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Purpose: Prenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with valproate (VPA). Our aim was to compare neurocognitive outcome at age 6-7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ), valproate (VPA) or levetiracetam (LEV) monotherapy., Methods: Eligible mother-child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6-7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex., Results: Of 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001)., Conclusions: Consistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Based on data from the EURAP observational International registry of antiepileptic drugs (AEDs) and pregnancy, we assessed changes in seizure control and subsequent AED changes in women who underwent attempts to withdraw valproic acid (VPA) during the first trimester of pregnancy. Applying Bayesian statistics, we compared seizure control in pregnancies where VPA was withdrawn (withdrawal group, n = 93), switched to another AED (switch group, n = 38), or maintained (maintained-therapy group, n = 1,588) during the first trimester. The probability of primarily or secondarily generalized tonic-clonic seizures (GTCS) was lower in the maintained-therapy group compared with the other two groups, both in the first trimester and for the entire duration of pregnancy. GTCS were twice as common during pregnancy in the withdrawal (33%) and switch groups (29%) compared with the maintained-treatment group (16%). Limitations in the data and study design do not allow to establish a cause-effect relationship between treatment changes and seizure outcome, but these observations provide a signal that withdrawal of, or switch from, VPA during the first trimester could lead to loss of seizure control, and highlight the need for a specifically designed prospective observational study., (Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.)

Since the serendipitous discovery of its anticonvulsant properties more than 50 years ago, valproic acid has become established as an effective broad-spectrum antiepileptic drug that is particularly useful for the management of generalised epilepsies, for which treatment alternatives are few. However, during the past few years increasing evidence has accumulated that intake of valproic acid during pregnancy is associated with a significant risk of dose-dependent teratogenic effects and impaired postnatal cognitive development in children. Because of these risks, valproic acid should not be used as a first-line drug in women of childbearing potential whenever equally or more effective alternative drugs are available-as in the case of focal epilepsy. In some generalised epilepsy syndromes, such as juvenile myoclonic epilepsy, valproic acid has better documented efficacy than alternative drugs and drug selection should be a shared decision between the clinician and the informed patient based on careful risk-benefit assessment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: To assess the risk of major congenital malformations (MCMs) in association with maternal use of valproic acid (VPA) in monotherapy or adjunctive therapy, and its relationship with dose., Methods: The analysis was based on prospectively acquired data from EURAP, a registry enrolling women treated with antiepileptic drugs (AEDs) in early pregnancy, in which the primary outcome is presence of MCMs at 1 year after birth. Exposure was defined as type and dose of AEDs at time of conception. A comparison was made among 3 exposure types: (1) VPA monotherapy (n = 1,224); (2) VPA combined with lamotrigine (LTG) (n = 159); and (3) VPA combined with another AED but not LTG (n = 205)., Results: The frequency of MCMs at 1 year after birth was 10.0% for VPA monotherapy, 11.3% for exposures to VPA and LTG, and 11.7% for exposures to VPA + another (non-LTG) AED. Regardless of exposure group, the frequency of MCMs increased with dose of VPA, being highest at doses ≥1,500 mg/d (24.0% for monotherapy, 31.0% for VPA + LTG, and 19.2% for VPA + other AEDs), and was similar across treatment groups at the lowest VPA dose level of <700 mg/d (5.9% for monotherapy, 7.0% for VPA + LTG, and 5.4% for VPA + other AEDs)., Conclusions: The risk of MCMs associated with VPA exposure increases with increasing VPA dose, both in the presence and in the absence of one concomitant AED, and appears to be related primarily to the dose of VPA., (© 2015 American Academy of Neurology.)

Purpose: To determine potential changes in total and unbound serum valproic acid (VPA) concentrations at steady-state during a cycle of intake of combined hormonal contraceptive (HC) steroids., Methods: Blood samples were collected from nine women stabilized on VPA monotherapy on two separate randomized occasions: (i) at the end of the 4- to 7-day HC-free interval, and (ii) on the last day of the HC intake period. Trough concentrations of VPA in serum and serum ultrafiltrates were determined by fluorescence polarization immunoassay., Results: In all women, total and unbound VPA concentrations were higher during the HC-free interval than during HC intake (means +/- SD: 425 +/- 184 vs. 350 +/- 145 micromol/L, respectively, for total VPA, p = 0.002, and 55 +/- 37 vs. 39 +/- 25 micromol/L, respectively, for unbound VPA, p = 0.005). Compared with the HC-free interval, HC intake was associated with a mean 21.5% increase in VPA total apparent oral clearance (from 8.0 +/- 5.2 to 9.7 +/- 6.4 ml/h/kg, p = 0.01) and a 45.2 % increase in VPA unbound apparent oral clearance (from 79 +/- 81 to 115 +/- 121 ml/h/kg, p = 0.029)., Conclusions: The apparent oral clearance of total and unbound VPA increases during the HC intake period compared with the HC-free interval, probably due to induction of glucuronosyltransferase by ethinylestradiol. The magnitude of the change varies across individuals, being potentially clinically relevant in some cases. Serum VPA concentrations should be monitored when adding or discontinuing HC steroids, and possibly during the on-off intervals of a HC cycle.

