Plasma levels and clinical effects of antiepileptic drugs in pregnant epileptic patients and their newborns.
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Publications and source records attributed to D Battino.
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Fifteen children (7 boys and 8 girls) with generalized tonic-clonic seizures (GTCS) and partial seizures with elementary or complex symptomatology, treated with carbamazepine (CBZ) alone (n = 7) or in combination with either phenobarbital (PB, n = 6) or clobazam (CLB, n = 2) given for at least 3 months at stable individualized doses and regimens, entered an open, within-patient, change-over study of consecutive periods, each lasting 2 weeks. During period 1, conventional CBZ was given; during period 2, a chewable CBZ formulation was substituted for conventional CBZ and given at the same total daily dosage with the same schedule as in period 1. Blood samples for measuring plasma concentration of both total CBZ and CBZ-10,11 epoxide (CBZ-E) were taken on the last day of each period. No significant difference between the two periods was noted in the mean +/- SD of Cmax, Css mean, and area under the curve (AUC) of total CBZ and CBZ-E. The two different CBZ formulations, administered at the same total daily dosage, can be considered bioequivalent.
The relationship between oral dose and plasma concentration of ethosuximide was evaluated retrospectively in 198 epileptic patients aged 2.5 to 34 years. Age appears to be a major factor in determining the ethosuximide plasma level/dose (L/D) ratio. Children younger than 10 years had men L/D ratios significantly lower (p less than 0.0003) than adolescents (10 to 15 years of age) and adults (16 to 34 years of age). Associated antiepileptic therapy reduced the ethosuximide L/D ratio: mean ethosuximide L/D ratios were significantly lower in patients also taking primidone (p less than 0.0005) or valproic acid (p less than 0.02). The correlation between the dose of ethosuximide administered and the plasma concentration was significant in the 3 age groups considered (p less than 0.0004), but the wide scattering of individual plasma concentrations makes it impossible to predict what plasma concentration of ethosuximide will be obtained after a given dose. For this reason, routine monitoring of ethosuximide plasma concentrations still appears to be necessary, especially in children and patients on polytherapy.
Plasma concentrations of primidone and its metabolite phenobarbitone were monitored in 9 pregnant epileptic patients treated with primidone (and in 3 cases other antiepileptic drugs) given at constant doses throughout pregnancy and the puerperium. Phenobarbitone plasma concentrations were monitored in another 6 patients given phenobarbitone itself. A trend towards increasing primidone plasma concentrations during the second quarter of pregnancy was evident in all patients, with a concomitant significant decrease in primidone-derived phenobarbitone plasma concentrations. A trend towards a lowering of plasma concentrations of phenobarbitone administered as such was confirmed. These results suggest the usefulness of a careful monitoring of primidone and primadone-derived phenobarbitone during pregnancy and the puerperium. Discrepancies of findings with primidone and phenobarbitone are discussed in view of the possible mechanism involved.
Plasma concentrations of carbamazepine were monitored in 9 pregnant epileptic patients treated with the drug alone at constant doses during pregnancy and for at least 3 months after delivery. In addition, plasma concentrations of the metabolite, carbamazepine 10,11-epoxide were measured in 6 of the 9 patients. Plasma carbamazepine concentrations were fairly stable during pregnancy, and carbamazepine relative plasma clearances were significantly higher in weeks 4 to 24 than in weeks 25 to 32. After the end of the second trimester, there were no variations in plasma carbamazepine 10,11-epoxide concentrations and carbamazepine 10,11-epoxide:carbamazepine ratios. Both parameters were significantly higher in weeks 4 to 24 than in weeks 25 to 32 of pregnancy.
The interaction between epilepsy and pregnancy has been studied for many years; nonetheless the risk associated with individual antiepileptic drug has not been adequately characterized up to date. Moreover, virtually nothing is known about the possible human teratogenicity of the newer antiepileptic drugs. Because of the complexity of the mechanisms involved, the crucial evidence needed can only come from very large population based studies, and a collaborative European multicentre investigation has been set up to this purpose. Specific objectives include the evaluation of the risk of major foetal malformations and of delay in prenatal growth following exposure to antiepileptic drugs, assessment of the pattern of congenital abnormalities associated with older and newer antiepileptic drugs and their combinations, and identification of possible relationships with dosage and with a variety of other risk factors. All women exposed to antiepileptic drugs at the time of conception are eligible for entry. The protocol is purely observational and does not entail any change in prescribing pattern or management policies, which are left to the discretion of the treating physician. Data obtained during prospective monitoring for up to 1 year after birth are regularly collected in especially designed forms and entered into Regional Registries prior to transfer to a Central European Registry of Antiepileptic Drugs and Pregnancy (EURAP). Evaluations of incidence and prevalence of teratogenic endpoints will be based exclusively on cases enrolled before foetal outcome is known and in any case not after the 16th week of pregnancy. Cases enrolled after birth, after the 16th week of pregnancy or after prenatal diagnosis will only be reported descriptively. The study is being implemented gradually in 19 countries in Western and Eastern Europe. Wide participation from interested physicians is essential for the achievement of the study objectives, which are expected to lead to important advances in pre pregnancy counselling and overall clinical management of women with epilepsy.