Intranasal administration of antiseizure medications in chronic and emergency treatment: Hopes and challenges.

Despite the availability of many antiseizure medications (ASMs), 30 % of patients experience pharmacoresistant seizures. High-throughput screening methods undoubtedly remain one of the most important approaches for discovering new molecules to treat seizures. However, the costly and time-consuming nature of drug development prompts us to explore alternative strategies to counteract drug-resistant seizures. One such approach is to consider intranasal administration of known molecules for seizure treatment. In the case of treating epileptic seizures, administering ASMs intranasally may enhance treatment effectiveness and minimize adverse effects. A good example of changes in drug administration is the intranasal administration of fentanyl, which has become a clinical standard in the emergency setting to treat moderate to severe pain in adults and children. This review discusses the utilization of intranasally administered ASMs for both acute and chronic seizures. It addresses various targeted pharmacokinetic approaches, challenges and prospects associated with these regimens. Brief neuroanatomical and molecular rationale for nose-to-brain drug transport is also presented. Furthermore, recent preclinical studies validating the efficacy and brain distribution following intranasal administration of the most commonly used drugs in chronic treatment are also discussed.

Adaptive Dosage Strategy of Levetiracetam in Chinese Epileptic Patients: Focus on Pregnant Women.

There is presently no efficient dose individualization strategy for the use of antiseizure medications in epileptic pregnant patients. This study aimed to develop a population pharmacokinetics model for levetiracetam and propose a tailored adaptive individualized dosage strategy for epileptic pregnant patients. A total of 322 levetiracetam plasma concentrations from 238 patients with epilepsy were included, including 216 women with epilepsy (20.83% of whom were pregnant). The levetiracetam plasma concentration was measured using a validated ultra-performance liquid chromatography-tandem mass spectrometry assay, and the data were modeled using a nonlinear mixed-effects model. The resultant model served as the basis for simulating the dosage adjustment strategy. A one-compartment model with first-order elimination best described the pharmacokinetic data of levetiracetam. The apparent clearance (CL/F) was 3.43 L/h (95% CI 3.30-3.56) and the apparent volume of distribution was 43.7 L (95% CI 40.4-47.0) for a typical individual of 57.2 kg. Pregnancy and body weight were found to be significant covariates of CL/F of levetiracetam. The recommended regimen of levetiracetam could be predicted by the population pharmacokinetic model based on body weight, gestational age, and the daily dose of levetiracetam taken before pregnancy.

Cenobamate enhances the anticonvulsant effect of other antiseizure medications in the DBA/2 mouse model of reflex epilepsy.

Clinical studies documented that cenobamate (CNB) has a marked efficacy compared to other antiseizure medications (ASMs) in reducing focal seizures. To date, different aspects of CNB need to be clarified, including its efficacy against generalized seizures. Similarly, the pattern of drug-drug interactions between CNB and other ASMs also compels further investigation. This study aimed to detect the role of CNB on generalized seizures using the DBA/2 mouse model. We have also studied the effects of an adjunctive CNB treatment on the antiseizure properties of some ASMs against reflex seizures. The effects of this adjunctive treatment on motor performance, body temperature, and brain levels of ASMs were also evaluated. CNB was able to antagonize seizures in DBA/2 mice. CNB, at 5 mg/kg, enhanced the antiseizure activity of ASMs, such as diazepam, clobazam, levetiracetam, perampanel, phenobarbital, topiramate, and valproate. No synergistic effects were observed when CNB was co-administered with some Na+ channel blockers. The increase in antiseizure activity was associated with a comparable intensification in motor impairment; however, the therapeutic index of combined treatment of ASMs with CNB was more favorable than the combination with vehicle except for carbamazepine, phenytoin, and oxcarbazepine. Since CNB did not significantly influence the brain levels of the ASMs studied, we suggest that pharmacokinetic interactions seem not probable. Overall, this study shows the ability of CNB to counteract generalized reflex seizures in mice. Moreover, our data documented an evident synergistic antiseizure effect for the combination of CNB with ASMs including phenobarbital, benzodiazepines, valproate, perampanel, topiramate, and levetiracetam.

Population Pharmacokinetics of Topiramate in Patients with Epilepsy Using Nonparametric Modeling.