Purpose: To evaluate the influence of aging on the pharmacokinetics of valproic acid (VPA) at steady-state and on the susceptibility of VPA metabolism to enzyme induction by antiepileptic comedication., Methods: The database of the therapeutic drug monitoring service of a large neurological hospital was searched to identify patients aged > or = 65 years stabilized on VPA therapy. Apparent VPA oral clearance (CL/F) calculated for each elderly patient was compared with that determined in an equal number of VPA-treated controls aged 20-50 years and matched for gender, body weight and antiepileptic drug (AED) comedication., Results: A total of 71 elderly patients aged 70.0+/-4.4 years, including 20 receiving enzyme inducing AEDs, was included in the main evaluation. In the absence of enzyme inducing comedication, VPA CL/F in the elderly was similar to that found in non-elderly controls (9.7+/-4.6 versus 10.2+/-4.6mlh(-1)kg(-1)). Elderly patients on enzyme inducing comedication, on the other hand, had lower CL/F values than enzyme induced younger controls (11.7+/-5.4 versus 16.0+/-6.3mlh(-1)kg(-1), p<0.05). Since VPA CL/F is known to increase with increasing dosage, a lower VPA dosage in elderly patients comedicated with enzyme inducers compared with controls may have contributed to differences in CL/F between the two groups., Conclusions: In the absence of enzyme inducing comedication, VPA clearance in the elderly was comparable to that observed in controls. VPA clearance in elderly patients receiving enzyme inducing AEDs was lower than in controls, the difference being probably due to an influence of age as well as to the fact that mean VPA dosage was lower in these patients than in controls. Since our measurements of clearance were based on total serum VPA concentrations and VPA binding to plasma proteins is known to be reduced in old age, it is likely that the clearance of unbound, pharmacologically active, VPA was decreased to an important extent in the elderly, presumably as a result of a decline in drug metabolizing capacity.

In June 2005, a team of experts participated in a workshop with the objective of reaching agreement on several important aspects of valproate in the treatment of elderly patients with epilepsy. Epilepsy in the elderly is relatively common and its incidence increases for each decade after age 60. The aetiology and manifestations of epilepsies in the elderly are complex because of comorbidity and other underlying risk factors. A consensus was reached that elderly patients who present with a seizure disorder should be referred rapidly to a specialist and that diagnosis should be improved by using a multidisciplinary team of cardiologists, neurologists and epilepsy experts (syncope, falls and seizure specialists). This is especially important to avoid mistreatment with antiepileptic drugs (AEDs). There was consensus that the elderly are generally more susceptible to the adverse effects of AEDs than younger adults. For these reasons, in older persons AEDs should be started at low dosages, and titrated slowly according to clinical response. Some of the most troublesome side effects of AEDs in the elderly include sedation and cognitive side effects, as well as osteoporosis. Drug-drug interactions should be given special consideration. There was consensus that the pharmacokinetics of all AEDs are altered in the elderly, and that the most significant change common to all AEDs is a moderate reduction in renal and metabolic clearance. Predicting pharmacokinetic changes in the individual, however, can be very difficult because multiple factors contribute to a high inter-patient variability. There was agreement on the advantages and disadvantages of the use of valproate in the elderly, and consensus that valproate is a useful option in this population. There was no consensus, however, on whether valproate should be considered among the preferred first-line treatments in the elderly.

Purpose: To compare the influence of enzyme-inducing comedication and valproic acid (VPA) on topiramate (TPM) pharmacokinetics and metabolism at steady state., Methods: Three groups were assessed: (a) patients receiving TPM mostly alone (control group, n =13); (b) patients receiving TPM with carbamazepine (CBZ; n = 13); and (c) patients receiving TPM with VPA (n = 12). TPM and its metabolites were assayed in plasma and urine by liquid chromatography-mass spectrometry (LC-MS)., Results: No significant differences were found in TPM oral (CL/F) and renal (CL(r)) clearance between the VPA group and the control group. Mean TPM CL/F and CL(r) were higher in the CBZ group than in controls (2.1 vs. 1.2 L/h and 1.1 vs. 0.6L/h, respectively; p < 0.05). In all groups, the urinary recovery of unchanged TPM was extensive and accounted for 42-52% of the dose (p > 0.05). Urinary recovery of 2,3-O-des-isopropylidene-TPM (2,3-diol-TPM) accounted for 3.5% of the dose in controls, 2.2% in the VPA group (p > 0.05), and 13% in the CBZ group (p < 0.05). The recovery of 10-hydroxy-TPM (10-OH-TPM) was twofold higher in the CBZ group than in controls, but it accounted for only <2% of the dose. The plasma concentrations of TPM metabolites were severalfold lower than those of the parent drug., Conclusions: Renal excretion remains a major route of TPM elimination, even in the presence of enzyme induction. The twofold increase in TPM-CL/F in patients taking CBZ can be ascribed, at least in part, to stimulation of the oxidative pathways leading to formation of 2,3-diol-TPM and 10-OH-TPM. VPA was not found to have any clinically significant influence on TPM pharmacokinetic and metabolic profiles.

