Efficacy, tolerability and pharmacokinetic variability of brivaracetam in adults with difficult-to-treat epilepsy.

PURPOSE: Brivaracetam (BRV) is one of our latest antiseizure medications (ASMs). It is an analogue of levetiracetam with limited real-life experience. The purpose of this study was to evaluate clinical experience with BRV with focus on efficacy, tolerability and pharmacokinetic variability among adult patients with difficult-to-treat epilepsy. METHODS: We retrospectively collected clinical and laboratory data from patients aged > 18 years who initiated treatment with BRV during 2016-2019 and were followed for > one year or cessation of BRV. RESULTS: The study cohort consisted of 120 adults with drug-resistant epilepsy. Serum concentrations of BRV were available in 72 patients. After one-year follow-up, the retention rate of BRV was 52%. Fifty-seven patients (48%) were responders (>50 reduction of seizure frequency), of whom six became seizure free. Adverse effects were reported in 78 patients (65%); 37 (31%) experienced psychiatric problems like increased irritability, anxiety and depressive symptoms. The mean daily BRV dose was 159 mg (SD 80 mg) and the mean serum concentration 5.4 µmol/L (SD 4.1 µmol/L). In 24 patients, BRV replaced levetiracetam. Pharmacokinetic variability between patients was considerable; 14-fold variation in concentration/dose (C/D)-ratios. Concomitant use of enzyme-inducing ASMs decreased the C/D-ratio by 48%. There were no significant differences in serum concentrations between responders vs. non-responders, or those who experienced adverse effects or not. CONCLUSION: After > 1 year of treatment with BRV, we found a responder rate of 48% in adult patients with difficult-to-treat epilepsy. The drug was largely well tolerated, but one third experienced psychiatric adverse effects. The combination of clinical and pharmacokinetic data provides insight into factors contributing to efficacy and tolerability of new ASMs.

The Impact of Pharmacokinetic Interactions With Eslicarbazepine Acetate Versus Oxcarbazepine and Carbamazepine in Clinical Practice.

BACKGROUND: Eslicarbazepine acetate (ESL) is a new anti-epileptic drug (AED) chemically related to oxcarbazepine (OXC) and carbamazepine (CBZ) and is increasingly used in clinical practice. The purpose of the study was to investigate 2-way pharmacokinetic interactions between ESL and other AEDs as compared to OXC and CBZ. METHODS: Anonymous data regarding age, gender, use of AEDs, daily doses and serum concentration measurements of ESL, OXC, CBZ and lamotrigine (LTG) and other AEDs were retrieved from 2 therapeutic drug monitoring (TDM) databases in Norway. Drugs were categorized according to their known potential for interactions. Concentration/dose (C/D) ratios were calculated. RESULTS: Data from 1100 patients were available. The C/D ratios of ESL and OXC were unchanged in combination with enzyme-inducing AEDs or valproate (VPA). The C/D ratio of CBZ decreased by 40% and 22% in combination with other enzyme-inducing AEDs or VPA, respectively, pointing to an increased clearance. ESL demonstrated no significant enzyme-inducing effect on LTG metabolism although there was a 20% and 34% decrease in the C/D ratio of LTG in combination with OXC and CBZ, respectively. CONCLUSIONS: Possible pharmacokinetic interactions have been studied for ESL as compared to OXC and CBZ. The pharmacokinetics of ESL is not affected by enzyme-inducing AEDs or VPA and does not affect the metabolism of LTG in contrast to OXC and CBZ. The study demonstrates the value of using TDM databases to explore the potential for pharmacokinetic interactions of new AEDs.

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 µmol·L·mg). 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.

Experience from therapeutic drug monitoring and gender aspects of gabapentin and pregabalin in clinical practice.

PURPOSE: Gabapentin and pregabalin are antiepileptic drugs (AEDs) with epilepsy and neuropathic pain indications. The purpose of this study was to investigate pharmacokinetic variability of gabapentin and pregabalin and indications for therapeutic drug monitoring (TDM) in clinical practice with focus on gender aspects. METHOD: Anonymous data from routine TDM-service at the National Center for Epilepsy regarding serum concentration measurements of gabapentin and pregabalin, 2009-2013, were utilised. All included samples were drug-fasting in the morning at steady-state. RESULTS: In total, 356 patients were included; gabapentin 189 (66% women), average age 53 years and pregabalin 167 (56% women), average age 50 years. For gabapentin, mean serum concentration/dose(C/D)-ratio was similar across genders. Only 13% of the patients had concentrations above the lower limit of the reference range (70-120 µmol/L), which indicates a need for reevaluation of the reference range. For pregabalin, the C/D-ratio in women (0.08±0.06) was 42% higher than in men (0.056±0.05; p<0.05). The pharmacokinetic variability (C/D-ratio) was >100-fold for both gabapentin and pregabalin. An indication of use (epilepsy/pain/other) was stated in only 26% of the cases (n=94). Epilepsy was assumed as indication when other AEDs were also measured (50% of patients). This was similar for both genders and for both AEDs. Indications for TDM were stated in 155 cases (44%) and were similar for gabapentin and pregabalin. CONCLUSION: Gabapentin and pregabalin are more used in women than in men, and routine use of TDM is most common in patients with epilepsy. Pharmacokinetic variability is extensive, highlighting a need for individualisation of therapy regardless of indication.

Long-term stability of GHB in post-mortem samples and samples from living persons, stored at -20°C, using fluoride preservatives.

PURPOSE: Reanalyses are frequently requested in forensic toxicology, and knowledge of the stability of drugs in biological samples is of major importance for the interpretation of the toxicological findings. Currently, the literature on stability of gammahydroxybutyrate (GHB) in blood samples from living subjects and in post-mortem blood is limited. The purpose of this study was to evaluate the long-term stability of GHB in both blood samples from persons suspected of drug use and post-mortem blood samples. METHODS: A total of 59 reanalyses were performed in whole blood samples, 27 samples from living subjects and 32 samples taken at autopsies. The samples were stored in the freezer between 0.4 and 7.2 years at -20°C in vials containing preservatives. Analyses were performed by GC-FID, and cut-off level was 10.3 mg/L. The concentrations in 22 of the samples were below cut-off. RESULTS: The mean change in concentration between initial analysis and reanalysis was -0.8% for the positive samples from living persons and -7.1% for the positive post-mortem samples. Changes ranged from -32.4% to 21.0% for samples from living and from -30.4% to 34.4% for post-mortem samples. All negative samples were still negative at the time of reanalysis. CONCLUSION: Reanalysis of these forensic whole blood samples stored several years at -20°C with fluoride preservation did not exhibit changes in GHB concentrations of practical significance for the interpretation of toxicological findings.