Effect of felbamate on clobazam and its metabolite kinetics in patients with epilepsy

The authors report preliminary findings on the effect of the new generation antiepileptic drug (AED) felbamate (FBM) on steady state plasma concentrat ions of clobazam (CLB), a benzodiazepine (frequently used as add-on therapy in patients with refractory epilepsy) and its active metabolite n-desmethy l-clobazam (N-CLB). The authors prospectively collected plasma samples from 66 children and adults with epilepsy receiving chronic CLB therapy. On the basis of concomitant AEDs, patients were divided into three subgroups othe rwise comparable for age and weight-adjusted daily dose of CLB: group A (n = 22), receiving CLB monotherapy or CLB plus AEDs without inducing properti es of cytochrome P450 (CYP) metabolism, namely valproic acid (VPA) or lamot rigine (LTG); group B (n = 28), receiving CLB plus AED inducer polytherapy (carbamazepine, phenobarbital, phenytoin), even associated with VPA (n = 9) or LTG (n = 12); group C (n = 16), receiving CLB plus FBM, associated with AED inducers, VPA or LTG. Level to weight-adjusted dose ratio (LID) of CLB in groups B and C was twofold lower compared to group A (p < 0.001). LID o f N-CLB was twofold higher in group B and fivefold in group C compared to g roup A (p < 0.001). The metabolite-to-parent drug ratio shifted from a medi an value of 2.8 in group A to 13 in group B, and up to 29 in patients recei ving polytherapy with FBM (p < 0.001). These data confirm previous reports of a significant increase in CLB clearance in patients receiving AED induce rs, leading to an accumulation of its main metabolite. They also provide no vel evidence of a further marked increase in N-CLB plasma concentrations in patients receiving FBM cotherapy. From a clinical point of view, this find ing should be kept in mind in explaining possible toxicity in patients on c omplex AED polytherapy. Furthermore, knowledge of the in vivo interaction b etween CLB and FBM could help in identifying the CYP isoforms involved in t he metabolism of both CLB and N-CLB.