Evaluation of the impact of sulfobutylether7 -ß-cyclodextrin on the liquid chromatography-mass spectrometry analysis of biological samples arising from in vivo pharmacokinetic studies.

The utility of cyclodextrin (CD) complexation in improving apparent solubility of drugs in parenteral formulations is well established. Administration of these formulations delivers CD directly into the systemic circulation, and it may be necessary to demonstrate unaltered in vivo disposition of a drug coadministered with a CD. Crucial to the undertaking of such a study is the need for bioanalytical assays in which CD presence does not impact drug quantitation. This is of particular importance when assessing the potential impact of in vivo CD complexation on the urinary excretion of a drug, as CDs are predominantly eliminated via glomerular filtration, and hence are present in urine at significantly higher concentration than would be present in blood and plasma. Of 23 publications (in the past 30 years) describing preclinical and clinical assessment of drug pharmacokinetics after i.v. administration of CD-enabled formulations, only two reports clearly stated that the presence of CD had no impact on assay performance. In this work, we describe the simple process involved in (1) predicting the maximum concentrations of a modified CD, sulfobutylether7 -ß-CD (SBE7 -ß-CD), in plasma and urine samples from preclinical studies, and (2) evaluating the impact of SBE7 -ß-CD on the quantitative liquid chromatography-mass spectrometry analysis of rimantadine.

The effect of intravenous sulfobutylether7 -ß-cyclodextrin on the pharmacokinetics of a series of adamantane-containing compounds.

Intravenously administered (i.v.) drug-cyclodextrin (CD) inclusion complexes are generally expected to dissociate rapidly and completely, such that the i.v. pharmacokinetic profile of a drug is unchanged in the presence of CD. The altered pharmacokinetics of a synthetic ozonide in rats has been attributed to an unusually high-binding affinity (2.3 × 10(6) M(-1) ) between the drug and sulfobutylether7 -ß-cyclodextrin (SBE7 -ß-CD) with further studies suggesting a significant binding contribution from the adamantane ring. This work investigated the binding affinity of three adamantane derivatives [amantadine (AMA), memantine (MEM) and rimantadine (RIM)] to SBE7 -ß-CD and the impact of complexation on their i.v. pharmacokinetics. In vitro studies defined the plasma protein binding, as well as the impact of SBE7 -ß-CD on erythrocyte partitioning of each compound. SBE7 -ß-CD binding constants for the compounds were within the typical range for drug-like molecules (10(2) -10(4) M(-1) ). The pharmacokinetics of AMA and MEM were unchanged; however, significant alteration of RIM plasma and urinary pharmacokinetics was observed when formulated with CD. In vitro studies suggested two factors contributing to the altered pharmacokinetics: (1) low plasma protein binding of RIM, and (2) decreased erythrocyte partitioning in the presence of high SBE7 -ß-CD concentrations. This work demonstrated the potential for typical drug-cyclodextrin interactions to alter drug plasma pharmacokinetics.

Absence of pharmacokinetic interaction between intravenous peramivir and oral oseltamivir or rimantadine in humans.

Peramivir, an intravenously administered neuraminidase inhibitor, may be used concomitantly with other influenza antivirals. Two studies were conducted to assess the potential for pharmacokinetic interactions of peramivir when coadministered with oseltamivir or rimantadine. Twenty-one healthy subjects were enrolled in each randomized, open-label, crossover study, and they received 1 intravenous dose of peramivir (600 mg), 1 oral dose of oseltamivir (75 mg) or rimantadine (100 mg), or a combination of peramivir with oseltamivir or rimantadine. Assessment of the 90% confidence interval for the geometric mean ratio of peramivir and oseltamivir carboxylate or rimantadine pharmacokinetic parameters showed no effect of oseltamivir or rimantadine on the pharmacokinetics of peramivir and no effect of peramivir on the pharmacokinetics of oseltamivir carboxylate or rimantadine. The drugs were well tolerated. These results suggest no reason to expect an effect of concomitant administration of oseltamivir or rimantadine on the safety profile of peramivir in patients with influenza.