BACKGROUND: Topiramate (TPM) is used for the treatment of various epileptic seizures and the prevention of migraine. This study aimed to develop a population pharmacokinetic model and identify covariates that influence TPM behavior in patients with epilepsy in Kuwait. METHODS: Data were collected retrospectively from 108 patients (2 years old and above) with epilepsy who were treated with oral TPM and 174 TPM blood samples from 3 hospitals in Kuwait from 2009 to 2016. Data were randomly divided into 2 groups for model development and validation. The population pharmacokinetic model was built using the nonparametric modeling algorithm (Pmetrics). The model was evaluated internally through the visual predictive check method and externally using a new data set. RESULTS: A 1-compartment model with first-order elimination fitted the data well. Covariates showing a significant effect on the elimination rate constant were renal function and coadministration of carbamazepine (CBZ). The mean estimated clearance was 2.11 L/h; this was 50% higher for patients coadministered with CBZ. Age and sex were essential covariates for the volume of distribution (V). The visual predictive check of the final model could predict the measured concentrations. External validation further confirmed the favorable predictive performance of the model with low bias and imprecision for predicting the concentration in a particular population. CONCLUSIONS: TPM elimination was increased with CBZ coadministration and was affected by renal function. Meanwhile, age and sex were the main predictors for V. The predictive performance of the final model proved to be valid internally and externally.

Pharmacokinetics and safety of Padsevonil in healthy Chinese subjects and comparison of two sampling methods for Padsevonil quantification.

OBJECTIVE: Padsevonil (PSL) is a novel antiepileptic drug candidate that inhibits seizure activity in both presynaptic and postsynaptic ways. The pharmacokinetic (PK) profiles and volumetric absorptive microsampling (VAMS) application of PSL in the Chinese population are limited. The objectives of this study were to evaluate the PK profile of PSL and its 2 metabolites, the safety of PSL, and compare the PK profile of PSL from samples collected using the VAMS technique with that of conventional venous samples in healthy Chinese subjects. SUBJECTS AND METHODS: In this randomized, double-blind, placebo-controlled single-dose study, the participants received either 200 mg PSL or placebo. Blood samples for the PK variables were collected using both the traditional venous method and the VAMS Mitra® technique at the scheduled time points. The PK parameters of PSL and 2 metabolites were calculated, and the concentration agreement of VAMS and venous samples were also evaluated. RESULTS: A total of 14 subjects were enrolled. The concentration-time profile of PSL showed rapid absorption with a median tmax of 1.25 h (range: 0.5 to 3.0), followed by an apparent biphasic disposition. For PSL, the geometric means of AUC(0-t), AUC, Cmax, and t1/2 were 6,573 h*ng/mL, 6,588 h*ng/mL, 1,387 ng/mL, and 5.275 h, respectively. The geometric mean body weight-normalized AUC(0-t), AUC, and Cmax were 5,712 h*ng/mL, 5,725 h*ng/mL, and 1,205 ng/mL, respectively. The AUC(0-t), AUC, Cmax of PSL and metabolites in VAMS-dried blood were all lower than those in plasma. The Passing-Bablok regression showed that the PSL and metabolite concentrations obtained by VAMS analysis were comparable to those obtained by plasma at some time points. The most frequently reported treatment-emergent adverse events (TEAEs) were somnolence and dizziness. There were no serious TEAEs, severe TEAEs, discontinuations due to TEAEs, or deaths reported during this study. No clinically significant laboratory, vital signs, electrocardiograph (ECG), or physical examination results were reported. CONCLUSIONS: PSL has a favorable PK profile after single-dose oral administration and good safety properties in healthy Chinese volunteers. The regression analysis results of VAMS and plasma indicated that the application of VAMS for therapeutic drug monitoring in novel antiepileptic drug development is promising and needs further validation.

Pharmacological aspects of antiseizure medications: From basic mechanisms to clinical considerations of drug interactions and use of therapeutic drug monitoring.

