Model-Based Bioequivalence Analysis to Assess and Predict the Relative Bioavailability of Valproic Acid Formulations.

BACKGROUND AND OBJECTIVE: Model-based bioequivalence (MBBE) encompasses the use of nonlinear mixed effect models supporting the estimation of pharmacokinetic endpoints to assess the relative bioavailability between multi-source drug products. This application emerges as a valuable alternative to the standard non-compartmental analysis (NCA) in bioequivalence (BE) studies in which dense sampling is not possible. In this work, we aimed to assess the application of MBBE compared to traditional methods in evaluating the relative bioavailability of two formulations with different drug release properties. Additionally, we sought to predict the performance of a modified-release formulation in a multiple-dose scenario, leveraging data from a single-dose study. METHODS: MBBE analysis was implemented to estimate the BE endpoints (90% CI for the Test/Reference geometric mean ratio, T/R GMR) in area under the concentration-time curve (AUC) and maximum concentration (Cmax) using data from a single-dose, 2-period, 2-sequence BE study performed in 14 healthy subjects between a locally developed valproic acid extended-release formulation (Test) and the brand-name delayed-release formulation (Reference). RESULTS: Results were compared with the standard approach, revealing that MBBE analysis achieved higher discrimination between formulations for Cmax, addressing limitations of the experimental sampling design and highlighting an advantage for this model-based analysis even when rich data are available. Additionally, the bioequivalence outcome under the multiple-dose scenario was predicted through a simulation-based study for both total and unbound valproic acid concentrations, considering the impact of valproic acid saturable binding on BE conclusions. CONCLUSIONS: The MBBE analysis was superior to the NCA approach in detecting product-related differences, overcoming limitations in the study experimental design. Predictions for the multiple-dose scenario preclude that the extended-release properties of the Test formulation would persist at steady state, resulting in lower peak-to-trough fluctuation and bioequivalent performance in terms of the extent of drug absorption. Overall, these results should discourage unnecessary experimentation in healthy subjects.

Predictors of valproic acid steady-state serum levels in adult and pediatric psychiatric inpatients: a comparative analysis.

RATIONALE: Valproic acid (VPA) is commonly used as a second-line mood stabilizer or augmentative agent in severe mental illnesses. However, population pharmacokinetic studies specific to psychiatric populations are limited, and clinical predictors for the precision application of VPA remain undefined. OBJECTIVES: To identify steady-state serum VPA level predictors in pediatric/adolescent and adult psychiatric inpatients. METHODS: We analyzed data from 634 patients and 1,068 steady-state therapeutic drug monitoring (TDM) data points recorded from 2015 to 2021. Steady-state VPA levels were obtained after tapering during each hospitalization episode. Electronic patient records were screened for routine clinical parameters and co-medication. Generalized additive mixed models were employed to identify independent predictors. RESULTS: Most TDM episodes involved patients with psychotic disorders, including schizophrenia (29.2%) and schizoaffective disorder (17.3%). Polypharmacy was common, with the most frequent combinations being VPA + quetiapine and VPA + promethazine. Age was significantly associated with VPA levels, with pediatric/adolescent patients (< 18 years) demonstrating higher dose-adjusted serum levels of VPA (ß = 7.6±2.34, p < 0.001) after accounting for BMI. Women tended to have higher adjusted VPA serum levels than men (ß = 5.08±1.62, p < 0.001). The formulation of VPA (Immediate-release vs. extended-release) showed no association with VPA levels. Co-administration of diazepam exhibited a dose-dependent decrease in VPA levels (F = 15.7, p < 0.001), suggesting a potential pharmacokinetic interaction. CONCLUSIONS: This study highlights the utility of population-specific pharmacokinetic data for VPA in psychiatric populations. Age, gender, and co-administration of diazepam were identified as predictors of VPA levels. Further research is warranted to establish additional predictors and optimize the precision application of VPA in psychiatric patients.

Pharmacogenetic Variants and Plasma Concentrations of Antiseizure Drugs: A Systematic Review and Meta-Analysis.