Pharmacokinetics and safety of coadministered oseltamivir and rimantadine in healthy volunteers: an open-label, multiple-dose, randomized, crossover study.

Preclinical data suggest increased antiviral activity and less viral resistance when neuraminidase inhibitors and adamantanes are used in combination to harness the complementary effects of their different mechanisms of action. Healthy volunteers were randomized to 5-day oral treatment with oseltamivir 75 mg or rimantadine 100 mg twice daily as monotherapy or to combination treatment. Each participant received all 3 regimens in 1 of 6 treatment sequences, with a minimum of 7 days' washout between periods. Final follow-up was 10 to 14 days after the final dose. Drug exposure, elimination, safety, and tolerability were assessed. There were no clinically relevant differences in 12-hour areas under the concentration-time curves of drug in plasma or peak plasma drug concentrations with combination versus monotherapy. Elimination half-life was unaffected by coadministration. There were no safety/tolerability concerns. One case of vomiting and 1 of paresthesia were considered remotely related to combination treatment, and 1 episode of toothache and 1 of acne were considered unrelated. There were no serious adverse events and no deaths. Combination therapy with oseltamivir and rimantadine at recommended dosages in adults had no discernible effect on the pharmacokinetics of either drug and raised no tolerability issues.

[Comparative pharmacokinetics of antigrippin-maximum administered in capsules and powder for preparing solutions].

Comparative pharmacokinetics of anti-influenza drug composition Antigrippin-maximum administered in capsules and a powder for preparing solutions has been studied after single administraton in a group of 18 healthy volunteers. Both preparations [manufactured by the Antiviral Research and Production Corporation (St Petersbutg) contain 6 active components, including paracetamol, rimantadine, loratadine, ascorbic acid, calcium gluconate, and rutoside in equal amounts. The concentrations of unchanged paracetamol, rimantadine, and loratadine in the blood plasma were degtermined by HPLC with mass-spectrometric and UV detection. The pharmacokinetic parameters of allindicated active components exhibited no detectable distinctions, except for the time to attaining maximum concentration ofparacetamol and the value of the maximum concentration of loratadine.

Determination of rimantadine in rat plasma by liquid chromatography/electrospray mass spectrometry and its application in a pharmacokinetic study.

A rapid and sensitive liquid chromatography/mass spectrometry (LC/MS) method was developed and validated for the determination of rimantadine in rat plasma. Rimantadine was extracted by protein precipitation with methanol, and the chromatographic separation was performed on a C(18) column. The total analytical run time was relatively short (4.6 min), and the limit of assay quantification (LLOQ) was 2 ng/mL using 50 microL of rat plasma. Rimantadine and the internal standard (amantadine) were monitored in selected ion monitoring (SIM) mode at m/z 180.2 and 152.1, respectively. The standard curve was linear over a concentration range from 2 to 750 ng/mL, and the correlation coefficients were greater than 0.999. The mean intra- and inter-day assay accuracy ranged from 100.1-105.0% to 100.3-104.0%, respectively, and the mean intra- and inter-day precision was between 1.3-2.3% and 1.8-3.0%, respectively. The developed assay method was successfully applied to a pharmacokinetic study in rats after oral administration of rimantadine hydrochloride at the dose of 20 mg/kg.

Simultaneous determination of amantadine and rimantadine by HPLC in rat plasma with pre-column derivatization and fluorescence detection for pharmacokinetic studies.

We investigated simultaneous high-performance liquid chromatographic (HPLC) determination of amantadine hydrochloride (AMA) and rimantadine hydrochloride (RIM) levels in rat plasma after fluorescent derivatization with o-phthalaldehyde and 2-mercaptoethanol. Afterwards, the method was applied to determine their pharmacokinetics. The retention times of AMA and RIM derivatives were 12.6 and 22.2 min and the lower limits of detection were 0.025 and 0.016 microg/mL, respectively. The coefficients of variation for intra- and inter-day assay of AMA and RIM were less than 5.1 and 7.6%, respectively. After i.v. administration of AMA or RIM to rats, the total body clearance and distribution volume at the steady-state of RIM were higher than those of AMA. Bioavailability of AMA and RIM was 34.9 and 37.2%, respectively. When AMA and RIM were p.o. co-administered, the area under the plasma concentration--time curve of RIM was significantly lower than that after RIM alone. On the other hand, pharmacokinetic parameters of AMA did not significantly change. These results indicate that our HPLC assay is simple, rapid, sensitive and reproducible for simultaneously determining AMA and RIM concentrations in rat plasma and is applicable to their pharmacokinetic studies. Also, co-administration of AMA and RIM may result in the lack of pharmacological effects of RIM.