Thirty-five years since its introduction into clinical use, valproate (valproic acid) has become the most widely prescribed antiepileptic drug (AED) worldwide. Its pharmacological effects involve a variety of mechanisms, including increased gamma-aminobutyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockade of voltage-gated sodium channels and modulation of dopaminergic and serotoninergic transmission. Valproate is available in different dosage forms for parenteral and oral use. All available oral formulations are almost completely bioavailable, but they differ in dissolution characteristics and absorption rates. In particular, sustained-release formulations are available that minimise fluctuations in serum drug concentrations during a dosing interval and can therefore be given once or twice daily. Valproic acid is about 90% bound to plasma proteins, and the degree of binding decreases with increasing drug concentration within the clinically occurring range. Valproic acid is extensively metabolised by microsomal glucuronide conjugation, mitochondrial beta-oxidation and cytochrome P450-dependent omega-, (omega-1)- and (omega-2)-oxidation. The elimination half-life is in the order of 9 to 18 hours, but shorter values (5 to 12 hours) are observed in patients comedicated with enzyme-inducing agents such as phenytoin, carbamazepine and barbiturates. Valproate itself is devoid of enzyme-inducing properties, but it has the potential of inhibiting drug metabolism and can increase by this mechanism the plasma concentrations of certain coadministered drugs, including phenobarbital (phenobarbitone), lamotrigine and zidovudine. Valproate is a broad spectrum AED, being effective against all seizure types. In patients with newly diagnosed partial seizures (with or without secondary generalisation) and/or primarily generalised tonic-clonic seizures, the efficacy of valproate is comparable to that of phenytoin, carbamazepine and phenobarbital, although in most comparative trials the tolerability of phenobarbital was inferior to that of the other drugs. Valproate is generally regarded as a first-choice agent for most forms of idiopathic and symptomatic generalised epilepsies. Many of these syndromes are associated with multiple seizure types, including tonic-clonic, myoclonic and absence seizures, and prescription of a broad-spectrum drug such as valproate has clear advantages in this situation. A number of reports have also suggested that intravenous valproate could be of value in the treatment of convulsive and nonconvulsive status epilepticus, but further studies are required to establish in more detail the role of the drug in this indication. The most commonly reported adverse effects of valproate include gastrointestinal disturbances, tremor and bodyweight gain. Other notable adverse effects include encephalopathy symptoms (at times associated with hyperammonaemia), platelet disorders, pancreatitis, liver toxicity (with an overall incidence of 1 in 20,000, but a frequency as high as 1 in 600 or 1 in 800 in high-risk groups such as infants below 2 years of age receiving anticonvulsant polytherapy) and teratogenicity, including a 1 to 3% risk of neural tube defects. Some studies have also suggested that menstrual disorders and certain clinical, ultrasound or endocrine manifestations of reproductive system disorders, including polycystic ovary syndrome, may be more common in women treated with valproate than in those treated with other AEDs. However, the precise relevance of the latter findings remains to be evaluated in large, prospective, randomised studies.

To evaluate the pharmacokinetic interaction between risperidone and the mood-stabilizing agents carbamazepine and valproic acid, steady state plasma concentrations of risperidone and 9-hydroxyrisperidone (9-OH-risperidone) were compared in patients treated with risperidone alone (controls, n = 23) and in patients comedicated with carbamazepine (n = 11) or sodium valproate (n = 10). The three groups were matched for sex, age, body weight, and antipsychotic dosage. Plasma concentrations of risperidone and 9-OH-risperidone did not differ between valproate-comedicated patients and controls. By contrast, the concentrations of both compounds were lower in patients taking carbamazepine, although the difference reached statistical significance only for the metabolite (p < 0.001). The sum of the concentrations of risperidone and 9-OH-risperidone in patients receiving carbamazepine (median 44 nmol/L) was also significantly lower than in patients receiving valproate (168 nmol/L) and in controls (150 nmol/L). In five patients assessed with and without carbamazepine comedication, dose-normalized plasma risperidone and 9-OH-risperidone concentrations were significantly lower when the patients received combination therapy than when they received risperidone alone. In three patients assessed with and without valproate, no major changes in the levels of risperidone and its metabolite were observed. These findings demonstrate that carbamazepine markedly decreases the plasma concentrations of risperidone and its active 9-OH-metabolite, probably by inducing CYP3A4-mediated metabolism. This interaction is likely to be clinically significant. Conversely, valproic acid does not cause any major change in plasma antipsychotic levels.

