosome, Trypanosoma brucei, is sensitive to the anti-influenza virus drug rimantadine. In the present report we describe the trypanocidal properties of a further 62 aminoadamantane and aminoalkylcyclohexane derivatives. Seventeen of the compounds were found to be more active than rimantadine, with four inhibiting growth in vitro of T. brucei by >90% at concentrations of 1 M. The most active derivative (1-adamantyl-4-amino-cyclohexane) was about 20 to 25 times more effective than rimantadine. We observed a correlation between structural features of the derivatives and their trypanocidal properties; hydrophobic substitutions to the adamantane or cyclohexane rings generally enhanced activity. As with rimantadine, the activity in vitro varied with the pH. T. brucei was more sensitive in an alkaline environment (including a normal bloodstream pH of 7.4) and less sensitive under acidic conditions. Tests for activity in vivo were carried out with a mouse model of infection with a virulent strain of T. brucei. Although the parasitemia was not eliminated, it could be transiently suppressed by >98% with the most active compounds tested. These results suggest that aminoadamantane derivatives could have potential as a new class of trypanocidal agents.