Bioequivalence of two rimantadine tablet formulations in healthy male volunteers after single dose administration.

AIM: The bioequivalence of two rimantadine tablet formulations was determined. METHODS: The study was designed as a randomized, two-period, two-sequence, crossover study. Twenty-four healthy male volunteers received a single 100 mg dose of rimantadine hydrochloride as test (Rimantadin Lachema 100 tbl. obd., produced by Lachema, a.s., Brno, Czech Republic) and reference formulations (Elumadine 100 tbl. obd., produced by Forest Pharmaceuticals, St. Louis, USA). The two administrations were separated by 14 days and were performed in the fasting state. Blood samples were obtained at 15 time points during the interval 0-120 h after administration. Rimantadine plasma concentrations were determined by gas chromatography with electron-capture detection. RESULTS: The geometric mean concentration-time profiles of rimantadine after administration of the two formulations were superimposable. The following pharmacokinetic parameters refer to the geometric mean [exp(mean +/- SD)] values for the test and reference formulations, respectively: Cmax (ng/ml) 70.5 (60.0-82.7) vs. 70.0 (59.9 to 81.7), AUC(0-infinity) (ng x h/ml) 2872 (2224 to 3707) vs. 2849 (2195-3699), AUC(0-120 h) 2744 (2184-3448) vs. 2712 (2138-3441), t(1/2) (h) 25.8 (20.1-33.0) vs. 25.7 (20.6 to 32.1). Median (range) tmax (h) values were 4.5 (2.0-8.0) and 6.0 (2.0-8.0). Parametric 90% confidence intervals for the expected mean percentage ratios (test/reference) of the pharmacokinetic variables were within the range of 97% to 105%. The median (91.1% confidence interval) difference in tmax was -0.3 h (-2.0-0.5). The point and interval estimates were identical when truncated AUCs (0-96 h, 0-72 h, 0-48 h and 0-24 h) were used in calculations. CONCLUSION: The two rimantadine formulations were equivalent in both the rate and extent ofbioavailability and they were also well tolerated. This study confirms the findings of other studies showing that for immediate release formulations of drugs with long half-lives shortening the duration over which blood samples are collected improves the economics, is more ethical and does not impair the quality of data.

Influenza en el año 2000 / Influenza at year 2000

Cada año, la influenza se asocia a una significativamortalidad y morbilidad especialmente entre los ancianos.La vacuna contra la influenza reduce los riesgos de enfermar. El éxito en la prevención de la mortalidad y morbilidad por influenza reside principalmente en la administración oportuna de la vacuna antiviral a los grupos de alto riesgo. En algunas situaciones puede estar indicado el uso de quimioprofilaxis antiviral con rimantadina o amantadina

Pharmacokinetics and therapeutic efficacy of rimantadine in horses experimentally infected with influenza virus A2.

