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1.
Epilepsy Behav ; 138: 109018, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36528008

RESUMEN

First, a short history is given of the use of the EEG as a biomarker of efficacy in anti-seizure medication (ASM) development. The generalized epileptiform EEG response to Intermittent Photic Stimulation (IPS), the photoparoxysmal EEG response or PPR, in particular, is a reliable reproducible measure since the 1950s. Over time, a "Photosensitivity Model", testing within the same patients the impact of potential new oral ASMs, along with dose-ranging data, on PPRs, has been developed successfully. The classical Photosensitivity Model consists of IPS and blood sampling for ASM measurement performed hourly between 8 AM and 5 PM over three consecutive days. This single-blind, placebo-controlled, pharmacokinetic-pharmacodynamic (PK/PD) Model is now commonly utilized as a Proof-of-Concept Phase 2a trial. For Generalized Tonic-Clonic Status Epilepticus (GTCSE), it is especially relevant to know the time for CNS entry and effect minutes after i.v. ASM treatment, since "time is brain". We, therefore, adapted successfully the Model to a time-efficient Model with the determination of photosensitivity ranges in minutes after equivalent doses of iv brivaracetam (BRV) and levetiracetam (LEV). This modified design allows one to monitor the time to CNS effect (i.e., PPR elimination) of a quickly-acting FDA-approved ASM given i.v., a crucial element in status epilepticus treatment. This paper was presented at the 8th London-Innsbruck Colloqium on Status Epilepticus and Acute Seizures held in September 2022.


Asunto(s)
Trastornos por Fotosensibilidad , Estado Epiléptico , Humanos , Anticonvulsivantes/uso terapéutico , Levetiracetam/uso terapéutico , Pirrolidinonas/uso terapéutico , Método Simple Ciego , Estado Epiléptico/tratamiento farmacológico , Resultado del Tratamiento
2.
Neurochem Res ; 41(4): 758-69, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-26542150

RESUMEN

Ion channels are targets of various antiepileptic drugs. In cerebral presynaptic nerve endings Na(+) and Ca(2+) channels are particularly abundant, as they control neurotransmitter release, including the release of glutamate (Glu), the most concentrated excitatory amino acid neurotransmitter in the brain. Several pre-synaptic channels are implicated in the mechanism of action of the pro-convulsive agent, 4-aminopyridine (4-AP). In the present study the effects of levetiracetam and other established and newer (vinpocetine) anti-epileptic drugs, as well as of the anti-depressant, sertraline on the increase in Ca(2+) induced by 4-AP in hippocampal isolated nerve endings were investigated. Also the effects of some of the anti-seizure drugs on the selective increase in Ca(2+) induced by high K(+), or on the selective increase in Na(+) induced by veratridine were tested. Sertraline and vinpocetine effectively inhibited the rise in Ca(2+) induced by 4-AP, which was dependent on the out-in Na(+) gradient and tetrodotoxin sensitive. Carbamazepine, phenytoin, lamotrigine and oxcarbazepine inhibited the rise in Ca(2+) induced by 4-AP too, but at higher concentrations than sertraline and vinpocetine, whereas levetiracetam, valproic acid and topiramate did not. The three latter antiepileptic drugs also failed in modifying other responses mediated by the activation of brain presynaptic Na(+) or Ca(2+) channels, including Glu release. This indicates that levetiracetam, valproic acid and topiramate mechanisms of action are unrelated with a decrease in presynaptic Na(+) or Ca(2+) channels permeability. It is concluded that depolarized cerebral isolated nerve endings represent a useful tool to unmask potential antiepileptic drugs targeting presynaptic Na(+) and/or Ca(2+) channels in the brain; such as vinpocetine or the anti-depressant sertraline, which high effectiveness to control seizures in the animal in vivo has been demonstrated.