Importance: Precise estimation of a patient's drug metabolism capacity is important for antiseizure dose personalization. Objective: To quantify the differences in plasma concentrations for antiseizure drugs associated with variants of genes encoding drug metabolizing enzymes. Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to September 30, 2023, without language restrictions. Study Selection: Two reviewers performed independent study screening and assessed the following inclusion criteria: appropriate genotyping was performed, genotype-based categorization into subgroups was possible, and each subgroup contained at least 3 participants. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for data extraction and subsequent quality, validity, and risk-of-bias assessments. The results from the included studies were pooled with random-effect meta-analysis. Main Outcomes and Measures: Plasma concentrations of antiseizure drugs were quantified with the dose-normalized area under the concentration-time curve, the dose-normalized steady state concentration, or the concentrations after a single dose at standardized dose and sampling time. The ratio of the means was calculated by dividing the mean drug plasma concentrations of carriers and noncarriers of the pharmacogenetic variant. Results: Data from 98 studies involving 12 543 adult participants treated with phenytoin, valproate, lamotrigine, or carbamazepine were analyzed. Studies were mainly conducted within East Asian (69 studies) or White or European (15 studies) cohorts. Significant increases of plasma concentrations compared with the reference subgroup were observed for phenytoin, by 46% (95% CI, 33%-61%) in CYP2C9 intermediate metabolizers, 20% (95% CI, 17%-30%) in CYP2C19 intermediate metabolizers, and 39% (95% CI, 24%-56%) in CYP2C19 poor metabolizers; for valproate, by 12% (95% CI, 4%-20%) in CYP2C9 intermediate metabolizers, 12% (95% CI, 2%-24%) in CYP2C19 intermediate metabolizers, and 20% (95% CI, 2%-41%) in CYP2C19 poor metabolizers; and for carbamazepine, by 12% (95% CI, 3%-22%) in CYP3A5 poor metabolizers. Conclusions and Relevance: This systematic review and meta-analysis found that CYP2C9 and CYP2C19 genotypes encoding low enzymatic capacity were associated with a clinically relevant increase in phenytoin plasma concentrations, several pharmacogenetic variants were associated with statistically significant but only marginally clinically relevant changes in valproate and carbamazepine plasma concentrations, and numerous pharmacogenetic variants were not associated with statistically significant differences in plasma concentrations of antiseizure drugs.

Effect of Age, Comedications, and CYP3A4/5 Polymorphisms on Perampanel Exposure in Chinese Pediatric Patients With Epilepsy.

Perampanel (PER) is a new type of antiseizure medication used for partial or generalized seizures. However, the plasma concentration shows obvious individual variability in children. The present study aims to ascertain the effect of age, comedications, and cytochrome P450 (CYP) 3A4/5 polymorphisms on PER exposure in Chinese pediatric patients with epilepsy. Clinical data were retrospectively collected in a tertiary children's hospital medical records system from January 2021 to December 2022. The influence factors on the daily dose, plasma concentration, and concentration-to-dose ratio (CDR) of PER were investigated. A total of 135 pediatric patients with 178 blood samples were involved. With a median daily dose of 4.0 mg (interquartile range, 3.0-5.0 mg), the median plasma concentration was 409.4 ng/mL (interquartile range, 251.7-639.4 ng/mL). The CDR in patients aged less than 4 years was significantly decreased by 48.0% and 39.1% compared with those aged 4-11 years and 12 years or older, respectively. Enzyme inducers significantly decreased the CDR of PER by 34.5%, while valproic acid showed an increase of 71.7%. In addition, genotype CYP3A5*3/*3 carriers presented a significant increase of 21.5% compared to the CYP3A5*1/*3 expresser. No correlations were observed between the CDR and CYP3A4∗1G polymorphism. PER showed high variations in individual plasma concentrations. Age younger than 4 years, comedication with enzyme inducers or valproic acid, and possession of the CYP3A5*3 genotype potentially predicted PER exposure in pediatric patients with epilepsy.