OBJECTIVE: To determine pharmacokinetics of single and multiple doses of rimantadine hydrochloride in horses and to evaluate prophylactic efficacy of rimantadine in influenza virus-infected horses. ANIMALS: 5 clinically normal horses and 8 horses seronegative to influenza A. PROCEDURE: Horses were given rimantadine (7 mg/kg of body weight, i.v., once; 15 mg/kg, p.o., once; 30 mg/kg, p.o., once; and 30 mg/kg, p.o., q 12 h for 4 days) to determine disposition kinetics. Efficacy in induced infections was determined in horses seronegative to influenza virus A2. Rimantadine was administered (30 mg/kg, p.o., q 12 h for 7 days) beginning 12 hours before challenge-exposure to the virus. RESULTS: Estimated mean peak plasma concentration of rimantadine after i.v. administration was 2.0 micrograms/ml, volume of distribution (mean +/- SD) at steady-state (Vdss) was 7.1 +/- 1.7 L/kg, plasma clearance after i.v. administration was 51 +/- 7 ml/min/kg, and beta-phase half-life was 2.0 +/- 0.4 hours. Oral administration of 15 mg of rimantadine/kg yielded peak plasma concentrations of < 50 ng/ml after 3 hours; a single oral administration of 30 mg/kg yielded mean peak plasma concentrations of 500 ng/ml with mean bioavailability (F) of 25%, beta-phase half-life of 2.2 +/- 0.3 hours, and clearance of 340 +/- 255 ml/min/kg. Multiple doses of rimantadine provided steady-state concentrations in plasma with peak and trough concentrations (mean +/- SEM) of 811 +/- 97 and 161 +/- 12 ng/ml, respectively. Rimantadine used prophylactically for induced influenza virus A2 infection was associated with significant decreases in rectal temperature and lung sounds. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of rimantadine to horses can safely ameliorate clinical signs of influenza virus infection.

Rimantadine: a clinical perspective.

OBJECTIVE: To provide a review of rimantadine, including its antiviral activity, pharmacokinetics, efficacy, adverse effects, drug interactions, and dosage and administration. Information on influenza A virus and clinical features of influenza disease are presented. Comparative data on rimantadine and amantadine are described. DATA SOURCES: A MEDLINE search restricted to English-language literature published from 1966 through 1994 and an extensive review of journals was conducted. DATA EXTRACTION: The data on antiviral activity, pharmacokinetics, adverse effects, and drug interactions were obtained from various articles on rimantadine in open and controlled studies. Controlled double-blind studies were evaluated to assess the efficacy of rimantadine in prophylaxis and treatment of influenza A infection. DATA SYNTHESIS: Over 90% of a rimantadine dose was absorbed in 3-6 hours in healthy adults. Steady-state plasma concentrations have ranged from 0.10 to 2.60 micrograms/mL at doses of 3 mg/kg/d in infants to 100 mg twice daily in the elderly. Nasal fluid concentrations of rimantadine at steady-state were 1.5 times higher than plasma concentrations, which may explain the effectiveness of rimantadine despite a low plasma concentration. Over 75% of a rimantadine dose was metabolized in the liver, and the parent compound and metabolites were almost completely eliminated by the kidneys. The elimination half-life ranged from 24.8 to 36.5 hours, which allows once-daily dosing. Dosage adjustment is recommended for patients with severe renal impairment (creatinine clearance < or = 0.17 mL/s), severe hepatic dysfunction, or elderly nursing home patients. Drug-resistant strains of influenza A virus to rimantadine occurred in several studies with children and/or adults. Clinical significance of drug-resistant strains has not been established. Rimantadine appeared to be effective in 85-90% of individuals for prevention of influenza A illness and in 50-65% for prevention of influenza A infection. Rimantadine reduced the time to a 50% reduction in symptoms by 1-3 days versus placebo. Differences in symptom reduction between rimantadine and placebo after the first 3 days of treatment was not generally clinically significant. The most common adverse effects of rimantadine administration were associated with the central nervous system (CNS) and the gastrointestinal (GI) tract. CNS-related adverse effects occurred in 3.2% of children younger than 10 years of age and 8.4% of adults. In elderly patients, the incidence of CNS-related adverse effects ranged from 4.9% at 100 mg/d to 12.5% at 200 mg/d. GI adverse effects occurred in 8.4% of children younger than 10 years of age, 3.1% of adults, and 2.9% at 100 mg/d and 17.0% at 200 mg/d in the elderly. CONCLUSIONS: Rimantadine offers some desirable features for the treatment and prophylaxis of influenza A infection. It appears to be an attractive choice in elderly patients with a history of CNS adverse effects from amantadine and in patients with mild or moderate renal impairment. Although approved for twice-daily dosing, rimantadine has a pharmacokinetic profile that would allow once-daily dosing. It is effective for prophylaxis (not postexposure prophylaxis) and treatment of influenza A virus. It also has a low incidence of adverse effects.