Purpose: To assess the comparative therapeutic value of valproate (VPA), lamotrigine (LTG), and their combination in patients with complex partial seizures resistant to other established antiepileptic drugs (AEDs)., Methods: After a 3-month prospective baseline, 20 adults with refractory complex partial seizures not exposed previously to VPA and LTG were scheduled to receive three consecutive add-on treatments with VPA, LTG, or their combination, according to an open, response-conditional, crossover design. Each period consisted of a 6- to 12-week dose optimization followed by 3-month evaluation at stabilized serum drug levels. Only patients not responding to one phase proceeded to the next., Results: A >50% reduction in seizure frequency was observed in three of 20 patients given VPA and in four of 17 patients given LTG. Of the remaining 13 patients, four became seizure free, and an additional four experienced seizure reductions of 62-78% when VPA and LTG were given in combination. Mild tremor was observed in three patients receiving VPA and in all patients taking the VPA--LTG combination. In patients responding to combination therapy, optimized dosages and peak serum levels of both VPA and LTG were lower than those during separate administration., Conclusions: A considerable proportion of patients who failed to respond to VPA and LTG separately improved when the two drugs were combined, although serum levels of both agents were lower during combination therapy. Despite methodologic limitations in the nonrandomized treatment sequence, these findings suggest that VPA and LTG exhibit a favorable pharmacodynamic interaction in patients with refractory partial epilepsy. The dosage of both drugs, however, may need to be reduced to minimize the risk of intolerable side effects.

Two separate studies were carried out to assess the effect of valproic acid on the steady-state plasma concentrations of clozapine and its major metabolites norclozapine and clozapine N-oxide in psychotic patients. In the first study, concentrations of clozapine and metabolites were compared between patients treated with clozapine in combination with sodium valproate (n = 15) and control patients treated with clozapine alone (n = 22) and matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with valproate tended to have higher clozapine levels and lower norclozapine levels, but the differences did not reach statistical significance. In a subsequent study, plasma concentrations of clozapine and its metabolites were determined in 6 patients with schizophrenia stabilized on clozapine therapy (200-400 mg/d) before and after treatment with sodium valproate (900-1200 mg/d) for 4 weeks. Mean plasma concentrations of clozapine and its metabolites did not change significantly throughout the study, but there was a trend for clozapine levels to be higher and for norclozapine levels to be lower after valproate. Overall, these findings suggest that valproic acid may have an inhibiting effect on the CYP1A2- or CYP3A4-mediated conversion of clozapine to norclozapine. However, the interaction is unlikely to be clinically significant.

Purpose: To describe an 11-year-old girl with symptomatic localization-related epilepsy and normal intelligence who developed reversible mental deterioration and pseudoatrophic brain changes while receiving valproate (VPA)., Methods: Assessment of mental function using Wechsler Intelligence Scale for Children-III (WISC) and Raven's Progressive Matrices (PM), EEG recordings while awake and asleep, and brain magnetic resonance imaging (MRI), were performed at the beginning of VPA therapy, after 2 years and 8 months of treatment and following VPA discontinuation., Results: After 2 years and 6 months on VPA (< or = 26 mg/kg/day) the girl insidiously developed mental deterioration (loss of 18 IQ points and drop in age-adjusted PM score from the 95th to the 50th percentile) associated with MRI-documented pseudoatrophy of the brain. Onset of severe cognitive impairment coincided with serum VPA concentrations near 100 microg/ml. There were no other manifestations of drug toxicity or hyperammonemia. Background EEG activity was normal. Reduction of VPA dosage and subsequent discontinuation 4 months later resulted in disappearance of clinical symptoms with a 20-point improvement at IQ testing and recovery of previous PM score. Repeat MRI showed disappearance of pseudoatrophic changes., Conclusions: The striking cognitive improvement and reversal of pseudoatrophic brain changes following VPA discontinuation strongly suggest a drug-induced condition. Based on this and previous reports, the syndrome of VPA-associated mental deterioration and pseudoatrophy of the brain appears to encompass different but possibly related clinical entities, which include parkinsonism with cognitive deterioration, mental deterioration with signs of VPA-toxicity, and isolated mental deterioration, as seen in our patient. A drug-induced effect should be considered whenever cognitive deterioration and imaging findings of brain atrophy occur in VPA-treated patients.

Subjective and objective measures of daytime sleepiness and psychomotor function were determined in normal control subjects and in epileptic patients on chronic monotherapy with phenobarbital or valproate (n = 10 in each group). All patients had primary generalized epilepsy with a normal resting EEG and were seizure-free for at least 1 year. After nocturnal polysomnographic recording, each subject was evaluated at 2 h intervals between 10:00 and 16:00 h by using multiple sleep latency tests (MSLT), a visual analogue rating scale for alertness (VARS), an anxiety scale (STAI-X1) and a battery of psychomotor tests. Nocturnal sleep parameters before daytime assessment were comparable in the 3 groups. At MSLT, patients on phenobarbital showed a shorter mean sleep latency (9.0 +/- 1.7 min) compared with the valproate group (12.5 +/- 1.3 min) and controls (12.9 +/- 1.2 min), though within-group variability was considerable. Compared with controls, patients on phenobarbital showed longer motor movement times, impaired attention (cancellation test, CT), reduced processing speed (digit-symbol substitution, DSS) and a trend towards lower critical flicker fusion threshold. Patients on valproate showed some impairment in attention and a trend towards longer motor movement time. In patients, no correlation was found between assessed parameters and serum drug concentrations, which were 19.3 +/- 1.7 micrograms/ml for phenobarbital and 85.7 +/- 4.7 micrograms/ml for valproic acid.