Asunto(s)
Anticonvulsivantes/farmacología , Canales de Calcio/metabolismo , Hipocampo/efectos de los fármacos , Canales de Sodio/metabolismo , Animales , Calcio/metabolismo , Ácido Glutámico/metabolismo , Hipocampo/metabolismo , Técnicas In Vitro , Masculino , Terminales Presinápticos/metabolismo , Ratas Wistar
3.
Epilepsy Behav ; 28 Suppl 1: S81-6, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23756489

RESUMEN

Juvenile myoclonic epilepsy (JME) is a common form of epilepsy and a fairly lifelong disorder that may significantly lower a patient's expectations and potential for a full life. Luckily, it is also a highly treatable disorder, and up to 85% of patients with JME will enjoy satisfactory seizure control. Among anticonvulsants, valproate still stands out as the most efficacious drug, but may be poorly tolerated by some, and is considered unsafe for the fetuses of pregnant women. Alternatives have emerged in recent years, especially levetiracetam, but also topiramate, zonisamide or lamotrigine. In some cases, combination therapy may be useful or even required. One should not forget the potential aggravation induced not only by some commonly used anticonvulsants, especially carbamazepine and oxcarbazepine, but also, in some patients, by lamotrigine. In special settings, older drugs like benzodiazepines and barbiturates may be useful. But the management of JME should also include intervention in lifestyle, with strict avoidance of sleep deprivation and the management of copathologies, including the cognitive and psychiatric problems that are often encountered. With adequate management, there will only remain a small proportion of patients with uncontrolled epilepsy and all of its related problems. Juvenile myoclonic epilepsy is a condition in which the clinician has a fair chance of significantly helping the patient with medication and counseling.


Asunto(s)
Manejo de la Enfermedad , Epilepsia Mioclónica Juvenil/diagnóstico , Epilepsia Mioclónica Juvenil/terapia , Electroencefalografía , Femenino , Humanos , Masculino
4.
Epilepsy Behav ; 28 Suppl 1: S87-90, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23756490

RESUMEN

An international workshop on juvenile myoclonic epilepsy (JME) was conducted in Avignon, France in May 2011. During that workshop, a group of 45 experts on JME, together with one of the founding fathers of the syndrome of JME ("Janz syndrome"), Prof. Dr. Dieter Janz from Berlin, reached a consensus on diagnostic criteria and management of JME. The international experts on JME proposed two sets of criteria, which will be helpful for both clinical and scientific purposes. Class I criteria encompass myoclonic jerks without loss of consciousness exclusively occurring on or after awakening and associated with typical generalized epileptiform EEG abnormalities, with an age of onset between 10 and 25. Class II criteria allow the inclusion of myoclonic jerks predominantly occurring after awakening, generalized epileptiform EEG abnormalities with or without concomitant myoclonic jerks, and a greater time window for age at onset (6-25years). For both sets of criteria, patients should have a clear history of myoclonic jerks predominantly occurring after awakening and an EEG with generalized epileptiform discharges supporting a diagnosis of idiopathic generalized epilepsy. Patients with JME require special management because their epilepsy starts in the vulnerable period of adolescence and, accordingly, they have lifestyle issues that typically increase the likelihood of seizures (sleep deprivation, exposure to stroboscopic flashes in discos, alcohol intake, etc.) with poor adherence to antiepileptic drugs (AEDs). Results of an inventory of the different clinical management strategies are given. This article is part of a supplemental special issue entitled Juvenile Myoclonic Epilepsy: What is it Really?


Asunto(s)
Consenso , Manejo de la Enfermedad , Epilepsia Mioclónica Juvenil/diagnóstico , Epilepsia Mioclónica Juvenil/terapia , Humanos , Cooperación Internacional
5.
SAGE Open Med ; 10: 20503121221099359, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35652035

RESUMEN

Objectives: Acute kidney injury is common among the critically ill. However, the incidence, medication use, and outcomes of acute kidney injury have been variably described. We conducted a single-center, retrospective cohort study to examine the risk factors and correlates associated with acute kidney injury in critically ill adults with a particular focus on medication class usage. Methods: We reviewed the electronic medical records of all adult patients admitted to an intensive care unit between 1 February and 30 August 2020. Acute kidney injury was defined by the 2012 Kidney Disease: Improving Global Outcomes guidelines. Data included were demographics, comorbidities, symptoms, laboratory parameters, interventions, and outcomes. The primary outcome was acute kidney injury incidence. A Least Absolute Shrinkage and Selection Operator regression model was used to determine risk factors associated with acute kidney injury. Secondary outcomes including acute kidney injury recovery and intensive care unit mortality were analyzed using a Cox regression model. Results: Among 226 admitted patients, 108 (47.8%) experienced acute kidney injury. 37 (34.3%), 39 (36.1%), and 32 patients (29.6%) were classified as acute kidney injury stages I-III, respectively. Among the recovery and mortality cohorts, analgesics/sedatives, anti-infectives, and intravenous fluids were significant (p-value < 0.05). The medication classes IV-fluid electrolytes nutrition (96.7%), gastrointestinal (90.2%), and anti-infectives (81.5%) were associated with an increased odds of developing acute kidney injury, odd ratios: 1.27, 1.71, and 1.70, respectively. Cox regression analyses revealed a significantly increased time-varying mortality risk for acute kidney injury-stage III, hazard ratio: 4.72 (95% confidence interval: 1-22.33). In the recovery cohort, time to acute kidney injury recovery was significantly faster in stage I, hazard ratio: 9.14 (95% confidence interval: 2.14-39.06) cohort when compared to the stage III cohort. Conclusion: Evaluation of vital signs, laboratory, and medication use data may be useful to determine acute kidney injury risk stratification. The influence of particular medication classes further impacts the risk of developing acute kidney injury, necessitating the importance of examining pharmacotherapeutic regimens for early recognition of renal impairment and prevention.