Amantadine and rimantadine prophylaxis of influenza A in nursing homes. A tolerability perspective.

Amantadine and rimantadine are recommended for the treatment and prophylaxis of influenza A infections, and constitute an integral component of influenza control measures in the nursing home setting. However, optimal use necessitates a thorough understanding of the toxicity profiles of these agents, as well as strategies to reduce the risk of adverse reactions. Adverse reactions of these compounds predominantly involve the gastrointestinal tract and the central nervous system (CNS), including hyperexcitability, slurred speech, tremors, insomnia, dizziness, mood disturbance, ataxia, psychosis and fatigue. Based on data from comparative trials, rimantadine appears to exhibit a lesser propensity to cause adverse CNS reactions than amantadine, but a similar propensity to cause adverse gastrointestinal reactions. Factors enhancing the risk of adverse reactions to these agents include reduced renal function (especially for amantadine), drug-drug interactions with cationic drugs, which inhibit amantadine renal tubular secretion (e.g. trimethoprim, triamterene, and possibly cimetidine and procainamide), elevated peak and trough plasma concentrations, and a history of seizures. Careful attention to published dosage adjustment guidelines for these compounds, avoidance of interacting drugs and avoiding these agents in patients with a history of seizures may be the best means to reduce the risk of toxicity in elderly patients. Rimantadine may have an advantage over amantadine in the elderly population in light of its lesser propensity to cause adverse reactions, less complex dosage adjustment in the case of renal impairment and probable lack of drug-drug interaction potential with cationic drugs.

[Amantadine and rimantadine against influenza A]. / Amantadin og rimantadin mot influensa A.

Amantadine and the analogue rimantadine have an antiviral effect on influenza A virus and are approximately 60% effective in preventing illness. The drugs are administered orally, and peak plasma concentration is achieved at two hours after a single dose. Side effects occur in 5-20% of the cases, but generally mild and transient and seen mainly with doses of more than 200 mg a day. This paper describes the mechanism of action and the pharmacokinetics of the drugs, and refers to some important clinical trials. Amantadine has been used in Norway to treat Parkinson's disease since 1972. The licensing of the amantadine and rimantadine for use against influenza A in this country is also discussed.

Safety and pharmacokinetics of rimantadine small-particle aerosol.

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 micrograms/liter of air was associated with nasal burning and irritation in normal volunteers. A concentration of 20 micrograms/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 less than 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 micrograms/liter of air was well tolerated in normal volunteers and in those with acute influenza and was associated with high local concentrations.

Effect of cimetidine on the disposition of rimantadine in healthy subjects.

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 less than 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.

Multiple-dose pharmacokinetics of rimantadine in elderly adults.

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-stratified 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 100 +/- 14 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.

Pharmacokinetics and metabolism of rimantadine hydrochloride in mice and dogs.

We studied the pharmacokinetics and metabolism of rimantadine hydrochloride (rimantadine) following single-dose oral and intravenous administration in mice and dogs. Absorption of the compound in mice was rapid. Maximum concentrations in plasma occurred at less than 0.5 h after oral administration, and the elimination half-life was 1.5 h. Peak concentrations in plasma following oral administration were markedly disproportional to the dose (274 ng/ml at 10 mg/kg, but 2,013 ng/ml at 40 mg/kg). The bioavailability after an oral dose of 40 mg/kg was 58.6%. Clearance was 4.3 liters/h per kg, and the volume of distribution was 7.6 liters/kg at 40 mg/kg. In contrast to the results observed in mice, absorption of the compound in dogs was slow. Maximum concentrations in plasma occurred at 1.7 h after oral administration, and the elimination half-life was 3.3 h. A further difference was that peak concentrations in plasma were approximately proportional to the dose. Following administration of a single oral dose of 5, 10, or 20 mg/kg, maximum concentrations in plasma were 275,800, and 1,950 ng/ml, respectively. The bioavailability after an oral dose of 5 mg/kg was 99.4%. The clearance was 3.7 liters/h per kg, and the volume of distribution was 13.8 liters/kg at 5 mg/kg. Mass balance studies in mice, using [methyl-14C]rimantadine, indicated that 98.7% of the administered dose could be recovered in 96 h. Less than 5% of the dose was recovered as the parent drug in dog urine within 48 h. Finally, gas chromatography-mass spectrometry studies, done with mouse plasma, identified the presence of two rimantadine metabolites. These appeared to be ring-substituted isomers of hydroxy-rimantadine.