Antiseizure medications (ASMs) are the cornerstone of treatment for patients with epilepsy. Several new ASMs have recently been introduced to the market, making it possible to better tailor the treatment of epilepsy, as well as other indications (psychiatry and pain disorders). For this group of drugs there are numerous pharmacological challenges, and updated knowledge on their pharmacodynamic and pharmacokinetic properties is, therefore, crucial for an optimal treatment outcome. This review focuses on educational approaches to the following learning outcomes as described by the International League Against Epilepsy (ILAE): To demonstrate knowledge of pharmacokinetics and pharmacodynamics, drug interactions with ASMs and with concomitant medications, and appropriate monitoring of ASM serum levels (therapeutic drug monitoring, TDM). Basic principles in pharmacology, pharmacokinetic variability, and clinically relevant approaches to manage drug interactions are discussed. Furthermore, recent improvements in analytical technology and sampling are described. Future directions point to the combined implementation of TDM with genetic panels for proper diagnosis, pharmacogenetic tests where relevant, and the use of biochemical markers that will all contribute to personalized treatment. These approaches are clinically relevant for an optimal treatment outcome with ASMs in various patient groups.

Therapeutic Drug Monitoring of Perampanel in Children With Refractory Epilepsy: Focus on Influencing Factors on the Free-Perampanel Concentration.

BACKGROUND: This study aimed to assess the effect of perampanel dose, age, sex, and antiseizure medication cotherapy on steady-state free-perampanel concentration in children with refractory epilepsy, as well as the relationship between inflammation and the pharmacokinetics of perampanel. METHODS: This prospective study in China included 87 children with refractory epilepsy treated with adjunctive perampanel therapy. Free and total perampanel concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Free-perampanel concentration was compared among patients with various potential influencing factors. RESULTS: A total of 87 pediatric patients (44 female children) aged 2-14 years were enrolled. The mean free-perampanel concentration and free concentration-to-dose (CD) ratio in plasma were 5.7 ± 2.7 ng/mL (16.3 ± 7.7 nmol/L) and 45.3 ± 21.0 (ng/mL)/(mg/kg) [129.6 ± 60.1 (nmol/L)/(mg/kg)], respectively. The protein binding of perampanel in plasma was 97.98%. A linear relationship was observed between perampanel dose and free concentration in plasma, and a positive relationship was found between the total and free-perampanel concentrations. Concomitant use of oxcarbazepine reduced the free CD ratio by 37%. Concomitant use of valproic acid increased the free CD ratio by 52%. Five patients had a plasma high-sensitivity C-reactive protein (Hs-CRP) level of >5.0 mg/L (Hs-CRP positive). The total and free CD ratios of perampanel were increased in patients with inflammation. Two patients with inflammation developed adverse events, which disappeared as the Hs-CRP level returned to normal, and neither required perampanel dose reduction. Age and sex did not influence the free-perampanel concentration. CONCLUSIONS: This study found complex drug interactions between perampanel and other concomitant antiseizure medications, providing valuable information to enable clinicians to apply perampanel in the future reasonably. In addition, it may be important to quantify both the total and free concentrations of perampanel to assess complex pharmacokinetic interactions.

Development and Validation of Physiologically Based Pharmacokinetic Model of Levetiracetam to Predict Exposure and Dose Optimization in Pediatrics.

Levetiracetam (Lev) is an antiepileptic drug that has been increasingly used in the epilepsy pediatric population in recent years, but its pharmacokinetic behavior in pediatric population needs to be characterized clearly. Clinical trials for the pediatric drug remain difficult to conduct due to ethical and practical factors. The purpose of this study was to use the physiologically based pharmacokinetic (PBPK) model to predict changes in plasma exposure of Lev in pediatric patients and to provide recommendations for dose adjustment. A PBPK model of Lev in adults was developed using PK-Sim® software and extrapolated to the entire age range of the pediatric population. The model was evaluated using clinical pharmacokinetic data. The results showed the good fit between predictions and observations of the adult and pediatric models. The recommended doses for neonates, infants and children are 0.78, 1.67 and 1.22 times that of adults, respectively. Moreover, at the same dose, plasma exposure in adolescents was similar to that of adults. The PBPK models of Lev for adults and pediatrics were successfully developed and validated to provide a reference for the rational administration of drugs in the pediatric population.

Pharmacogenomics of oxcarbazepine in the treatment of epilepsy.

Oxcarbazepine (OXC) is one of the preferred drugs for partial seizures and generalized tonic-clonic seizures. However, clinical studies have found that there are considerable differences among different populations in OXC therapeutic efficacy or safety that result from the function changes of metabolic enzymes, transporters and other receptors involved in pharmacokinetics and pharmacodynamics in vivo. The authors collected all the information on the clinically reported associations between variants of common genes (e.g., UGT1A9, HLA-B, ABCB1) and OXC. In conclusion, these associations based on variants are beneficial for adjusting the medication regimen, which could be useful for individualized treatment with OXC.

