Pharmacokinetics of Amantadine Hydrochloride in Subjects with Normal and Impaired Renal Function

Abstract

Amantadine is useful for the prevention and treatment of influenza A and for the treatment of Parkinson's disease and drug-induced extrapyramidal disorders. We have compared the pharmacokinetics of amantadine in patients with impaired or negligible renal function to that in normal subjects. The half-life of elimination in subjects with normal renal function was 11.8 +/- 2.1 hours (range, 9.7 to 14.5 h). Eight patients with various degrees of renal insufficiency (creatinine clearance from 43.1 to 5.9 mL/min . 1.73 m2) had half-lives of elimination from 18.5 h to 33.8 days. We also studied 10 patients on thrice-weekly hemodialysis. Assuming complete bioavailability of the drug, less than 5% of the dose was removed by each 4-hour hemodialysis. The mean half-life of elimination during chronic hemodialysis was 8.3 days (range, 7.0 to 10.3). We present guidelines for use of amantadine in patients with impaired renal function, including those on maintenance hemodialysis.

Pharmacokinetics of ADS-5102 (Amantadine) Extended Release Capsules Administered Once Daily at Bedtime for the Treatment of Dyskinesia

“…For amantadine IR, the findings are consistent with those reported by other researchers in healthy persons taking various amantadine IR regimens [16][17][18]. For ADS-5102, the findings versus amantadine IR were obtained (in study 2) using the highest dose strength of ADS-5102 capsules (137 mg), administered once (for single-dose PK assessment) and then oncedaily (for steady-state PK assessment).…”

“…To relate creatinine clearance to amantadine clearance, a relationship between the amantadine K e and creatinine clearance was established with data from four prior publications [16][17][18][19]. Simulations of the plasma amantadine concentration-time profile for ADS-5102 dosing were then conducted using a one-compartment linear model [20] with first-order absorption and first-order elimination, so as to compare the profile for healthy individuals with a creatinine clearance of 121 mL/min/1.73 m 2 and the profile for potential patients with a creatinine clearance of 70 mL/ min/1.73 m 2 , similar to the value observed in PD patients (Fig.…”

Protective efficacy of low-dose amantadine in adults challenged with wild-type influenza A virus

“…The 100-mg dose regimen of amantadine did not cause side effects in the young adults in our study. The absence of side effects may be due to the lower levels in blood achieved with the 100-mg dose as compared with the levels for the 200-mg dose, reported to be 40% higher (7,8). The lower levels in blood with the 100-mg dose may account for the reduced toxicity in the elderly.…”

“…Controlled trials have shown that a 200-mg daily dose of amantadine is effective for prophylaxis against and treatment of illness caused by influenza A virus, yet the drug is underused for influenza prevention (5,10,11,(19)(20)(21). This is caused, in part, by concern about drug toxicity; central-nervous-system symptoms occur in approximately 5 to 10% of recipients (4,7,8). Side effects with the 200-mg dose appear to occur more frequently (or are noticed more often) in the elderly, the population at highest risk for severe influenza illness (1-3).…”

Severe Reversible Neurological Complications following Amantadine Treatment in Three Elderly Patients with Renal Insufficiency

“…Because approximately 90% of the drug is excreted unchanged in the urine, it accumulates in various organs in patients with renal dysfunction [7,8] . The half-life of drug elimination is 11.8 8 2.1 h (range: 9.7-14.5 h) in subjects with normal renal function, and 8.3 days (range: 7.0-10.3 days) in patients on hemodialysis [9] . Furthermore, the half-life in patients whose creatinine clearance is reduced to 50, 30, and 10 ml/min, has been reported to be 23 h, 40 h, and 7.4 days, respectively [9] .…”