Concentrations of stiripentol in children and adults with epilepsy: the influence of dose, age, and comedication.

BACKGROUND: Stiripentol (STP) was approved as an orphan drug in 2007 in Europe as adjunctive therapy with valproic acid (VPA) and clobazam (CLB) for Dravet syndrome. Dravet syndrome is a highly pharmacoresistant form of epilepsy, which starts in early childhood. Data about STP pharmacokinetics and interactions are still limited and in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily STP dose per body weight (milligrams per kilogram), VPA, CLB, and enzyme-inducing antiepileptic drugs on STP concentration-to-dose ratio (CDR), STP clearance, and STP trough concentrations. METHODS: Retrospectively, 220 STP serum concentrations in 75 patients from 3 German Epilepsy Centers were analyzed. Analysis of variance, regression analysis, and generalized estimating equations were used for statistical analysis. RESULTS: Our findings confirm the nonlinear STP pharmacokinetics. At steady state, STP CDR increased with daily STP doses. Compared with patients older than 12 years, STP concentrations were decreased by 39.6% in children aged 6-12 years (P < 0.001) and by 57.5% in children younger than 6 years (P < 0.001). Phenobarbital and phenytoin decreased STP concentrations by 63.2%. This effect was highly significant (P < 0.001), despite the small number of patients (n = 7) treated with phenobarbital or phenytoin. VPA had no significant effect on STP serum concentrations, whereas STP serum concentrations were moderately but significantly increased by CLB (24.6%, P = 0.011). CONCLUSIONS: Therapeutic drug monitoring of STP seems to be useful because of the wide variation of STP CDR, the nonlinear concentration-to-dose relationship, age-dependent pharmacokinetics, and drug-drug interactions.

Serum concentrations of rufinamide in children and adults with epilepsy: the influence of dose, age, and comedication.

Rufinamide (RUF) is an orphan drug for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in persons aged 4 years and older. Several studies have investigated the pharmaconkinetics of RUF, but information about interactions is still limited and the results are in part inconsistent. The aim of our study was to analyze the effect of age, gender, daily RUF dose per body weight (mg/kg), valproic acid (VPA), and enzyme-inducing antiepileptic drugs (EIAEDs) on RUF concentration-to-dose ratio (RUF serum concentration/RUF dose per body weight), RUF clearance (RUF dose/RUF serum concentration), and RUF trough concentrations. Different statistical methods were used to evaluate 292 blood samples from 119 patients who fulfilled the inclusion criteria. In summary, the results using generalized estimating equation regression models confirm a moderate but statistically significant nonlinear RUF concentration-dose relationship. At steady state, the trough concentrations of RUF increase in a less than dose proportional manner. Children (younger than 12 years) had significantly lower RUF concentrations (19.0%, P < 0.001) than adults (18 years or older) on comparable RUF doses per body weight. VPA was the most frequent comedication (51%) in our patient group. Mean RUF concentrations were 86.6% higher when VPA concentrations were greater than 90 µg/mL (P < 0.001) and 45.4% higher when VPA concentrations were between 50 and 90 µg/mL (P < 0.001) but not significantly different at VPA concentrations less than 50 µg/mL (4.4%, P > 0.1) compared with combinations without VPA. In combination with EIAEDs, mean RUF concentrations were 21.8% lower (P = 0.002) compared with combinations without EIAEDs. However, the group of AEDs classified as EIAEDs was heterogeneous and the number of patients, especially of children with EIAEDs, was relatively small. Our data indicate that oxcarbazepine and, especially, methsuximide decrease RUF concentrations as well. Therapeutic drug monitoring might be helpful because RUF concentrations differ markedly in patients on comparable RUF doses.

Levetiracetam in children with refractory epilepsy: a multicenter open label study in Germany.

PURPOSE: To evaluate the efficacy and tolerability of Levetiracetam (LEV) in a large pediatric cohort with drug-resistant epilepsy from a prospective multicenter observational study. METHODS: We report the results of a multicenter observational survey of a cohort of 285 pediatric patients (mean: 9.9 years, range: 0; 6-17; 11) with refractory generalized and focal epilepsy who received Levetiracetam as an add-on open label treatment trial. The average duration of epilepsy was 6.0 years and the patients were treated with a mean of 7.0 antiepileptic drugs (AED) before LEV was introduced. RESULTS: No serious persistent adverse events were reported. Reversible colitis and an apnoea syndrome in a child with phosphorylase-A-kinase-deficiency were noted. Mild to moderate side effects were reported in 128 patients (44.9%), consisting most frequently of somnolence (23.9%), general behavioral changes (15.4%), aggression (10.5%) and sleep disturbances (3.2%). In 209 patients, efficacy was analyzed over a treatment period of at least 12 weeks compared to a baseline of 2 weeks. Thirteen patients (6.2%) became seizure free, 39 (18.7%) responded with a seizure reduction of more than 50% following introduction of LEV. No response to LEV was reported in 65.1% (n=136). A decrease of initial treatment effect was seen in 37 patients (17.8%) while in 6.7% the seizure frequency doubled to the baseline (n=14). In seven patients (3.3%), the effect of LEV on seizure frequency could not be evaluated. A positive psychotropic effect was observed in 18 patients (8.6%). Mental retardation was associated with poor response and associated with more side effects and earlier discontinuation of LEV therapy. CONCLUSION: LEV is a well-tolerated new AED that may effectively improve seizure control as an add-on drug in resistant epilepsy in childhood with good tolerability. However, neurologically handicapped children appear at increased risk for reversible neurocognitive side effects and have a poorer treatment response.