6.
CNS Drugs ; 34(10): 1075-1086, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32949370

RESUMEN

INTRODUCTION: Both levetiracetam (LEV) and brivaracetam (BRV) eliminate the electroencephalogram photoparoxysmal response (PPR) in the human phase IIa photosensitivity model of epilepsy. The physiochemical properties of BRV differ from those of LEV, having higher potency and lipophilicity plus 10- to 15-fold greater affinity for synaptic vesicle glycoprotein 2A. OBJECTIVE: We compared the rapidity of the effects of both drugs in the central nervous system (CNS) of patients with photosensitive epilepsy using time to PPR elimination post-intravenous infusion as a pharmacodynamic endpoint. METHODS: Using a randomized, double-blind, two-period, balanced, crossover design, we tested patients with photosensitive epilepsy with equipotent milligram doses of intravenous LEV 1500 mg versus BRV 100 mg post-15-min intravenous infusion (part 1) and post-5-min intravenous infusion (part 2, same doses). Eight patients per part were deemed sufficient with 80% power to determine a 70% reduction for intravenous BRV:LEV intrapatient time ratio to PPR elimination, with a 0.05 two-sided significance level. Plasma antiseizure medicine concentrations were measured using liquid chromatography/mass spectrometry. RESULTS: Nine patients [six women; mean age 27.8 years (range 18-42)] completed the study; seven of these participated in both parts 1 and 2. In 31 of 32 instances, patients experienced PPR elimination. In mixed-effects model time analysis, BRV eliminated PPRs more quickly than did LEV (median 2 vs. 7.5 min, respectively). However, no statistically significant difference in BRV:LEV time ratio to PPR elimination was observed for two of our multiple primary outcomes: for the 15-min infusion alone (p = 0.22) or the 5-min infusion alone (p = 0.11). However, BRV was faster when we excluded an outlier patient in part 1 (p = 0.0016). For our remaining primary outcome, parts 1 and 2 data combined, the median intrapatient BRV:LEV time ratio was 0.39 [95% confidence interval (CI) 0.16-0.91], i.e., PPR elimination was 61% faster with BRV, p = 0.039. PPR was completely eliminated in ≤ 2 min in 11 patients with BRV and in four patients with LEV. No period or carryover effects were seen. No serious or severe adverse effects occurred. At PPR elimination (n = 16), median plasma [BRV] was 250 ng/mL (range 30-4100) and median plasma [LEV] was 28.35 µg/mL (range 1-86.7). CONCLUSION: Outcome studies directly comparing LEV and BRV are needed to define the clinical utility of the response with BRV, which was several minutes faster than that with LEV. CLINICAL TRIALS: ClinTrials.gov Identifier = NCT03580707; registered 07-09-18.


Asunto(s)
Anticonvulsivantes/administración & dosificación , Epilepsia Refleja/tratamiento farmacológico , Levetiracetam/administración & dosificación , Pirrolidinonas/administración & dosificación , Adolescente , Adulto , Anticonvulsivantes/efectos adversos , Anticonvulsivantes/farmacología , Cromatografía Liquida , Estudios Cruzados , Método Doble Ciego , Electroencefalografía , Epilepsia Refleja/fisiopatología , Femenino , Humanos , Infusiones Intravenosas , Levetiracetam/efectos adversos , Levetiracetam/farmacología , Masculino , Espectrometría de Masas , Pirrolidinonas/efectos adversos , Pirrolidinonas/farmacología , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
7.
J Clin Psychopharmacol ; 29(5): 492-5, 2009 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-19745651

