PHARMACOKINETICS OF A NEW ANTICONVULSANT(CGP 33101) IN EPILEPTIC MALE PATIENTS AND HEALTHY MALE SUBJECTS AFTER SINGLE ASCENDING ORAL DOSES OF 400–1200 mg

Brunner, Linda A.; Harrigan, E.P.; John, Vivian A.; Powell, Mark L.

doi:10.1097/00045391-199410000-00008

Cited by 13 publications

(5 citation statements)

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“…Plasma rufinamide concentrations were determined using a validated high‐performance liquid chromatography (HPLC) assay with ultraviolet (UV) or tandem mass spectrometry (MS) detection (Brunner & Powell, 1992; Brunner et al, 1994). Routes of elimination were investigated using 14 C‐labelled rufinamide.…”

Section: Methodsmentioning

confidence: 99%

Rufinamide: Clinical pharmacokinetics and concentration–response relationships in patients with epilepsy

et al. 2008

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SUMMARYRufinamide is a new, orally active antiepileptic drug (AED), which has been found to be effective in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome. When taken with food, rufinamide is relatively well absorbed in the lower dose range, with approximately dose-proportional plasma concentrations up to 1,600 mg/day, but less than dose-proportional plasma concentrations at higher doses due to reduced oral bioavailability. Rufinamide is not extensively bound to plasma proteins. During repeated dosing, steady state is reached within 2 days, consistent with its elimination half-life of 6-10 h. The apparent volume of distribution (V d /F) and apparent oral clearance (CL/F) are related to body size, the best predictor being body surface area. Rufinamide is not a substrate of cytochrome P450 (CYP450) enzymes and is extensively metabolized via hydrolysis by carboxylesterases to a pharmacologically inactive carboxylic acid derivative, which is excreted in the urine. Rufinamide pharmacokinetics are not affected by impaired renal function. Potential differences in rufinamide pharmacokinetics between children and adults have not been investigated systematically in formal studies. Although population pharmacokinetic modeling suggests that in the absence of interacting comedication rufinamide CL/F may be higher in children than in adults, a meaningful comparison of data across age groups is complicated by age-related differences in doses and in proportion of patients receiving drugs known to increase or to decrease rufinamide CL/F. A study investigating the effect of rufinamide on the pharmacokinetics of the CYP3A4 substrate triazolam and an oral contraceptive interaction study showed that rufinamide has some enzyme-inducing potential in man. Findings from population pharmacokinetic modeling indicate that rufinamide does not modify the CL/F of topiramate or valproic acid, but may slightly increase the CL/F of carbamazepine and lamotrigine and slightly decrease the CL/F of phenobarbital and phenytoin (all predicted changes were <20%). These changes in the pharmacokinetics of associated AEDs are unlikely to make it necessary to change the dosages of these AEDs given concomitantly with rufinamide, with the exception that consideration should be given to reducing the dose of phenytoin. Based on population pharmacokinetic modeling, lamotrigine, topiramate, or benzodiazepines do not affect the pharmacokinetics of rufinamide, but valproic acid may increase plasma rufinamide concentrations, especially in children in whom plasma rufinamide concentrations could be increased substantially. Conversely, comedication with carbamazepine, vigabatrin, phenytoin, phenobarbital, and primidone was associated with a slight-to-moderate decrease in plasma rufinamide concentrations, ranging from a minimum of −13.7% in female children comedicated with vigabatrin to a maximum of −46.3% in female adults comedicated with phenytoin, phenobarbital, or primidone. In population modeling using data from plac...

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Section: Methodsmentioning

confidence: 99%

Rufinamide: Clinical pharmacokinetics and concentration–response relationships in patients with epilepsy

et al. 2008

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“…4 The pharmacokinetics do not change with multiple dosing. There is moderate intersubject variability.…”

Section: Pharmacokineticsmentioning

confidence: 99%

Rufinamide

Arroyo

2007

Neurotherapeutics

120

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Summary:Rufinamide is a triazole derivative structurally unrelated to currently marketed antiepileptic drugs. Rufinamide was profiled for anticonvulsant activity at the National Institutes of Health and showed broad-spectrum anticonvulsant properties at nontoxic doses in animal models. The principal mechanism of action of rufinamide is considered to be the modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide provides an efficacious and well-tolerated treatment option for use as adjunctive therapy in patients with partial seizures and with Lennox-Gastaut syndrome (LGS). In LGS, rufinamide is effective in controlling multiple seizure types and in reducing the severity of the seizures. The most commonly observed (Ն10%) adverse experiences seen in association with rufinamide are headache, dizziness, fatigue, somnolence and nausea. Rufinamide is generally well tolerated, and its safety profile is well-established.

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“…The pharmacokinetic parameters of single ascending doses of rufinamide (0, 400, 800, 1200 mg) have also been compared between 3 healthy subjects and 16 patients with epilepsy receiving enzyme-inducing AEDs (Brunner et al 1994). Absorption rates were comparable, and both groups showed dose-related increases in C max and exposure.…”

Section: Pharmacology and Pharmacokinetics Of Rufinamidementioning

confidence: 99%

Role of rufi namide in the management of Lennox-Gastaut syndrome (childhood epileptic encephalopathy)

Kluger¹,

Bauer²

2007

Neuropsychiatric Disease and Treatment

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Rufinamide, a triazole derivative that is structurally distinct from currently marketed antiepileptic drugs (AEDs), is in development for the adjunctive treatment of Lennox-Gastaut syndrome (LGS) in children and adults. Rufinamide is well absorbed after oral administration, demonstrates low protein binding, and is metabolized by enzymatic hydrolysis without involvement of cytochrome P450 enzymes, conferring a low drug interaction potential. In a randomized, double-blind trial involving 138 adult and pediatric patients with LGS, compared with placebo, rufinamide 45 mg/kg/day resulted in significantly superior reductions in drop attacks (median change -42.5% vs +1.4% with placebo) and total seizures (-32.1% vs -11.7% with placebo), accompanied by significantly higher responder rates. These results are comparable with findings reported for other AEDs in randomized, controlled clinical trials in patients with LGS. Rufinamide produced statistically significant seizure reduction which was maintained during long-term therapy and accompanied by good tolerability. The most frequently reported adverse events from a pooled safety database evaluating short-and longterm therapy were headache (22.9% and 29.5%), dizziness (15.5% and 22.5%) and fatigue (13.6% and 17.7%). Rufinamide therefore presents a favorable efficacy and tolerability profile and is a promising candidate for the adjunctive therapy of LGS.

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PHARMACOKINETICS OF A NEW ANTICONVULSANT(CGP 33101) IN EPILEPTIC MALE PATIENTS AND HEALTHY MALE SUBJECTS AFTER SINGLE ASCENDING ORAL DOSES OF 400–1200 mg

Cited by 13 publications

References 0 publications

Rufinamide: Clinical pharmacokinetics and concentration–response relationships in patients with epilepsy

Rufinamide: Clinical pharmacokinetics and concentration–response relationships in patients with epilepsy

Rufinamide

Role of rufi namide in the management of Lennox-Gastaut syndrome (childhood epileptic encephalopathy)

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