The mechanism responsible for the valproate (VPA)-induced elevation of serum carbamazepine-10,11-epoxide (CBZ-E) levels was investigated in 6 normal subjects who received single oral doses of CBZ-E (100 mg) in a control session and during concurrent treatment with sodium VPA [500 mg twice daily (b.i.d.)]. VPA caused a significant prolongation of CBZ-E terminal half-life (t1/2 from 6.3 +/- 1.2 to 9.0 +/- 2.0 h, mean values +/- SD) and decreased CBZ-E clearance (from 90.6 +/- 18.8 to 63.2 +/- 16.1 ml h-1 kg-1, mean values +/- SD) without affecting CBZ-E apparent volume of distribution (from 0.82 +/- 0.19 to 0.81 +/- 0.24 l kg-1, mean values +/- SD). These findings indicate that VPA impairs the elimination of CBZ-E, presumably by inhibiting its metabolism.

The pharmacokinetics of a single 400 mg oral dose of valnoctamide (VCD) has been investigated in seven healthy, adult, male volunteers. VCD was not biotransformed rapidly to its corresponding acid valnoctic acid (VCA), unlike its isomer valpromide (VPD). It had a mean residence time of 13.2 h and a terminal half-life of 9.3 h. Throughout the study, only low plasma levels of VCA could be detected. Thus, unlike VPD, which is a pro-drug of the corresponding acid, (valproic acid, VPA). VCD appears to act as a drug in its own right, and it does not undergo similar hydrolysis. The pharmacokinetic difference may account for the different pharmacological activities of the two isomers.

The total and free (nonprotein-bound) concentration of valproic acid (VPA) was determined in plasma samples collected at two different times of the day (before the morning dose and 3 h later) in 62 epileptic children receiving maintenance single-drug therapy with sodium valproate. Both the total and the free concentrations were lower in the early than in the late morning samples (total VPA: 394.4 +/- 150.0 vs. 556.9 +/- 175.2 mumol/L; free VPA: 20.1 +/- 11.1 vs. 31.3 +/- 17.4 mumol/L). The average free fraction of the drug was also lower in the early morning (4.8 +/- 1.3 vs. 5.4 +/- 1.6%, p less than 0.001). At both sampling times, the free fraction was positively correlated (p less than 0.01) with the total concentration. Evidence is presented that, at equal total plasma VPA concentration, the free fraction of the drug is significantly (p = 0.01) higher in the early than in the late morning samples. The rise in plasma free fatty acids (acting as displacing agents) after the overnight fast is probably responsible for this difference in free fraction. The implications of these findings with respect to the monitoring of free plasma VPA levels are discussed.

The diurnal fluctuations in free and total plasma concentrations of valproic acid (VPA) were determined by taking serial blood samples at 2-h intervals in six epileptic patients receiving maintenance therapy with sodium valproate (9.6-24.0 mg/kg in three divided daily doses). Both the free and the total concentrations fluctuated markedly during the period examined (0800-1800 h). The fluctuation of the free drug was about twice as great as that of the total drug (79 +/- 27% versus 47 +/- 21%, p less than 0.01). There was a considerable inter- and intrapatient variability in free VPA fraction. In at least four of six patients the free fraction increased in proportion to the increase in total concentration. These findings are in line with available evidence that the binding of VPA to plasma proteins is saturable within the clinically occurring concentration range. The changing and unpredictable relationship between total and free concentration suggests that VPA therapy can be monitored more rationally by measuring the free drug.

1 The effect of valproic acid on the distribution and elimination kinetics of intravenously administered phenytoin has been investigated in eight normal volunteers. 2 In each of the subjects studied the volume of distribution of phenytoin increased significantly during treatment with sodium valproate (1200 mg daily for 7 days). 3 Phenytoin clearance was markedly increased in presence of valproic acid as compared to control values (0.52 +/- 0.17 v 0.38 +/- 0.11 ml min-1 kg-1 respectively, P less than 0.02). 4 It is suggested that the increase of the volume of distribution and of the serum clearance are secondary to displacement of phenytoin from plasma protein binding sites by valproic acid.

The effect of sample incubation and storage on the protein binding of the antiepileptic drug valproic acid (VPA) and on the concentration of free fatty acids (FFA) was investigated in serum and plasma collected from four normal volunteers. Both the free fraction of VPA and the concentration of FFA increased progressively with time when samples were incubated at 4 to 37 degrees C. These effects occurred to the same extent in both serum and heparinized plasma. At 4 degrees C and at room temperature, the increase in free drug fraction was relatively small (18 and 25% respectively at 24 h), whereas at 37 degrees C it was quite considerable (24% at 8 h and 40% at 24 h). At room temperature, FFA rose on average by 22% at 4 h, 34% at 8 h, and 86% at 24 h, whereas at 37 degrees C the increases at the same incubation times were 59, 90, and 160%, respectively. There was a strong positive relationship between changes in free VPA fraction and FFA content of the samples. The time-dependent changes in VPA binding capacity described in this study may lead to overestimation of the actual free concentration in vivo, especially when this is estimated by equilibrium dialysis or ultracentrifugation techniques requiring long incubation (centrifugation) times at 37 degrees C.

