Differences in side effects of amantadine hydrochloride and rimantadine hydrochloride relate to differences in pharmacokinetics

Abstract

In a double-blind, placebo-controlied study, the comparative toxicities and blood concentrations of amantadine hydrochloride and rimantadine hydrochloride were determined. Healthy, working adults ingested either 200 (n = 52) or 300 mg (n = 1%) per day in divided doses for 4.5 days. Mean plasma drug concentrations at 4 h after the first dose were lower in rimantadine recipients given 100-(140 versus 300 ng/ml for rimantadine and amantadine, respectively; P < 10-5) or 200-mg doses (310 versus 633 ng/ml; P < 10-5). The plasma drug concentrations after the first dose correlated significantly with total symptom sources for both amantadine and rimantadine, but the plasma levels of toxic and nontoxic subjects overlapped extensively. At 300-mg/day dosage amantadine was associated more often with adverse central nervous system symptoms (33% of amantadine versus 9% of rimantadine recipients; P < 0.001) and sleep disturbance (39 versus 13%; P < 0.001), but not gastrointestinal symptoms (19.5 versus 16.0o). However, no differences between the drugs were noted in symptom frequency or scores in volunteers with similar plasma concentrations. Amantadine and rimantadine differ in their pharmacokinetics but not in their potential for side effects at comparable plasma concentrations.Clinical trials have documented that amantadine hydrochloride (8,12,16,20,28) and its analog rimantadine hydrochloride (6,12,23,28,29) are effective drugs for the prophylaxis and treatment of influenza A virus infection. However, widespread use of amantadine has been limited in part by concern about its side effects.Most studies of amantadine prophylaxis have documented minimal toxicity at a dosage of 200

Amantadine inhibits platelet-activating factor induced clathrin-mediated endocytosis in human neutrophils

“…Rimantadine is an analog of amantadine, differing only in the replacement of the amino group at position one with a methyl amine group; rimantadine pretreatment significantly inhibited PAF priming of the fMLP-activated respiratory burst at concentrations 10-fold lower (70). The C max of rimantadine is 74 ng/ml (0.3 M) 6 h after an initial dose of 100 mg, indicating that physiologic concentrations are close to the in vitro concentrations required to inhibit PAF-mediated changes in PMN physiology (25,43). Thus, rimantadine may provide a better means to curtail the effect of PMN-mediated organ injury, e.g., the acute respiratory distress syndrome and postinjury organ failure, yet its effects on other clathrin-dependent and -independent endocytotic mechanisms in different tissues need to be more clearly defined.…”

“…Furthermore, rimantadine appears to be a more physiological inhibitor than amantadine because of its ability to inhibit PAF priming at clinically relevant concentrations (25,43), and may represent an effective pharmacological approach to reduce PMN-mediated tissue damage in the injured or critically ill patient.…”

“…Amantadine has been further described to inhibit neural proton channel activity (28) and acts as a low-affinity N-methyl-Daspartate (NMDA) receptor antagonist (39,48); however, its specificity inhibiting CME of the PAF receptor is not well understood although it is frequently used as a clathrin inhibitor (3,29,47,50,52,65). Recent work has characterized the early events in PAF-mediated CME (25) including internalization of the ligand:receptor complex and sequestration of these ligated receptors to clathrin-coated vesicle (CCVs) (55). In addition, the PMN is unique for it does not contain caveolin and thus serves as an excellent cellular model to study CME (56).…”

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

“…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).…”

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

“…In a more recent study, PD patients who switched to placebo after amantadine IR treatment for a mean of 3.4 years showed significant worsening of dyskinesia at a median of 7 days, suggesting that some patients derived benefit over this duration [10]. Although most patients with PD can tolerate amantadine IR doses of 81-161 mg daily (equivalent to 100-200 mg daily of amantadine hydrochloride [HCl]) (electronic supplementary Table 1), higher doses that may provide greater antidyskinetic benefit are associated with increased frequency of central nervous system (CNS) adverse events (AEs) [7,11]. Therefore, amantadine IR is typically administered in divided doses, even though its relatively long half-life (* 17 h) might support once-daily dosing [12].…”