As a new-generation aromatic antiepileptic drug, oxcarbazepine (OXC) is often used for epilepsy treatment. It is known that when OXC is absorbed, it is reduced to an active metabolite in the liver and enters the brain through the blood circulation to play an antiepileptic role. Therefore, the variations of proteins participating in the process, including drug metabolic enzymes, transporters, drug targets and other receptors, have an effect on the efficacy and safety of OXC in vivo. In this study, the associations of some variants of common genes with OXC are summarized to provide epileptic patients an appropriate dose of OXC or reduce the risk of OXC-induced toxicity, which are in favor of personalized OXC treatment for patients with epilepsy.

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.

Effects of UGT1A, CYP2C9/19 and ABAT polymorphisms on plasma concentration of valproic acid in Chinese epilepsy patients.

Aim: To evaluate the association between genetic polymorphisms and plasma concentration-to-dose ratio of valproic acid (CDRV) in Chinese epileptic patients. Methods: A total of 46 epileptic patients treated with valproic acid therapy were enrolled. 18 SNPs in nine genes related to valproic acid were directly sequenced with Sanger methods. Results: Patients carrying UGT1A6 heterozygous genotypes had significantly lower CDRV than those carrying the wild-type genotypes. In contrast, patients with the homozygote genotypes of CYP2C9 and ABAT had higher CDRV than those with the wild-type genotypes and patients with the heterozygous genotypes of CYP2C19 had higher CDRV. Conclusion: Detection of genetic polymorphism in these genes might facilitate an appropriate dose of valproic acid for epileptic patients. Further studies with larger cohorts are necessary to underpin these observations.

Antiseizure Effects of Scoparone, Borneol and Their Impact on the Anticonvulsant Potency of Four Classic Antiseizure Medications in the Mouse MES Model-An Isobolographic Transformation.

Numerous botanical drugs containing coumarins and terpenes are used in ethnomedicine all over the world for their various therapeutic properties, especially those affecting the CNS system. The treatment of epilepsy is based on antiseizure medications (ASMs), although novel strategies using naturally occurring substances with confirmed antiseizure properties are being developed nowadays. The aim of this study was to determine the anticonvulsant profiles of scoparone (a simple coumarin) and borneol (a bicyclic monoterpenoid) when administered separately and in combination, as well as their impact on the antiseizure effects of four classic ASMs (carbamazepine, phenytoin, phenobarbital and valproate) in the mouse model of maximal electroshock-induced (MES) tonic-clonic seizures. MES-induced seizures were evoked in mice receiving the respective doses of the tested natural compounds and classic ASMs (when applied alone or in combinations). Interactions for two-drug and three-drug mixtures were assessed by means of isobolographic transformation of data. Polygonograms were used to illustrate the types of interactions occurring among drugs. The total brain content of ASMs was measured in mice receiving the respective drug treatments with fluorescent polarization immunoassay. Scoparone and borneol, when administered alone, exerted anticonvulsant properties in the mouse MES model. The two-drug mixtures of scoparone with valproate, borneol with phenobarbital and borneol with valproate produced synergistic interactions in the mouse MES model, while the remaining tested two-drug mixtures produced additivity. The three-drug mixtures of scoparone + borneol with valproate and phenobarbital produced synergistic interactions in the mouse MES model. Verification of total brain concentrations of valproate and phenobarbital revealed that borneol elevated the total brain concentrations of both ASMs, while scoparone did not affect the brain content of these ASMs in mice. The synergistic interaction of scoparone with valproate observed in the mouse MES model is pharmacodynamic in nature. Borneol elevated the brain concentrations of the tested ASMs, contributing to the pharmacokinetic nature of the observed synergistic interactions with valproate and phenobarbital in the mouse MES model.

Evaluating the efficacy of prototype antiseizure drugs using a preclinical pharmacokinetic approach.