To evaluate the comparative effects of valproic acid (VPA) and valpromide (VPM) on plasma levels and protein binding of carbamazepine (CBZ) and CBZ-10,11-epoxide (CBZ-E), 12 adult epileptic patients stabilized on CBZ monotherapy were divided into two groups. One group (n = 6) received sodium valproate (1,100 mg/day) for 2 weeks, while the other group (n = 6) was given, for the same period, a dosage of VPM (1,200 mg/day) expected to produce VPA levels equivalent to those achieved with valproate. Plasma CBZ levels were not affected by either treatment. In the valproate-treated group, plasma CBZ-E levels increased by 101% (range, 29-238%) within 1 week of combined therapy (p less than 0.02) and returned to baseline values after VPA treatment was stopped. In the VPM-treated patients, the elevation of plasma CBZ-E levels was much greater. In this group, plasma CBZ-E increased by 330% (range, 110-864%), and this was associated in two patients with the appearance of adverse effects which subsided after reducing the VPM dosage. The plasma protein binding of CBZ and CBZ-E was not affected significantly by VPM or valproate therapy. Plasma VPA levels were similar in the two groups. It is concluded that VPM is not simply a prodrug of VPA. Although both VPA and VPM increase CBZ-E levels--probably by inhibiting the enzyme epoxide hydrolase--the interaction caused by VPM is of much greater magnitude and potential clinical significance.

The single oral dose pharmacokinetics of carbamazepine-10, 11-epoxide (CBZ-E) were investigated in six normal volunteers during a control session and during concurrent treatment with valpromide (VPM) (300 mg twice daily for 8 days). VPM caused a prolongation of the CBZ-E half-life from 6.4 +/- 1.4 to 20.5 +/- 6.3 h and decreased CBZ-E clearance from 73.5 +/- 20.0 to 23.5 +/- 4.0 ml h-1 kg-1 (P less than 0.01). These results suggest that the elevation of plasma CBZ-E levels in patients receiving carbamazepine and VPM in combination is due to inhibition of epoxide hydrolase in the liver.

The effect of naproxen on the kinetics of free and total plasma valproic acid (VPA) was investigated in 6 normal volunteers by using a recently developed simple ultrafiltration technique associated with an immuno-enzymatic assay (Free Level System I, Syva). Each subject received a single oral dose of sodium valproate on two occasions: a) on a control day and b) during concurrent treatment with naproxen (500 mg b.i.d. for 5 consecutive days). Naproxen caused a slight but significant decrease in total plasma VPA levels but left free VPA levels essentially unchanged. The free VPA fraction increased with increasing total VPA concentrations: at equivalent values of total VPA, however, the free fraction was higher in the presence of naproxen. It is concluded that naproxen exerts a moderate displacing effect on protein bound VPA, thereby increasing the clearance of total drug but leaving essentially unchanged the clearance of free drug.

The binding of diazepam, phenytoin and valproic acid to serum proteins in vitro has been compared in pregnant women of different gestational ages and in controls. The unbound fraction of each of three drugs was elevated during pregnancy (particularly during the last 8 weeks) probably due, at least in part, to a fall in serum albumin concentration. These findings may provide a partial explanation for the increase in the clearance of certain drugs during pregnancy and need to be taken into account when interpreting serum drug levels in clinical practice.

The mechanism underlying the impaired serum protein binding of valproic acid (VPA) in pregnancy was examined in samples collected from 24 healthy women in the last 3 weeks of gestation and 15 age-matched nonpregnant female controls. Experiments were performed in vitro using a rapid equilibrium dialysis technique free from in vitro alterations in free fatty acids (FFA). At a total drug concentration of approximately 420 mumol/L, the free VPA fraction was 10.2 +/- 2.9% (SD) in pregnant women and 4.8 +/- 1.0% in controls (p less than 0.001). Pregnancy was associated with a marked reduction in serum albumin levels but with only a slight, nonsignificant elevation in FFA. Free VPA fraction was negatively correlated with serum albumin levels. A positive correlation between free VPA fraction and FFA was observed in the pregnant group but not in the controls. The only sample collected during labour showed a striking elevation of both free VPA fraction and FFA, in spite of a normal albumin concentration. Scatchard's plots showed VPA bound to two classes of binding sites on the albumin molecule. The number of primary (n1) and secondary (n2) binding sites in pregnant women (n1 = 2.0; n2 = 10.7) was virtually identical to that observed in the controls (n1 = 1.9; n2 = 9.8). The association constants of the primary (k1) and secondary (k2) sites were lower in pregnant women (15.9 X 10(3) and 0.19 X 10(3) L/mol, respectively, vs. 22.6 X 10(3) and 0.33 X 10(3) L/mol in controls) but the difference was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

