Ethosuximide lowers lamotrigine serum concentrations: Evidence for a clinically relevant interaction.

We investigated the effect of comedication with ethosuximide (ESM) on lamotrigine (LTG) blood levels. Based on observations from clinical practice, we hypothesized that ESM reduces the LTG serum concentration. We additionally evaluated this effect in the presence of concomitant valproic acid (VPA). We retrospectively analyzed samples of inpatients from our department who had been treated with a combination of ESM and LTG between 2017 and 2021. We additionally used data on LTG serum concentrations from a previously published cohort from our center. Generalized estimation equations (GEEs) were used for statistical analyses. We included 523 samples from 209 patients. GEE analyses showed that LTG trough serum concentrations were significantly lower in samples with ESM comedication and significantly higher in samples with concomitant VPA. The effect of ESM was moderated by patients' age; in children and adolescents, LTG serum concentrations were 37% lower than in samples without ESM, whereas in adults, LTG serum concentrations were 14% lower. The effect we found in our data is relevant to daily clinical practice, if patients are not seizure-free despite typical daily LTG dosage, or if they develop side effects during ESM withdrawal. It should be considered especially in children and adolescents.

A retrospective non-interventional study evaluating the pharmacokinetic interactions between cenobamate and clobazam.

Cenobamate is an antiseizure medication (ASM) approved for the treatment of partial-onset seizures in adults. As both an inductor and an inhibitor of hepatic enzymes, cenobamate affects the metabolism of other ASMs, among which is clobazam. To our knowledge, the extent of interaction between cenobamate and clobazam and its clinical significance have not been studied yet. In this retrospective study we assessed serum concentrations of clobazam and N-desmethylclobazam (NCLB)in five patients before and after co-medication with cenobamate and calculated the percentage increase in concentration-to-dose ratio (CDR) of both. We were able to demonstrate that the addition of cenobamate resulted in an increase in serum concentration and consequently in CDR of NCLB in all patients. However this occurred in variable degrees: NCLB concentration showed an increase of 1208 µg/L (CDR145%) in one patient and between 1691 µ/L (CDR 819%) and 3995 µ/L (CDR 1852%) in the other four. This resulted in fatigue, which improved after dose reduction of CLB. Therefore, it is to be concluded that concomitant administration of cenobamate and clobazam can lead to a substantial increase in serum concentrations of NCLB. This can have a positive therapeutic effect on one hand; however, on the other hand, this can lead to unwanted fatigue.

Validation of Conversion Factors for Therapeutic Drug Monitoring of Lacosamide, Lamotrigine, and Levetiracetam in Dried Capillary Blood.

BACKGROUND: Estimation of serum concentrations of antiseizure medications (ASMs) based on dried capillary blood is an alternative method for therapeutic drug monitoring of epilepsy. The aim of this study was to validate the conversion factors for lacosamide (LCM), lamotrigine (LTG), and levetiracetam (LEV), which were determined in an independent patient sample in a previous study, and identify the most accurate conversion method (simple ratio and regression). METHODS: Venous and capillary blood samples were collected from adult inpatients with epilepsy treated with LCM (n = 25), LTG (n = 27), and/or LEV (n = 29) before the morning dose (T1) and approximately 2 hours after (T2). Capillary blood was collected using volumetric absorptive microsampling, and the ASM concentrations were measured using a validated liquid chromatography-mass spectrometry method for dried blood samples. Serum concentrations were estimated using conversion factors and compared with those measured using routine laboratory methods. RESULTS: For all 3 ASMs, the simple ratio approach performed better than the regression approach. Intraclass correlation coefficients revealed a high agreement between the estimated and measured serum concentrations (LCM T1: 0.93, T2: 0.90; LTG T1: 0.91, T2: 0.91; and LEV T1: 0.97, T2: 0.94). The criteria of the European Medicines Agency for cross-validation were fulfilled for LCM (T1: 72%; T2: 75%) and LEV (T1: 86%; T2: 75%), whereas for LTG, this was only true for capillary blood concentrations ≤11 µ g/mL [42.9 µ mol/L; T1: 72% (vs. 63% for total range), T2: 67% (vs. 62%)]. CONCLUSIONS: Estimating serum concentrations using capillary blood concentrations is feasible and accurate for LCM and LEV over a wide concentration range, as found in clinical practice. The applicability of this mehod for LTG is limited by its greater variability at higher concentrations; however, acceptable results were achieved for the large proportion of patients with low and medium LTG concentrations.

Therapeutic Drug Monitoring of Lamotrigine, Lacosamide, and Levetiracetam in Dried Capillary Blood-Determination of Conversion Factors for Serum-Based Reference Ranges.