RESUMEN

Divalproex (DVP) delayed release and DVP extended release (DVP ER) are approved by the Food and Drug Administration for bipolar disorder, epilepsy, and migraine prophylaxis. Divalproex ER is given once daily, improving compliance and reducing adverse events. Overnight switch to DVP ER is advised in the package insert but could produce more adverse events in this susceptible population. In this pilot study, we compared tolerability of overnight versus gradual switching to DVP ER in 16 adults with intellectual and developmental disabilities receiving DVP, in 9 for epilepsy and in all 16 for comorbid bipolar disorder. The study design was open with parallel groups. Sixteen subjects with intellectual and developmental disabilities were randomized to overnight or gradual conversion for 4 to 6 days. A blinded rater completed the Multidimensional Observation Scale for Elderly Subjects on days +1, +4, and +8 after the switch began. We found no major differences between the 2 groups at each time point. Neither group of subjects, except for 1 subject in the overnight group, manifested sedation, seizures, worsening of tremor, or gastrointestinal adverse events. One subject in the overnight group manifested acute diarrhea and vomiting, followed by a very brief tonic leg seizure 6 days later. Larger studies are warranted.


Asunto(s)
Discapacidad Intelectual/tratamiento farmacológico , Ácido Valproico/administración & dosificación , Ácido Valproico/efectos adversos , Adulto , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/efectos adversos , Esquema de Medicación , Femenino , Humanos , Discapacidad Intelectual/sangre , Discapacidad Intelectual/psicología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Recuento de Plaquetas , Convulsiones/inducido químicamente , Adulto Joven
8.
Eur J Drug Metab Pharmacokinet ; 44(3): 389-408, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30460522

RESUMEN

BACKGROUND AND OBJECTIVES: Lamotrigine (Lamictal®) is a broad-spectrum antiepileptic drug available in both immediate-(IR) and extended-release (XR) formulations. Here, we present a new physiologically based pharmacokinetic (PBPK) model for IR and XR formulations of lamotrigine to predict disposition in adults and children, plus drug-drug interactions (DDIs). METHODS: Models for lamotrigine IR and XR formulations were constructed using a Simcyp® Simulator. Concentration-time profiles were simulated for lamotrigine IR single (SD) and steady-state (SS) doses ranging from 25 to 200 mg in adults, as well as 2 mg/kg (SD), and 7.7-9.4 mg/kg (SS) in children aged between 4 and 17 years. Lamotrigine XR profiles were simulated for SD and SS doses ranging from 250 to 400 mg. DDI prediction with lamotrigine was simulated in adults with enzyme-inducing drugs, rifampin (rifampicin) and ritonavir, as well as the enzyme inhibitor, valproic acid. RESULTS: The lamotrigine model predicted adult area-under-the-curve (AUC) and peak plasma concentration (Cmax) results for IR SD within 35% of observed data; lamotrigine IR SS dosing was within 10% and 30% of observed data, respectively. Pediatric lamotrigine IR SD AUC and Cmax values were within 10% and 15% of observed data, respectively. AUC and Cmax values for lamotrigine XR SD simulated in adults were within 20% of observed data; similarly lamotrigine XR SS parameters were within 10%. Concerning DDI simulation in adults, predicted-to-observed lamotrigine AUC ratios [AUCDDI/AUCalone] were within 15% for ritonavir and rifampin, and 20% for valproic acid. CONCLUSIONS: Our developed PBPK lamotrigine profile accurately predicts DDIs and lamotrigine IR/XR formulation disposition in adults and children. This PBPK model will be helpful in designing future DDI studies for co-administration of lamotrigine with other drugs and in designing individualized patient dosing regimens.


Asunto(s)
Anticonvulsivantes/farmacocinética , Simulación por Computador , Lamotrigina/farmacocinética , Modelos Biológicos , Adulto , Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/sangre , Área Bajo la Curva , Disponibilidad Biológica , Niño , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Humanos , Lamotrigina/administración & dosificación , Lamotrigina/sangre , Valor Predictivo de las Pruebas
9.
Eur J Pharm Sci ; 111: 465-481, 2018 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-29030176