1 Serum levels of valproic acid have been determined at fixed intervals after the administration of single oral and intravenous doses (800 mg) to six epileptic patients receiving chronic treatment with other antiepileptic drugs. 2 Serum levels declined monoexponentially shortly after the intravenous administration. Biological half-lives averaged 9.0 +/- 1.4 h (s.d.). Volumes of distribution were 0.175 +/- 0.025 l/kg. There was a statistically significant negative correlation between volumes of distribution and serum half-lives (P less than 0.005). 3 After oral doses serum levels rose rapidly to peak values within 0.5--2 h. Biological availability was 96 +/- 9%. 4 Comparison with a previous study performed according to the same protocol in healthy volunteers showed significantly increased volumes of distribution and rates of elimination in the patients. Total serum clearance was 85% higher in the patients as compared to the healthy subjects (P less than 0.001). Possible explanations for these findings are discussed.

The serum protein binding of valproic acid (VPA) and phenytoin (PHT) was determined in spiked serum samples collected from 17 patients with insulin-dependent diabetes mellitus and 16 healthy control subjects. The free fraction of VPA was significantly greater in patients than in controls (7.6 +/- 1.6% vs. 6.2 +/- 1.2%, p less than 0.01); for PHT, free fraction values were similar in the two groups (8.2 +/- 1.1% vs. 8.4 +/- 1.2%). The free fraction of VPA in diabetic patients was positively correlated with free fatty acid (FFA) concentration (r = 0.79, p less than 0.01). No significant relationships could be found between free drug fraction and either serum albumin or glycosylated protein concentration.

The diurnal variation in total and free plasma phenytoin (PHT) concentration at steady state was examined in eight epileptic patients receiving combination therapy with tid valproic acid (VPA) as sodium salt. Eight patients treated with PHT, but not with VPA, were studied for comparison purposes. In the absence of VPA coadministration, total and free PHT concentrations did not change significantly during the day and showed only minor intrapatient fluctuations (14 and 13%, respectively). In patients receiving VPA, the mean total PHT did not change significantly, whereas the free PHT increased during the day (p less than 0.05). The fluctuations in total and free PHT in these patients were 16 and 17% on average. In the presence of VPA, the free PHT fraction was higher than in controls (13.9 +/- 2.3% versus 8.3 +/- 1.9%; p less than 0.01) and fluctuated to a greater extent (29 versus 14% in controls; p less than 0.01), mainly as a result of combined opposite swings in both total and free concentration. The diurnal changes in free PHT concentration and fraction correlated positively with the changes in plasma VPA. An inverse relationship between total PHT concentration and plasma VPA was found in some patients. These data demonstrate that the displacement interaction between PHT and VPA is subject to diurnal variation, probably as a result of the fluctuation in plasma VPA. The implications of these findings are discussed.

The unbound fraction of valproic acid (VPA) was found to be significantly lower in cord serum (6.0 +/- 0.8%) than in maternal serum collected before oxytocin (12.2 +/- 2.7%) or after delivery (9.9 +/- 2.3%). The difference was probably due to the concentration of free fatty acids (acting as displacing agents) being higher in maternal serum. The transplacental binding gradient explains the clinical observation that total VPA levels at delivery are higher in the newborn than in the mother.

The kinetics of a single oral dose of sodium valproate was studied in six healthy elderly patients (age 68-89 years) and six young control subjects (age 24-26 years). The profiles of total plasma valproic acid (VPA) concentrations were very similar in the elderly and in the young. Half-lives (15.3 +/- 0.7 s.e. mean in the elderly vs 13.0 +/- 1.0 h in the young), volumes of distribution (0.16 +/- 0.01 l/kg in the elderly vs 0.14 +/- 0.01 l/kg in the young) and clearance (7.5 +/- 0.9 ml h-1 kg-1 in the elderly vs 7.7 +/- 0.6 ml h-1 kg-1 in the young) did not differ significantly between the two groups. Free VPA concentrations were significantly increased in the elderly. The clearance of the free drug (intrinsic clearance) was reduced from 127.0 +/- 12 ml h-1 kg-1 (control value in the young) to 77.7 +/- 5.5 ml h-1 kg-1 (P less than 0.02). Free VPA fraction was 9.5 +/- 0.6% in the elderly and 6.6 +/- 0.5% in the young (P less than 0.02). These findings suggest that the pharmacokinetic alterations of VPA in old age are complex and include at least two separate mechanisms: a decrease in plasma protein binding and a reduction of drug metabolizing capacity resulting in decreased clearance of free drug by the liver.