Do Glut1 (glucose transporter type 1) defects exist in epilepsy patients responding to a ketogenic diet?

In the recent years, several neurological syndromes related to defects of the glucose transporter type 1 (Glut1) have been descried. They include the glucose transporter deficiency syndrome (Glut1-DS) as the most severe form, the paroxysmal exertion-induced dyskinesia (PED), a form of spastic paraparesis (CSE) as well as the childhood (CAE) and the early-onset absence epilepsy (EOAE). Glut1, encoded by the gene SLC2A1, is the most relevant glucose transporter in the brain. All Glut1 syndromes respond well to a ketogenic diet (KD) and most of the patients show a rapid seizure control. Ketogenic Diet developed to an established treatment for other forms of pharmaco-resistant epilepsies. Since we were interested in the question if those patients might have an underlying Glut1 defect, we sequenced SLC2A1 in a cohort of 28 patients with different forms of pharmaco-resistant epilepsies responding well to a KD. Unfortunately, we could not detect any mutations in SLC2A1. The exact action mechanisms of KD in pharmaco-resistant epilepsy are not well understood, but bypassing the Glut1 transporter seems not to play an important role.

Clinical pharmacokinetics of oxcarbazepine.

Oxcarbazepine is an antiepileptic drug with a chemical structure similar to carbamazepine, but with different metabolism. Oxcarbazepine is rapidly reduced to 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), the clinically relevant metabolite of oxcarbazepine. MHD has (S)-(+)- and the (R)-(-)-enantiomer, but the pharmacokinetics of the racemate are usually reported. The bioavailability of the oral formulation of oxcarbazepine is high (>95%). It is rapidly absorbed after oral administration, reaching peak concentrations within about 1-3 hours after a single dose, whereas the peak of MHD occurs within 4-12 hours. At steady state, the peak of MHD occurs about 2-4 hours after drug intake. The plasma protein binding of MHD is about 40%. Cerebrospinal fluid concentrations of MHD are in the same range as unbound plasma concentrations of MHD. Oxcarbazepine can be transferred significantly through the placenta in humans. Oxcarbazepine and MHD exhibit linear pharmaco-kinetics and no autoinduction occurs. Elimination half-lives in healthy volunteers are 1-5 hours for oxcarbazepine and 7-20 hours for MHD. Longer and shorter elimination half-lives have been reported in elderly volunteers and children, respectively. Mild to moderate hepatic impairment does not appear to affect MHD pharmacokinetics. Renal impairment affects the pharmacokinetics of oxcarbazepine and MHD. The interaction potential of oxcarbazepine is relatively low. However, enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbital or carbamazepine can reduce slightly the concentrations of MHD. Verapamil may moderately decrease MHD concentrations, but this effect is probably without clinical relevance. The influence of oxcarbazepine on other antiepileptic drugs is not clinically relevant in most cases. However, oxcarbazepine appears to increase concentrations of phenytoin and to decrease trough concentrations of lamotrigine and topiramate. Oxcarbazepine lowers concentrations of ethinylestra-diol and levonorgestrel, and women treated with oxcarbazepine should consider additional contraceptive measures. Due to the absent or lower enzyme-inducing effect of oxcarbazepine, switching from carbamazepine to oxcarbazepine can result in increased serum concentrations of comedication, sometimes associated with adverse effects. The effect of oxcarbazepine appears to be related to dose and to serum concentrations of MHD. In general, daily fluctuations of MHD concentration are relatively slight, smaller than would be expected from the elimination half-life of MHD. However, relatively high fluctuations can be observed in individual patients. Therapeutic monitoring may help to decide whether adverse effects are dependent on MHD concentrations. A mean therapeutic range of 15-35 mg/L for MHD seems to be appropriate. However, more systematic studies exploring the concentration-effect relationship are required.