BACKGROUND: Drug concentrations of antiepileptic drugs (AEDs) are routinely determined from blood serum or plasma at trough levels (before intake of morning dose). In capillary blood collection, blood is taken from the fingertip with the aid of a disposable tool and dried on absorbent material. The volumetric absorptive microsampling technique offers several advantages over the use of filter paper cards. The aim of this study was to determine conversion factors for the estimation of AED serum concentrations from capillary blood concentrations. METHODS: Venous and capillary blood samples were collected from adult inpatients with epilepsy who were treated with lacosamide (LCM, n = 30), lamotrigine (LTG, n = 40), and/or levetiracetam (LEV, n = 36). A validated liquid chromatography-mass spectrometry (LC-MS) method for dried blood samples for these AEDs was compared with routine serum laboratory methods. Method agreement was evaluated using different regression techniques, and the conversion factors were calculated. RESULTS: Regression analyses revealed a linear relationship between serum and capillary blood concentrations for all 3 AEDs (r ≥ 0.95). For LTG, the regression intercept was significantly different from 0, indicating that the relationship was linear, but not necessarily proportional. Although LEV and LCM concentrations tended to be lower in capillary blood than in serum (mean ratio of serum concentration to capillary blood concentration: 1.14 and 1.22, respectively), LTG concentrations were higher in capillary blood (mean ratio = 0.85). CONCLUSIONS: The estimation of serum concentrations from measured capillary blood concentrations is feasible for LCM, LTG, and LEV. A simple ratio approach using the mean ratio and Passing-Bablok regression showed the best results for all 3 AEDs. The volumetric absorptive microsampling technique facilitates the quantitative sample collection of capillary blood and overcomes the drawbacks associated with the classical dried blood spot technique.

Development and validation of an LC-MS/MS method for relevant drugs in epilepsy patients using dried blood spots.

Epilepsy is one of the most common diseases of the central nervous system globally. To ensure the correct dosage of antiepileptic treatment, it is helpful to check the blood levels of the administered substances regularly. The analysis of the capillary dried blood samples provides a promising and less-invasive alternative to venous blood collection. Therefore, the aim of the present study was to develop an LC-MS method for the quantification of 22 commonly used drugs in patients with an epileptic syndrome and 5 drug metabolites in one dried blood spot (DBS). The calibration ranges were selected in such a way that the therapeutic reference ranges in serum for the respective substances were completely covered. The analytical validation was successfully performed according to relevant guidelines with a consideration of requirements for DBS analysis. Proof of concept of the developed method was obtained by the analysis of DBSs from 282 authentic leftover ethylenediaminetetraacetic acid blood samples, which were compared with the corresponding serum concentrations. Altogether, the results show a dependency on the blood/plasma (b/p) ratios of the respective analytes so that for drugs with b/p ratios close to one, for example, lacosamide, levetiracetam, brivaracetam, and sertraline, a good accordance was observed.

Influence of dose and antiepileptic comedication on brivaracetam serum concentrations in patients with epilepsy.

The aim of this study was to investigate the influence of concomitant antiepileptic drugs (AEDs) on brivaracetam (BRV) trough serum concentrations. A total number of 368 routinely collected blood samples from 148 inpatients from Mara Hospital (Bethel Epilepsy Center) and von Bodelschwingh Foundation Bethel were retrospectively evaluated. Generalized estimation equations (GEEs) were used for statistical analysis. GEE analyses showed that BRV trough serum concentrations were significantly lower in patients with strong enzyme-inducing AEDs (carbamazepine, phenytoin, and/or phenobarbital/primidone, -49%), but were not affected by concomitant intake of oxcarbazepine or eslicarbazepine. Age and gender did not have a significant effect. An alternative GEE model analyzing the BRV level-to-dose ratios yielded comparable results. Our results from routine therapeutic drug monitoring data indicate that the effect of enzyme-inducing AEDs on BRV serum concentrations is stronger than the 20%-30% reduction in BRV exposure previously reported in pharmacokinetics studies. Further research is necessary to evaluate these differences and to elucidate possible clinical consequences.

E-64c-hydrazide: a lead structure for the development of irreversible cathepsin†C inhibitors.

Cathepsin C is a papain-like cysteine protease with dipeptidyl aminopeptidase activity that is thought to activate various granule-associated serine proteases. Its exopeptidase activity is structurally explained by the so-called exclusion domain, which blocks the active-site cleft beyond the S2 site and, with its Asp 1 residue, provides an anchoring point for the N terminus of peptide and protein substrates. Here, the hydrazide of (2S,3S)-trans-epoxysuccinyl-L-leucylamido-3-methylbutane (E-64c) (k2/Ki =140±5 M(-1) s(-1)) is demonstrated to be a lead structure for the development of irreversible cathepsin C inhibitors. The distal amino group of the hydrazide moiety addresses the acidic Asp 1 residue at the entrance of the S2 pocket by hydrogen bonding while also occupying the flat hydrophobic S1'-S2' area with its leucine-isoamylamide moiety. Furthermore, structure-activity relationship studies revealed that functionalization of this distal amino group with alkyl residues can be used to occupy the conserved hydrophobic S2 pocket. In particular, the n-butyl derivative was identified as the most potent inhibitor of the series (k2/Ki =56 000±1700 M(-1) s(-1)).

Structure-Activity Relationship for Thiirane-Based Gelatinase Inhibitors.

An extensive structure-activity relationship study with the template of 2-(4-phenoxyphenylsulfonylmethyl)thiirane (1), a potent and highly selective inhibitor for human gelatinases, is reported herein. Syntheses of 65 new analogs, each in multistep processes, allowed for exploration of key structural components of the molecular template. This study reveals that the presence of the sulfonylmethylthiirane and the phenoxyphenyl group were important for gelatinase inhibition. However, para- and some meta-substitutions of the terminal phenyl ring enhanced inhibitory activity, and led to improve metabolic stability. This agrees with the result from metabolism studies with compound 1 that the primary route of biotransformation is oxidation, mainly at the para position of the phenyl ring and alpha position of the sulfonyl group in the aliphatic side chain.