Summary:Purpose: P-glycoprotein (P-gp) has been implicated in the causation of refractory epilepsy. The expression and efflux efficiency of P-gp is influenced by a polymorphism (C3435T) in the encoding gene (MDR1). Recent evidence suggests that the homozygous C-variant, which is associated with higher expression and increased activity of P-gp, is more common in patients with pharmacoresistant epilepsy. We have investigated the prevalence of this polymorphism in a series of patients attending a specialist epilepsy clinic.Methods: DNA samples were obtained from 400 patients, irrespective of seizure type or drug treatment. Genotype of the C3435T polymorphism was determined by traditional polymerase chain reaction (PCR) followed by restriction digest. Classification of response to treatment was determined in a blinded fashion by an independent physician. Results were expressed as genotype and allele frequencies per response group and compared by logistic regression analysis. Results:In total, 170 patients were classified as responders, with ≥12 months seizure freedom on current treatment. The remaining 230 patients were classified as nonresponders. Comparison of responders and nonresponders revealed no significant difference in allele frequency (C vs. T; odds ratio, 1.03; 95% CI, 0.78-1.37; p = 0.83) or genotype frequency (CC vs TT; odds ratio, 1.07; 95% CI, 0.60-1.91; p = 0.81). Subanalyses of individual seizure types were similarly unremarkable.Conclusions: This study failed to corroborate a previously reported association between the C3435T polymorphism in the human MDR1 gene and pharmacoresistant epilepsy. Whether the C3435T polymorphism can act as a marker for the natural history of treated epilepsy remains to be determined.
Summary:Purpose: Pregabalin (PGB) is an α 2 -δ ligand with demonstrated efficacy in epilepsy, neuropathic pain, and anxiety disorders. PGB is highly efficacious as adjunctive therapy in patients with refractory partial seizures.Methods: Given its efficacy as adjunctive therapy, the potential for interaction of PGB with other antiepileptic drugs (AEDs) was assessed in patients with partial epilepsy in open-label, multipledose studies. Patients received PGB, 600 mg/day (200 mg q8h) for 7 days, in combination with their individualized maintenance monotherapy with valproate (VPA), phenytoin (PHT), lamotrigine (LTG), or carbamazepine (CBZ).Results: Trough steady-state concentrations of CBZ (and its epoxide metabolite), PHT, LTG, and VPA were unaffected by concomitant PGB administration. Likewise, PGB steady-state pharmacokinetic parameter values were similar among patients receiving CBZ, PHT, LTG, or VPA and, in general, were similar to those observed historically in healthy subjects receiving PGB alone. The PGB-AED combinations were generally well tolerated. PGB may be added to VPA, LTG, PHT, or CBZ therapy without concern for pharmacokinetic drug-drug interactions.
Summary:Purpose: To determine at steady state (in the same group of patients): (a) the pharmacokinetics (PK) of lamotrigine (LTG) with LTG monotherapy, (b) the PK of LTG concomitantly administered with topiramate (TPM) at three escalating TPM doses (100, 200, and 400 mg/day), (c) the PK of TPM at three escalating TPM doses while receiving fixed-dose LTG therapy, and (d) the PK of TPM with TPM monotherapy. Methods:This was an open-label, sequential, single-group, dose-escalating PK study in which 13 patients with epilepsy not optimally controlled with LTG received stable-dose LTG monotherapy for 2 weeks, followed by stable-dose LTG therapy combined with escalating doses of TPM for ≤16 weeks, stabledose TPM therapy combined with tapered-dose LTG therapy for 4 weeks, and stable-dose TPM monotherapy for 2 weeks. Serial blood and urine samples were collected before and during TPM dosing, and safety data were collected throughout the study. Results:The exposure, or area under the plasma LTG concentration-time curve within a dosing interval at steady state (AUC ss ), did not change in the presence of TPM, with mean AUC ss values ranging at each TPM dose level between 66 and 81 mg×h/L with concomitant LTG/TPM therapy compared with 77 mg×h/L with LTG monotherapy. No significant change was found in the steady-state peak (C max ) and trough (C min ) plasma levels of LTG in the presence and absence of TPM. The mean (±SD) oral clearance (CL/F) of TPM (400 mg/day) was 2.6 ± 1.1 L/h when given alone and 2.7 ± 0.7 L/h when given with LTG. The similarity of CL/F values also was reflected by the similar exposure (AUC ss ), C max , and C min values of TPM in the absence, and presence of LTG.Conclusions: The results of this study show that no PK interaction between TPM and LTG was observed at the doses used in this study. Key Words: Topiramate-Lamotrigine-Antiepileptic drugs (AEDs)-Drug interactions-Epilepsy.Topiramate (TPM, TOPAMAX ) is an antiepileptic drug (AED) that has been approved in >75 countries worldwide as adjunctive therapy for refractory partialonset seizures, primary generalized tonic-clonic seizures and Lennox-Gastaut syndrome and as monotherapy in refractory partial-onset seizures and newly diagnosed epilepsy in adults (1-4). It is currently being evaluated for its effect in various neurologic and psychiatric disorders.The pharmacokinetics (PK) of TPM is characterized by linear PK (in a dose range of 100-800 mg), low oral clearance (22-36 ml/min), which in monotherapy is pre- dominantly through renal excretion (renal clearance, 10-20 ml/min), and a long half-life (19-25 h), which is reduced when coadministered with inducing AEDs such as phenytoin (PHT) and carbamazepine (CBZ) (4-9). The absolute bioavailability or oral availability of TPM is 81-95% and was not affected by food (6). Although TPM is not extensively metabolized when administered in monotherapy (fraction metabolized, <20%) (4,10), its metabolism is induced during polytherapy with CBZ and PHT, and consequently, its fraction metabolized increases (5,8,9)....
This proof-of-principle study suggests that genetic variants in EPHX1 can be used to predict maintenance doses of carbamazepine. A large-scale prospective investigation of genetic influences on drug dosing strategies in epilepsy, with specific focus on whole gene variability for those proteins involved in the pharmacokinetics and pharmacodynamics of antiepileptic agents, is warranted.
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