Rufinamide: Clinical Pharmacokinetics and concentration-response relationships in patients with epilepsy

Institute of Neurology IRCCS C. Mondino Foundation and Clinical Pharmacology Unit, University of Pavia, Pavia, Italy.
Epilepsia (Impact Factor: 4.57). 07/2008; 49(7):1123-41. DOI: 10.1111/j.1528-1167.2008.01665.x
Source: PubMed


Rufinamide 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 placebo-controlled trials, a positive correlation has been identified between reduction in seizure frequency and steady-state plasma rufinamide concentrations. The probability of adverse effects also appears to be concentration-related.

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    • "Several drugs like carboxyamidotriazole, cefatrizine, tazobactam bear 1,2,3-triazole in their structure. Moreover, Rufinamide, the amide of 1-(2,6- difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid is an antiepileptic drug, which is used in the treatment of partial seizures and drop attacks associated with the Lennox-Gastaut syndrome [12]. "
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    • "CK - MDR1 = 29 , LLC - WT = 92 , LLC - MDR1 = 20 ) ( Fig . 1C ) , which confirmed the functional activity of Pgp in MDR1 - transfected cell lines . RFM , ZNS , and PGB were tested in CETA . The concentra - tions tested were 5 , 10 and 20 ␮g / ml for RFM and PGB , and 10 , 20 , 40 ␮g / ml for ZNS , which are in the range of clinical plasma levels ( Perucca et al . , 2008 ; Krasowski , 2010 ) . There was no significant difference between apical and basolateral concentrations after exposing LLC - MDR1 cell monolayers to RFM ( Fig . 2 ) , PGB ( Fig . 3 ) , or ZNS ( Fig . 4 ) for up to 4 h ."
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    ABSTRACT: Objective Epilepsy is resistant to treatment with antiepileptic drugs (AEDs) in about one third of epilepsy patients. AED export by P-glycoprotein (Pgp) overexpressed in the blood-brain barrier may contribute to AED resistance. The Pgp transport status of many of the recently approved AEDs remains unknown. We investigated whether several new AEDs--zonisamide (ZNS), pregabalin (PGB), and rufinamide (RFM)--are human Pgp substrates. Methods MDCKII and LLC-PK1 cells transfected with the human MDR1 gene, which encodes the Pgp protein, were used in concentration equilibrium transport assays (CETA) to determine the substrate status of ZNS, PGB, and RFM. For each drug, an equal concentration was added to apical and basal chambers, and the concentration in both chambers was measured up to 4 hours. Results RFM, ZNS, and PGB were not transported by MDR1-transfected cells from basolateral to apical sides in CETA. Conclusions ZNS, RFM, and PGB are not substrates of human Pgp. These data suggest that resistance to these drugs may not be attributed to increased Pgp activity in resistant patients.
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    • "Rufinamide is metabolized extensively by non–cytochrome P450 (CYP450) systems and exhibits a broad spectrum of activity in animal models of epilepsy (Glauser et al., 2008). Pharmacokinetic studies show it has a relatively short half-life of 6–10 h, thereby minimizing fluctuations in plasma concentrations with twice-daily dosing (Perucca et al., 2008). Rufinamide has a higher safety index than valproate, phenytoin, and phenobarbital in animal models of epilepsy (White et al., 2008). "
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