OBJECTIVE: Pharmacokinetics (PK) of a drug drive its exposure, efficacy, and tolerability. A thorough preclinical PK assessment of antiseizure medications (ASMs) is therefore essential to evaluate the clinical potential. We tested protection against evoked seizures of prototype ASMs in conjunction with analysis of plasma and brain PK as a proof-of-principle study to enhance our understanding of drug efficacy and duration of action using rodent seizure models. METHODS: In vivo seizure protection assays were performed in adult male CF-1 mice and Sprague Dawley rats. Clobazam (CLB), N-desmethyl CLB (NCLB), carbamazepine (CBZ), CBZ-10,11-epoxide (CBZE), sodium valproate (VPA), and levetiracetam (LEV) concentrations were quantified in plasma and brain using liquid chromatography-tandem mass spectrometry. Mean concentrations of each analyte were calculated and used to determine PK parameters via noncompartmental analysis in Phoenix WinNonLin. RESULTS: NCLB concentrations were approximately 10-fold greater than CLB in mice. The antiseizure profile of CLB was partially sustained by NCLB in mice. CLB concentrations were lower in rats than in mice. CBZE plasma exposures were approximately 70% of CBZ in both mice and rats, likely contributing to the antiseizure effect of CBZ. VPA showed a relatively short half-life in both mice and rats, which correlated with a sharp decline in efficacy. LEV had a prolonged brain and plasma half-life, associated with a prolonged duration of action in mice. SIGNIFICANCE: The study demonstrates the utility of PK analyses for understanding the seizure protection time course in mice and rats. The data indicate that distinct PK profiles of ASMs between mice and rats likely drive differences in drug efficacy between rodent models.

Simulations of topiramate dosage recommendations for poor compliance events.

PURPOSE: To determine the influences of one or two consecutive missed topiramate (TPM) doses on TPM pharmacokinetics and to suggest the proper TPM replacement dosing schemes using Monte Carlo simulations. METHODS: Monte Carlo simulations were performed for various replacement dosing schemes using the parameters from the published population pharmacokinetic models. The lowest percentage of deviation of simulated concentrations outside the reference range of 5-20 mg/L from the compliance scenario for each replacement dosing scheme was used as a criterion for choosing the proper replacement dosing scheme. RESULTS: For the one missed dose, the replacement with an immediate regular dose and a partial dose resulted in the lowest and highest percentages of concentration below 5 mg/L, respectively. While the opposite results were observed for the upper bound of the reference range (20 mg/L). For the two consecutive missed doses, the replacement with one and a half-missed doses resulted in a lower percentage of deviation of concentrations below 5 mg/L from the compliance scenario than the replacement with one regular dose. CONCLUSIONS: For the one missed dose, taking an immediate regular dose might be suitable for patients who require higher TPM levels, while for patients who require lower TPM levels, an immediate partial dose could be used. For the two consecutive missed doses, an immediate one and a half regular dose might be suitable. However, these results were merely based on simulations; thus, they should be used alongside the clinician's justification based on seizure control.

Clinical Pharmacokinetic Monitoring of Free Valproic Acid Levels: A Systematic Review.

BACKGROUND: Current guidelines recommend therapeutic drug monitoring as a critical component of valproic acid (VPA) therapy. Due to high protein binding, the active unbound (free) portion of VPA can be misrepresented by total VPA serum levels in certain clinical scenarios. Monitoring free VPA serum levels may be warranted when assessing the clinical response to VPA therapy. OBJECTIVES: The aims were to conduct a systematic review to identify a therapeutic range for free VPA serum levels; to explore the correlation of free VPA serum levels with clinical toxicity and therapeutic benefit; and to examine predictors of discordance between free and total VPA levels. METHODS: Medline, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), PsycINFO, BIOSIS Previews, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from the time of database inception to June 20, 2021. Randomized controlled trials and observational studies that evaluated any patient receiving VPA with free VPA level monitoring were included. RESULTS: Of 189 citations, we identified 27 relevant studies, which included 14 observational studies, two case series, and 11 case reports. Three studies provided a therapeutic range for free VPA levels between 20 and 410 µmol/L. Two studies suggested the occurrence of hyperammonemia and thrombocytopenia at free VPA serum levels above 60 µmol/L and 103.3 µmol/L, respectively. Two studies suggested an upper limit for neurotoxicity at free VPA serum levels of 70 µmol/L and 207.9 µmol/L. Hypoalbuminemia was identified as a predictor of therapeutic discordance. CONCLUSIONS: This review demonstrates a paucity of data informing the clinical utility of free VPA serum levels. Further high-quality trials are needed to validate an optimal therapeutic range for free VPA levels.