RESUMEN

Valproic acid (VPA) is an older first-line antiepileptic drug with a complex pharmacokinetic (PK) profile, currently under investigation for several novel neurologic and non-neurologic indications. Our study objective was to design and validate a mechanistic model of VPA disposition in adults and children; and evaluate its predictive performance of drug-drug interactions (DDIs). This study expands upon existing physiologically based pharmacokinetic (PBPK) models for VPA by incorporating UGT enzyme kinetics and an advanced dissolution, absorption, and metabolism (ADAM) model for extended-release (ER) formulation. PBPK models for VPA IR and ER formulations were constructed using Simcyp Simulator (Version 15). First-order absorption was used for the immediate-release (IR) formulation and the ADAM model, including a controlled-release profile, for ER. Data from twenty-one published clinical studies were used to assess model performance. The model accurately predicted the concentration-time profiles of IR formulation for single-dose and steady-state doses ranging from 200mg to 1000mg. Similarly profiles were also simulated for ER formulation after a single-dose and steady-state doses of 500mg and 1000mg, respectively. In addition, simulated PK profiles agreed well with the observed data from studies in which VPA ER formulation was given to pediatric patients and VPA IR formulation to adult patients with cirrhosis. The model was further validated with individual adult data from a Phase I clinical trial consisting of eight cohorts after IV infusion of VPA with doses ranging from 15 to 150mg/kg. Co-administrations of VPA as an enzyme-inhibitor with victim drug phenytoin or lorazepam, as well as a substrate with enzyme inducer carbamazepine or phenobarbital, were simulated with the model to evaluate drug-drug interaction. The simulated serum concentration-time profiles were within the 5th and 95th percentiles, and the majority of the predicted area-under-the-curve (AUC) and peak plasma concentration (Cmax) values were within 25% of the reported average values. The comprehensive VPA PBPK model defined by this study may be used to support dosage regimen optimization to improve the safety and efficacy profile of this agent under different scenarios.


Asunto(s)
Anticonvulsivantes/farmacocinética , Ácido Valproico/farmacocinética , Anticonvulsivantes/administración & dosificación , Células CACO-2 , Simulación por Computador , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Humanos , Modelos Biológicos , Método de Montecarlo , Distribución Tisular , Ácido Valproico/administración & dosificación
10.
Epilepsy Res ; 73(3): 275-83, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17208410

RESUMEN

Five oral formulations of valproic acid (VPA)/divalproex sodium are approved and commonly used in the US for treatment of epilepsy, mania/bipolar disorder and migraine prophylaxis. These formulations have unique pharmacokinetic and formulation characteristics and are designed to treat distinct patient populations. We compared the absorption characteristics of all five oral VPA/divalproex formulations currently available in the US. Plasma VPA concentration-time profiles, following single oral dose (250mg) administration of five VPA/divalproex formulations under fasting conditions, from three pharmacokinetic studies in healthy subjects (N=9-15 each) were compared. The five VPA/divalproex formulations demonstrated marked absorption differences. The rate of absorption, as characterized by maximum concentration (C(max)) and time to C(max) (T(max)), may be rank-ordered as: VPA syrup (34.2mg/L, 0.9h)>VPA capsule (31.4mg/L, 2.2h)>divalproex sodium sprinkle capsule (20.7mg/L, 4.0h; lag-time congruent with1h) congruent withdivalproex sodium enteric-coated delayed-release tablet (26.0mg/L, 3.4h; lag-time congruent with2h)>divalproex sodium extended-release (divalproex-ER) tablet (11.8mg/L, 19.7h). Divalproex-ER had approximately 11% lower exposure (AUC). The comparable AUC across the five formulations, when corrected for bioavailability differences, demonstrates that formulation primarily affects the drug-release and in vivo absorption of VPA. Only divalproex-ER demonstrated true sustained-release characteristics.


Asunto(s)
Anticonvulsivantes/farmacocinética , Epilepsia/tratamiento farmacológico , Ácido Valproico/farmacocinética , Absorción , Administración Oral , Anticonvulsivantes/administración & dosificación , Área Bajo la Curva , Combinación de Medicamentos , Composición de Medicamentos , Humanos , Estados Unidos , Ácido Valproico/administración & dosificación
11.
Epilepsy Res ; 133: 113-120, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28034485