Rimantadine pharmacokinetics in healthy subjects and patients with end-stage renal failure.

The single-dose (two 100 mg doses) pharmacokinetics of rimantadine hydrochloride were compared in eight patients with end-stage renal disease who were on hemodialysis and seven age-matched healthy subjects. Plasma and urine rimantadine concentrations were determined by a GC/MS method. The plasma half-life (43.6 vs 27.5 hours) and AUC (9.9 +/- 2.1 vs 6.0 +/- 1.6 micrograms.hr/ml) were significantly (p less than 0.05) increased in the patient population. No significant differences were noted in the maximum rimantadine concentration, time of maximum concentration, or apparent volume of distribution. Urinary excretion of unchanged rimantadine accounted for 16% of the dose in the healthy subjects. Hemodialysis did not appreciably remove rimantadine. These findings suggest that rimantadine dosage may need to be reduced in patients with end-stage renal disease but supplemental doses on dialysis days are not required.

Transport of amantadine and rimantadine through the blood-brain barrier.

The unidirectional transport of amantadine and rimantadine across cerebral capillaries, the anatomical locus of the blood-brain barrier, was measured with an in situ rat brain perfusion technique. Both rimantadine and, to a lesser extent, amantadine were transported principally across the blood-brain barrier by a saturable transport system with a one-half saturation concentration of about 1.0 mM (either rimantadine or amantadine). The permeability surface area constants were 8.5 x 10(-2) sec-1 (rimantadine) and 1.1 x 10(-2) sec-1 (amantadine) with concentrations of less than 1.0 microM in the perfusate. The extraction of rimantadine and amantadine from the perfusate at low concentrations (less than 1.0 microM) was 88 and 26%, respectively, of the extraction of diazepam which is 100% extracted. Amantadine and rimantadine transport through the blood-brain barrier was significantly inhibited by weakly basic drugs (e.g., diphenhydramine) but not choline (10 mM), probenecid (1 mM) or leucine (1 mM). Inasmuch as both the pKa and percentage ionized at pH = 7.4 of rimantadine (10.4 and 99.9%, respectively) are much higher than that of amantadine (pKa = 9.0 and 97.5%, respectively), and inasmuch as rimantadine is transported into brain much more readily than amantadine, our results suggest that the carrier-mediated transport of the ionized moiety is the crucial process determining the penetration of amantadine and rimantadine through the blood-brain barrier.

Relative bioavailability of rimantadine HCl tablet and syrup formulations in healthy subjects.

Twenty healthy male subjects completed an open-label randomized crossover design to assess the bioavailability of 100 mg of rimantadine HCl in tablet and syrup forms relative to an oral solution. Blood samples were drawn and rimantadine plasma concentrations were determined by a GC-MS method. The maximum plasma concentration (Cmax), the time to Cmax (tmax), the area under the plasma concentration-time curve (AUC), and k were compared among treatments using an analysis of variance and the Hauck-Anderson test for bioequivalence. The Hauck-Anderson test was satisfied when the syrup and solution were compared. The relative bioavailability of the syrup was 96%. Both Cmax and AUC were significantly (p less than 0.05) increased (23 and 17%, respectively) when the tablet was compared with the solution. The relative bioavailability of the tablet was 117%. This outcome was unusual and could not be explained. However, this was not anticipated to be of clinical consequence since the majority of the safety and efficacy of rimantadine HCl was established using a tablet.