Effects of CYP2C19 genetic polymorphisms on the pharmacokinetics of lacosamide in Korean patients with epilepsy.

OBJECTIVE: Many pharmacokinetic studies of lacosamide (LCM) have been reported, but no large-scale clinical study has been conducted on genetic polymorphisms that affect the metabolism of LCM. Therefore, we designed a pharmacogenetic study of LCM to explore the effect of genetic polymorphisms on serum LCM concentration. We evaluated the pharmacodynamic characteristics of LCM, including clinical efficacy and toxicity. METHODS: Adult patients with epilepsy who received LCM at Seoul National University Hospital were enrolled. Blood samples were obtained from 115 patients taking LCM for more than 1 month with unchanged doses and were used to analyze the serum LCM concentration, the concentration/dose (C/D) ratio and the single nucleotide polymorphisms (SNPs) of the cytochrome P450 (CYP)2C9 and CYP2C19 genes. In addition, clinical information-including efficacy, toxicity, and concomitant drugs-was collected. RESULTS: The serum LCM concentration showed a linear correlation with the daily dose (r = .66, p < .001). In genetic analysis, 43 patients (38.7%) were extensive metabolizers (EMs), 51 (45.9%) were intermediate metabolizers (IMs), and 17 (15.3%) were poor metabolizers (PMs). In the group comparison, mean serum concentrations and the C/D ratio showed significant differences between the three groups (p = .01 and p < .001, respectively). The C/D ratios of IM (27.78) and PM (35.6) were 13% and 39% higher than those of EM (25.58), respectively. In the pharmacodynamic subgroup analysis, patients in the ineffective LCM group had significantly lower serum concentrations (6.39 ± 3.25 vs. 8.44 ± 3.68 µg/ml, p = .024), whereas patients with adverse events had higher serum concentrations than those without adverse events (11.03 ± 4.32 vs. 7.4 ± 3.1 µg/ml, p < .001). Based on this, we suggest a reference range for LCM in the Korean population (6-9 µg/ml). SIGNIFICANCE: Genetic polymorphisms of the CYP2C19 gene affect the serum LCM concentration. Because efficacy and toxicity are apparently related to serum LCM levels, the genetic phenotype of CYP2C19 should be considered when prescribing LCM for patients with epilepsy.

Drug-drug interactions between psychotropic medications and oral contraceptives.

INTRODUCTION: This is a comprehensive overview of pharmacokinetic drug-drug interactions (DDIs) involving oral contraceptives (OCs) and psychotropic medications. AREAS COVERED: Medline and Embase from inception to April 2021 were searched for DDIs between OCs and psychotropic medications. They included case reports/series and cross-sectional, cross-over, placebo-controlled studies of patient cohorts and healthy females. We classified DDIs as: combined hormonal contraceptives (CHCs) acting as victim drugs (i.e. affected by psychotropic co-medications), CHCs as perpetrators, (i.e. affecting the activity of psychotropic co-medications), progestin-derivatives as victim drugs and progestin-derivatives affecting psychotropic co-medications. Alteration ratios reflecting changes in pharmacokinetic parameters before and after the DDI were estimated to approximate the extent of the DDI. EXPERT OPINION: Women taking antiepileptic agents with strong to moderate enzyme-inducing properties (carbamazepine, phenobarbital, phenytoin) or those with moderate to mild enzyme-inducing properties (cenobamate, clobazam, eslicarbazepine, felbamate, oxcarbazepine, rufinamide, topiramate) should avoid OCs. Daily doses of cytochrome P450 1A2 substrates including clozapine may need to be reduced by 50% in women taking concomitant CHCs. Compared to CHCs, the propensity of progestin-only pills for DDIs has been investigated less. We provide a summary table for clinicians containing recommendations based on literature and package inserts; whenever evidence was available, we provided dose-correction factors.

Effect of Nonadherence on Levetiracetam Pharmacokinetics and Remedial Dose Recommendations Using Monte Carlo Simulations.