The plasma protein binding of phenytoin was studied in nine epileptic patients before and during addition of sodium valproate to the drug therapy. The free phenytoin fraction in plasma was significantly greater during sodium valproate treatment. The mean free fraction rose from 0.135 +/- 0.019 (s.d.) to 0.182 +/- 0.030. Total plasma phenytoin concentration fell significantly from a range of 4.3-26.2 micrograms/ml to 3.4-19.8 micrograms/ml during sodium valproate treatment. Neither the free plasma concentration nor the saliva concentration of phenytoin was significantly altered by sodium valproate. No significant correlation was found between plasma valproic acid concentrations and the change in phenytoin binding. We conclude that valproic acid displaces phenytoin from plasma protein binding sites but does not inhibit its metabolism.

The effect of sodium valproate (400 mg three times daily) on the disposition kinetics of intravenous phenytoin (250 mg) was investigated in seven normal subjects. After valproate, the free (unbound) fraction of phenytoin in serum rose from 9.6 +/- 0.9% (SD) to 15.6 +/- 1.4% on average (p < 0.001). The effect was associated with an increase in systemic clearance and apparent volume of distribution of total drug. There was a strong positive correlation between percent increment in each of these parameters and percent increment in unbound drug in serum. Free phenytoin concentration in serum and phenytoin concentration in saliva increased during valproate administration. As a result, both the clearance and the apparent volume of distribution of free drug were reduced. There was an increase in the renal excretion of unchanged phenytoin during valproate administration, but the effect was too small to have an appreciable influence on the overall clearance of the drug. There were no consistent changes in the excretion of the major metabolite 5, p-hydroxyphenyl, 5-phenyl, hydantoin (pHPPH), in the urine. These results suggest that valproic acid may have two separate and opposing effects on phenytoin disposition: (1) displacing phenytoin from plasma protein binding sites, thereby enhancing the systemic clearance of total drug, and (2) inhibiting phenytoin metabolism, thereby increasing the concentration of free drug in the serum.

An equilibrium dialysis technique for the separation of the free (unbound) concentration of valproic acid (VPA) in plasma is described together with a sensitive gas chromatographic assay for the quantitative determination of the drug in the dialysate. The overall coefficient of variation of the method was below 10%. By using a high permeability membrane, equilibration of the drug between the plasma and the buffer compartments was obtained after about 45 min at 37 degrees C. With this dialysis time, dilutional changes in the plasma compartment were negligible and there was no significant change in the plasma-free fatty acid (FFA) concentration. No passage of protein into the buffer solution was detected. When dialysis was prolonged for up to 4 h, a significant elevation in plasma FFA (with a corresponding rise in free VPA fraction) was observed. Storage of plasma samples at temperatures ranging from 4 to 37 degrees C for 8 h or longer before dialysis also resulted in an increased value of free VPA fraction and FFA concentration. The two effects were significantly correlated. The free fraction of VPA was found to increase with increasing total plasma concentration. This effect was observed both in vitro and in vivo in the plasma of 91 patients receiving chronic VPA therapy. The methodological problems of using equilibrium dialysis techniques for determining the free fraction of VPA are highlighted.

Summary: Objective: To evaluate the pharmacokinetics of eslicarbazepine acetate (ESL) at steady-state in adults with partial-onset seizures who have taken ESL for at least 1 year with one or two concomitant antiepileptic drugs (AEDs). Methods: Blood samples for the pharmacokinetic assessment were taken at pre-dose, and 1, 2, 3, 4, 6, 8, 12 and 24h post-dose at steady-state in 51 patients stabilised on chronic (beyond 1 year) treatment with ESL 400mg (n =7), 800mg (n =26) or 1200mg (n =18) once-daily. Most patients (n =29, 56.9%) were receiving 2 concomitant AEDs, and most frequent co-medications were carbamazepine (n =34, 66.7%) and valproic acid (n =19, 37.3%). Plasma concentrations of ESL and its metabolites eslicarbazepine, R-licarbazepine and oxcarbazepine (OXC) were determined by a validated chiral method using liquid chromatography coupled to mass spectrometry. Results: Similarly to earlier findings in healthy subjects, plasma ESL concentrations were consistently below the lower limit of quantification (50ng/mL). The major compound in plasma was the active metabolite eslicarbazepine, which reached maximum concentrations (C max) 2h post-dose; thereafter, its plasma concentrations declined with a mean apparent half-life of 13, 14, and 20h in patients receiving ESL doses of 400, 800, and 1200mg once daily, respectively. Eslicarbazepine C max were 9.7, 15.5 and 23.0μg/mL, and areas under the plasma concentration–time curve over the dosing interval (AUC0–24) were 132.5, 205.4 and 336.1μgh/mL in patients receiving ESL doses of 400, 800 and 1200mg once-daily, respectively. Eslicarbazepine main pharmacokinetic parameters (C max and AUC0–24) were dose-proportional. R-licarbazepine and OXC were minor metabolites. Conclusions: Following once-daily oral administration of ESL 400mg, 800mg and 1200mg to epilepsy patients treated concomitantly with one or two other AEDs, ESL was rapidly converted to eslicarbazepine, which was the primary active compound found in plasma. Systemic exposure to eslicarbazepine was dose-proportional. [Copyright &y& Elsevier]