RESUMEN

The 'Photosensitivity Model' uses a standardized stimulation protocol of repeated intermittent photic stimulation (IPS) over a three-day period, with administration of a single dose of an investigational antiepileptic drug (AED) after a baseline IPS day in photosensitive patients, followed by a third IPS day to determine duration of effect. This 'Photosensitivity Model' has shown its value in the development of new AEDs. Levetiracetam (LEV), currently a first-line AED in new-onset focal epilepsies, was not effective in classical animal models, but showed dose-dependent efficacy in the human 'Photosensitivity Model'. Nevertheless, concerns have been expressed that AEDs selectively suppressing focal seizures might not suppress generalized photoparoxysmal EEG responses (PPR), the pharmacodynamic outcome measure in the Model. Herein, the following questions have been addressed: I. Can patients with generalized epileptiform discharges, evoked by IPS, so-called PPR, have focal epilepsy (focal seizures)? II. Are the photosensitive patients with focal epilepsy, who have participated in the photosensitivity trials, non-responsive to a new AED under investigation, as compared to those with generalized epilepsies? III. Are "focal epilepsy" AEDs effective both in the 'Photosensitivity Model' and in real life in photosensitive patients? We performed a systematic literature review of PPR in focal seizures and focal epilepsy and we analyzed data (published and unpublished) from 20 different potential AEDs studied prospectively in the 'Photosensitivity Model'. Finally, the PPR effects of Na+ channel-blocking AEDs (considered as the most typical AEDs for focal epilepsy) are discussed with unequivocal examples given of the focal nature of a patient's PPR. Based on the entire data evidence, we conclude that: 1. PPRs certainly exist in focal epilepsy (17% on average); 2. Clinical signs and symptoms of PPRs can be focal and 3. PPRs can definitely be used to identify or to prove efficacy of new AEDs for patients with focal epilepsy.


Asunto(s)
Anticonvulsivantes/uso terapéutico , Convulsiones/complicaciones , Animales , Electroencefalografía , Humanos , Estimulación Luminosa , Trastornos por Fotosensibilidad/complicaciones , Trastornos por Fotosensibilidad/tratamiento farmacológico , Convulsiones/tratamiento farmacológico
13.
Clin Drug Investig ; 26(12): 681-90, 2006.
Artículo en Inglés | MEDLINE | ID: mdl-17274675

RESUMEN

BACKGROUND: For many drugs, steady-state concentration-time profiles are often not optimally characterised by the intrinsic terminal elimination half-life for various reasons, including multiexponential disposition with minimal contribution of the terminal phase to steady-state exposure or use of controlled-release formulations with extended zero- or mixed zero-/first-order absorption. In such cases, 'effective' or 'functional' half-life (t((1/2)F)) has often been used to characterise steady-state pharmacokinetics. Valproic acid, commonly used in neuropsychiatry, has an elimination half-life of 4-16 hours in different populations (children vs adults, enzyme-induced vs uninduced). Divalproex-ER, a once-daily extended- release divalproex sodium formulation, is designed to release valproic acid over >18 hours. Hence the steady-state divalproex-ER concentration-time profiles have small peak-trough fluctuations that are not optimally characterised by valproic acid elimination half-life. In this study, the value of t((1/2)F) was calculated to characterise divalproex-ER steady-state concentration-time profiles. METHODS: The value of t((1/2)F), defined as the time taken for the concentration to drop by one-half during a dosing interval (tau) at steady state, was derived using steady-state maximum (C(max)) and minimum (C(min)) plasma concentration and tau values, and calculated as ln(2)/(ln [C(max)/C(min)]/tau). The t((1/2)F) values of valproic acid in adult hepatic enzyme-uninduced healthy subjects and enzyme-induced epilepsy patients were calculated from five pharmacokinetic studies in which divalproex-ER was administered once daily for 6-14 days. RESULTS: The estimated geometric mean t((1/2)F) in uninduced adults was 40.0 hours versus the expected elimination half-life of 12-16 hours in this population (including patients on valproic acid monotherapy); for induced patients, t((1/2)F) was 26.9 hours versus the expected elimination half-life of 6-12 hours. CONCLUSION: The t((1/2)F) of valproic acid optimally characterises the expected steady-state C(max) to C(min )decrease of 33% in uninduced and 45% in induced adults following once-daily administration of divalproex-ER.