BACKGROUND AND OBJECTIVE: Nonadherence to levetiracetam (LEV) use can result in subtherapeutic concentrations and increase the risk of the occurrence of seizures. The impact of missing LEV doses on its pharmacokinetics and evidence of the appropriate remedial dose is lacking. This study has determined the influence of missed LEV doses on its pharmacokinetics and has explored the appropriate remedial dosage regimens. METHODS: Monte Carlo simulation was used to assess the impacts of different remedial dosage regimens on LEV concentrations. Simulated LEV concentrations outside the individual therapeutic range were calculated for the compliance scenario and for each of the remedial dosage regimens. The percentage of deviation from the full compliance scenario was also calculated. The regimen with the lowest percentage of deviation was considered the most appropriate. RESULTS: The suitable LEV remedial dose varied across the delay times. For one missed dose, a remedial regimen with a regular dose followed by the usual dose was suitable for a delay time of less than 6 h, while a replacement with a regular dose followed by a partial dose appeared to be appropriate for a delay time of 6 h and longer. This was justified based on the concerns of LEV toxicity when the remedial dose is close to the next scheduled dose. For two consecutive missed doses, a remedial dose with one and a half of the regular dose was suitable if the gap between that and the next dose was greater than 6 h. CONCLUSIONS: The appropriate remedial dosage regimen for one and two consecutive missed doses of LEV have been proposed. These remedial regimens, however, should be applied with clinicians' judgment based on the clinical status of the patients.

Extrapolation of Efficacy from Adults to Pediatric Patients of Drugs for Treatment of Partial Onset Seizures: A Regulatory Perspective.

The US Food and Drug Administration (FDA) has concluded that the efficacy of drugs approved for the treatment of partial onset seizures (POS) in adults can be extrapolated to pediatric patients 1 month of age and above and that independent efficacy trials in this pediatric population are no longer needed. This paper focuses on the dosing, pharmacokinetic (PK), exposure-response, and clinical information that were leveraged from the approved drugs for the treatment of POS to conduct analyses that supported extrapolation of efficacy in pediatric patients. Clinical data from trials for eight drugs (levetiracetam, oxcarbazepine, topiramate, lamotrigine, gabapentin, perampanel, tiagabine, and vigabatrin) approved in both adults and pediatric patients for the treatment of POS were analyzed. Comparisons of exposures at approved doses, placebo response, and model-based exposure-response relationships were performed. Based on disease similarity, similar response to intervention, and similar exposure-response relationships in adults and pediatric patients, it was concluded that extrapolation of efficacy in pediatric patients aged 1 month and above is acceptable. PK analysis to determine pediatric dose and regimens that provide drug exposure similar to that known to be effective in adult patients with POS will be required, along with long-term open-label safety data in pediatric patients.

Influence of Umbelliferone on the Anticonvulsant and Neuroprotective Activity of Selected Antiepileptic Drugs: An In Vivo and In Vitro Study.

Umbelliferone (7-hydroxycoumarin; UMB) is a coumarin with many biological properties, including antiepileptic activity. This study evaluated the effect of UMB on the ability of classical and novel antiepileptic drugs (e.g., lacosamide (LCM), levetiracetam (LEV), phenobarbital (PB) and valproate (VPA)) to prevent seizures evoked by the 6-Hz corneal-stimulation-induced seizure model. The study also evaluated the influence of this coumarin on the neuroprotective properties of these drugs in two in vitro models of neurodegeneration, including trophic stress and excitotoxicity. The results indicate that UMB (100 mg/kg, i.p.) significantly enhanced the anticonvulsant action of PB (p < 0.01) and VPA (p < 0.05), but not that of LCM orLEV, in the 6-Hz test. Whether alone or in combination with other anticonvulsant drugs (at their ED50 values from the 6-Hz test), UMB (100 mg/kg) did not affect motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; grip strength; or passive avoidance tests, respectively. Pharmacokinetic characterization revealed that UMB had no impact on total brain concentrations of PB or VPA in mice. The in vitro study indicated that UMB has neuroprotective properties. Administration of UMB (1 µg/mL), together with antiepileptic drugs, mitigated their negative impact on neuronal viability. Under trophic stress (serum deprivation) conditions, UMB enhanced the neurotrophic abilities of all the drugs used. Moreover, this coumarin statistically enhanced the neuroprotective effects of PB (p < 0.05) and VPA (p < 0.001) in the excitotoxicity model of neurodegeneration. The obtained results clearly indicate a positive effect of UMB on the anticonvulsant and neuroprotective properties of the selected drugs.