Farmacocinesia de los medicamentos antiepilepticos / Antiepileptic drugs pharmacocinesia

Se hace una revisión de la literatura sobre la farmacología de los medicamentos anticomiciales. Se discute los aspectos más importantes de la farmacocinesia de las drogas a la luz de su importancia clínica. se examina algunos medicamentos por separado. Finalmete se presentan algunas recomendaciones sobre la suspensión de la medicación

Normorregulaçäo do humor e valpromida / Normoregulation of humor and valpromide

Normorregulaçäo do humor é uma propriedade farmacológica descrita inicialmente para o lítio. Atualmente ele é também observada para a carbamazepina e para a avalpromida, que é apresentada neste trabalho, mais detalhadamente

Epilepsia Mioclónica Juvenil (Síndrome de Janz) / Juvenile Myoclonic Epilepsy

Las convulsiones mioclónicas representan uno de los tipos de epilepsia, que aunque poco frecuentes, son importantes en la infancia. La epilepsia mioclónica juvenil es un síndrome epiléptico generalizado que ocurre en el 2.7 a 11 por ciento de todos los síndromes convulsivos en pediatría; puede tener un inicio tan temprano comolos ocho años y tan tardío como 24 y 40 años. Se caracteriza por sacudidas mioclónicas al despertar, ausencias típicas y crisis tónico-clónicas generalizadas, exploración neurológica normal y anomalías típicas en el electroencefalograma; la caída recordada y la conciencia es conservada durante el ataque. Los factores desencadenantes pueden ser detectados en el 93 por ciento de los pacientes y deben ser evitados. El fármaco de elección es el ácido valproico; este permite controlar las crisis en el 64 a 90 por ciento de los casos. En ocasiones se utiliza la terapia multidroga, principalmente cuando la respuesta clínica al ácido valproico como monoterapia no es la adecuada. El riesgo de recidivas, al interrumpir la farmacoterapia es de 75 a 100 por ciento

Estudio preliminar de la hepatotoxicidad del anticonvulsionante DL-4-hidroxi, 4-etil, 4-fenil butiramida (HEPB) y sus homólogos inferiores HEPP y HEPA / Preliminary study of the hepatotoxicity of the anticonvulsant DL-4-hydroxy, 4-ethyl, 4-phenyl butyramide (HEPB) and its inferior homologues HEPA and HEPP

En este trabajo los efectos hepatotóxicos del anticonvulsionantes 4-hidroxi,, 4-etil, 4-fenil butiramida (HEPB) y sus homólogos HEPA y HEPP fueron evaluados y comparados con los efectos del valproato de sodio y del fenobarbital en cultivos de hepatocitos de larga sobrevivencia. Los hepatocitos se sembraron sobre una monocapa alimentadora de células 3T3 letalmente tratadas con mitomicina C y fueron expuestos por una o dos semanas a los anticonvulsionantes (50-500 mg/ml). Se seterminó en el medio de cultivo la liberación de las enzimas citoplásticas transaminasa glutámico oxalacética (GOT). Transaminasa glutámico pirúvica (GPT) y deshidrogenasa láctica (LDH), se determinó también el contenido de triclicéridos (TG) mediante tinción con rojo oleoso O. HEPB produjo gotas intracitoplásmicas de lípidos, ensanchamiento de los espacios intercelulares y retracción de las células. HEPA y HEPP produjeron efectos similares pero en menor grado. El valproato de sodio causó retracción de las células, ensanchamiento de los espacios intracelulares y también vacuolización de las células. Después de una exposición de una semana el valproato de sodio produjo la liberación más alta de TGO, TGP y LDH. Los cultivos tratados con los otros anticonvulsionantes mostraron poca diferencia con los cultivos control. Después de dos semanas de exposición los efectos fueron menores. El mayor contenido de TG lo produjo el HEPB, mientras que el valpoatro de sodio produjo una disminución en el contenido de TG. Nuestros resultados muestran que el rango de toxicidad de los anticonvulsionantes probados es valproato de sodio >HEPB>HEPA>HEPP>fenobarbital

Terapêutica em epilepsia / Therapeutics in epilepsy

Esta revisão sumária sobre terapêutica em epilepsia aborda questões tais como quando começar o tratamento, qual a droga antiepilética (DAE) indicada para os diversos tipos de crise, quando retirar a DAE, sua posologia, frequência de tomadas, efeitos colaterais e idução/inibição enzimática da DAE, monitorização do tratamento e epilepsia refratária. Várias dessas questões são dependentes do conhecimento de farmacocinética e farmacodinâmica, fatos que também são considerados.