Asunto(s)
Ácido Valproico/farmacocinética , Área Bajo la Curva , Química Farmacéutica , Preparaciones de Acción Retardada , Semivida , Humanos , Ácido Valproico/administración & dosificación
14.
J Clin Pharmacol ; 44(7): 737-42, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15199078

RESUMEN

Conventional delayed-release, enteric-coated divalproex sodium tablet has an absolute bioavailability of approximately 100%. Divalproex sodium extended-release (ER) tablet is a novel formulation of valproic acid (VPA) designed to release the drug slowly at a constant zero-order rate. The purpose of this study was to evaluate the absolute bioavailability and absorption characteristics of divalproex ER. Healthy adult volunteers (n = 16) received divalproex ER and intravenous VPA in crossover fashion. Absolute bioavailability was calculated as the divalproex ER/intravenous VPA ratio of area under the curve extrapolated to infinity. The duration and rate of absorption of VPA from divalproex ER tablets were determined by deconvolution analysis. The geometric mean absolute bioavailability of divalproex ER was 0.896. The mean (coefficient of variation) duration of drug absorption from divalproex ER was 21.8 (17%) hours, and the zero-order absorption rate was 21.6 (24%) mg/h for a 500-mg tablet. Divalproex ER has a lower absolute bioavailability than conventional divalproex tablets but exhibits good extended-release characteristics without any dose dumping.


Asunto(s)
Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Ácido Valproico/administración & dosificación , Ácido Valproico/farmacocinética , Adolescente , Adulto , Disponibilidad Biológica , Estudios Cruzados , Preparaciones de Acción Retardada , Femenino , Humanos , Masculino , Persona de Mediana Edad
15.
Am J Health Syst Pharm ; 61(21): 2284-9, 2004 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-15552636

RESUMEN

PURPOSE: Computer simulations were used to analyze changes in steady-state total plasma valproic acid concentrations when a patient misses a dose of once-daily extended-release divalproex sodium, replaces it at a later time, and resumes scheduled therapy. METHODS: Valproic acid concentration-time profiles were simulated for 1000 hypothetical patients for each of two missed-dose scenarios using a one-compartment (assumes rapid distribution) population kinetic model with nonlinear protein binding. For each scenario, a lognormal distribution of clearance of unbound valproic acid, volume of distribution of unbound valproic acid, protein-binding values, and albumin concentration was generated. All simulations incorporated 20% interpatient variability and 10% residual error. RESULTS: Our pharmacokinetic simulations predicted that the chance for high plasma valproic acid concentrations resulting in clinical toxicity is low when extended-release divalproex doses are replaced within 12 hours followed by resumption of scheduled administration, perhaps due to the controlled, near zero-order absorption characteristics of the extended-release formulation. If a patient misses a dose of extended-release divalproex, it should be replaced as soon as the patient remembers. The next dose should be taken at the regularly scheduled time. A missed dose of extended-release divalproex may be replaced up to 12 hours later without any clinically significant change in plasma valproic acid concentrations in a majority of the patients. CONCLUSION: Simulation of two scenarios suggested that a missed dose of extended-release divalproex sodium may be replaced up to 12 hours later without any clinically significant perturbation in plasma valproic acid concentrations in the majority of adolescent and adult patients with epilepsy.


Asunto(s)
Anticonvulsivantes/administración & dosificación , Ácido Valproico/administración & dosificación , Ácido Valproico/sangre , Anticonvulsivantes/farmacocinética , Simulación por Computador , Preparaciones de Acción Retardada , Humanos , Modelos Biológicos , Ácido Valproico/farmacocinética
16.
Am J Health Syst Pharm ; 61(21): 2280-3, 2004 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-15552635

RESUMEN

PURPOSE: The pharmacokinetics and safety of 1000-mg extended-release divalproex sodium given once daily either in the morning or evening were compared. METHODS: Healthy volunteers 19-55 years of age were enrolled in this open-label, parallel-design study. Subjects were randomized to receive extended-release divalproex either in the morning or in the evening. Blood samples were taken immediately before and at 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 121, 122, 123, 124.5, 126, 127.5, 129, 130.5, 132, 133, 134, 135, 136.5, 138, 139.5, 141, 142.5, and 144 hours after the first dose of each six-day regimen. Plasma samples were assayed for total valproic acid concentrations using gas chromatography. Valproic acid pharmacokinetic values were measured, and the safety of each regimen was evaluated. RESULTS: Mean steady-state valproic acid exposure, maximum concentration, and minimum concentration were 1771 mg x hr/L, 86.9 mg/L, and 55.5 mg/L for the morning dosing and 1728 mg x hr/L, 84.8 mg/L, and 57.4 mg/L for the evening dosing regimens, respectively. Adverse events reported by two or more subjects were abdominal pain and somnolence for the morning dosing regimen and asthenia, headache, and pain for the evening dosing regimen. All adverse events were mild or moderate; none caused subject withdrawal from the study. There were no significant differences in the pharmacokinetic parameters (p > 0.51) and safety between groups. Diurnal variation in plasma valproic acid concentrations was minimal with once-daily administration of extended-release divalproex. CONCLUSION: Evening once-daily administration of extended-release divalproex was not associated with substantial differences in pharmacokinetics or safety compared with morning once-daily administration.


