Therapeutic Drug Monitoring of Clobazam and Its Metabolite-Impact of Age and Comedication on Pharmacokinetic Variability

Background:Clobazam (CLB) has been used as an antiepileptic drug for several decades. There is still insufficient data regarding its pharmacokinetic variability in clinical practice. The purpose of this study was to investigate pharmacokinetic variability of CLB with emphasis on the impact of age and comedication in patients with epilepsy.Methods:Serum concentration measurements of CLB and its metabolite N-desmethylclobazam (NCLB), as well as demographic and clinical data were retrieved from the routine therapeutic drug monitoring service at the National Center for Epilepsy, Norway, 2009-2013. NCLB/CLB and total (CLB + NCLB), CLB and NCLB concentration/dose (C/D) ratios were calculated.Results:550 patients (296 women/254 men), average age 27 years (range 1-86), were included. The interindividual pharmacokinetic variability was extensive, as illustrated by a 100-fold variability in serum concentration compared with dose (total C/D ratio 0.03-3.29 mu molL(-1)mg(-1)). The CLB C/D ratio was 36% lower in young children (2-9 years) than in adults (18-64 years), reflecting a higher clearance. In patients receiving phenytoin, felbamate, stiripentol, oxcarbazepine or eslicarbazepine acetate, valproate, phenobarbital, zonisamide or carbamazepine one or more of the calculated ratios were significantly different from that in patients receiving no or neutral comedications. The mean values for the different groups were in the order of 20%-230% of C/D ratios in the neutral group and 200%-950% of the NCLB/CLB ratio.Conclusions:The pharmacokinetic variability of CLB and its metabolite NCLB in clinical practice is extensive, and is influenced by drug-drug interactions, age, and pharmacogenetics. Therapeutic drug monitoring of CLB and NCLB is therefore valuable in patient management.