Asunto(s)
Anticonvulsivantes/administración & dosificación , Anticonvulsivantes/farmacocinética , Ácido Valproico/administración & dosificación , Ácido Valproico/farmacocinética , Adulto , Anticonvulsivantes/efectos adversos , Área Bajo la Curva , Preparaciones de Acción Retardada , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Comprimidos , Ácido Valproico/efectos adversos
17.
Clin Drug Investig ; 24(9): 495-508, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-17523712

RESUMEN

OBJECTIVE: Divalproex extended release (ER) tablets have lower bioavailability than conventional divalproex tablets. Objectives were to provide dose-increment justification for conversion of a patient from conventional enteric-coated divalproex to a once-daily divalproex ER regimen and to discuss the pharmacokinetic factors affecting these unequal total daily dose conversions. METHODS: Three bioavailability studies (two in healthy volunteers and one in epilepsy patients; total n = 69) compared equal total daily doses, and two studies (one each in healthy volunteers and epilepsy patients; total n = 99) compared 8-20% higher divalproex ER daily doses with corresponding divalproex total daily doses. In all five studies, multiple doses were administered over 6-14 days in each regimen. RESULTS: For equal total daily dose comparisons, the divalproex ER/divalproex bioavailability (area under the concentration-time curve [AUC] ratio) was ~0.89 and when the divalproex ER dose was higher, the two regimens were equivalent (AUC ratio ~1.0). Divalproex ER administered once daily had less fluctuation in valproic acid concentrations, i.e. divalproex ER achieved equal or significantly higher minimum concentrations and significantly lower maximum concentrations compared with divalproex administered multiple times daily. Divalproex ER predose trough concentration consistently represented the lowest concentration during a dosing interval, whereas for divalproex this was not true because of absorption lag time (from enteric coating), diurnal variation and multiple doses during a 24-hour interval. CONCLUSIONS: An 8-20% higher divalproex ER daily dose should be used when converting from a total daily dose of divalproex. The lower fluctuation of valproic acid concentrations, consistent time to trough concentration, and lower dosing frequency of divalproex ER should offer benefit to the patient by providing convenient once-daily administration, and to the clinician by facilitating easier and reliable therapeutic drug monitoring and improving patient adherence.

18.
Clin Drug Investig ; 24(9): 509-21, 2004.
Artículo en Inglés | MEDLINE | ID: mdl-17523713

RESUMEN

OBJECTIVE: To examine if, during conversion from conventional divalproex to once-daily divalproex extended-release (ER) tablets, plasma valproic acid (VPA) concentrations in the first 48 hours after conversion are maintained within the accepted therapeutic range (50-100 mg/L). METHODS: Four distinct 12-hourly (q12h) divalproex to once-daily divalproex ER conversion strategies were explored: immediate, delayed, stepwise and mixed conversion. These strategies were each used in simulations for hypothetical adult patients being treated under different conditions: monotherapy (uninduced, at 1500 mg/day divalproex ER) and polytherapy on enzyme-inducing co-medications (induced, at 3000 and 4500 mg/day divalproex ER). RESULTS: The proportion of uninduced patients expected to have minimum VPA concentrations (C(min)) >50 mg/L was 90% for immediate, 83% for stepwise and 82% for mixed-conversion strategies; only 52% undergoing a delayed-conversion strategy had C(min) >50 mg/L. More importantly, 33% of induced patients under-going delayed conversion to 3000 mg/day divalproex ER maintained an adequate VPA C(min). Maximum VPA concentrations (C(max)) attained after conversion to divalproex ER are unlikely to rise beyond the steady-state C(max) observed with divalproex q12h regimens with any conversion strategy tested in uninduced or induced patients. Marked perturbation in VPA concentration is not likely when converting to once-daily divalproex ER 'all-at-once' 12 hours after the last divalproex q12h dose. Stepwise and mixed-conversion strategies do not offer any advantage; delayed conversion may produce a large drop in VPA concentration. CONCLUSIONS: An ideal conversion strategy for q12h divalproex to once-daily divalproex ER appears to be an immediate conversion 12 hours after the last divalproex q12h dose; it causes the least perturbation in plasma VPA, even for patients required to take high divalproex ER doses.

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