José L. Herranz

Side Effects of Sodium Valproate in Monotherapy Controlled by Plasma Levels: A Study in 88 Pediatric Patients

Summary: The incidence of toxicity associated with the use of valproic acid (VPA) is considered remarkably low compared to other antiepileptic drugs. This study reports the toxicity of VPA administered as a single drug to 88 children in relation to the daily dose and drug plasma level. The frequency of side effects observed clinically was 42.0%, but it increased to 80.7% when a questionnaire was introduced. In spite of the limitations of this method, the results show the need to perform systematic surveillance for side effects of all antiepileptic drugs, similar to those made to assess their clinical effectiveness. Anorexia, vomiting, and sleep alterations were the most common side effects detected in the clinical record; patients who showed anorexia, hyperactivity, lassitude, sleep disturbances, and sadness had received daily doses significantly higher than patients not showing side effects. Similarly, the children who needed to reduce or discontinue the treatment were receiving the highest doses. No relation, however, could be established between the incidence of side effects and plasma levels of VPA except for lassitude and drowsiness. Severe or fatal toxicity was not detected.

Lamotrigine serum concentration-to-dose ratio: influence of age and concomitant antiepileptic drugs and dosage implications.

Using bivariate and multivariate methods, we retrospectively analyzed the influence of patient age and the use of concomitant antiepileptic drugs (AEDs) on the lamotrigine (LTG) concentration-to-dose (C/D) ratio in samples from 164 patients (68 children, 96 adults) with epilepsy receiving LTG alone (n = 28) or in combination with various antiepileptic drugs (n = 136). The LTG C/D ratio increased with age in children receiving LTG alone (r = 0.60, p < 0.01), but decreased with age in adults receiving LTG and inducers (r = -0.42, p < 0.001). In patients receiving LTG and inducers, the ratio was statistically lower in those younger than 9 years of age (0.23 +/- 0.08) and older than 30 years of age (0.32 +/- 0.15) than it was in those between 9 and 30 years of age (0.44 +/- 0.15). The mean LTG C/D ratio was 0.37 +/- 0.15 in patients receiving LTG and inducers (n = 92), 0.84 +/- 0.41 in patients receiving LTG alone (n = 28), 1.09 +/- 0.44 in those receiving LTG with VPA plus inducers (n = 17), and 3.41 +/- 1.18 in those receiving LTG and VPA (n = 27). Differences in the LTG C/D ratio between treatment groups were similar in children and in adults. We reached the following conclusions: The LTG C/D ratio increased with age in children but may decrease with age in adults receiving concomitant enzyme-inducing AEDs; the LTG C/D ratio was 10 times lower in patients receiving LTG and inducers than in those receiving LTG and VPA (in both children and adults), and this difference was higher than the four-fold difference described for LTG half-life and the two-fold differences currently used in LTG dosage.

UGT2B7_-161C>T polymorphism is associated with lamotrigine concentration-to-dose ratio in a multivariate study.

Lamotrigine (LTG) is metabolized by UGT1A4 but UGT2B7 also contributes to its glucuronidation. The aim of this study was to determine whether UGT2B7_− 161C>T and UGT2B7_372A>G polymorphisms contribute to the intersubject variability in LTG concentration-to-dose ratio (LTG-CDR) in epileptic patients. Fifty-three white epileptic patients attending the Neuropediatric and Neurology Services at the Marqués de Valdecilla University Hospital, in whom LTG serum concentration was to be measured for pharmacokinetic monitoring, were selected according to predefined criteria for LTG-CDR evaluation. All patients had at least one steady-state LTG serum concentration obtained before the first dose in the morning. Patients were classified in 3 groups of comedication: (1) LTG in combination with metabolism-inducer anticonvulsants (n = 22), (2) LTG in combination with valproate (n = 13), and (3) LTG as monotherapy (n = 16) or in combination with valproate and inducers (n = 2). Genotypes were determined by Applied Biosystems Genotyping Assays with TaqMan probes. A significant association was found between LTG-CDR and UGT2B7_−161C>T polymorphism (P = 0.021) when patient age and concomitant antiepileptic drugs were taken into account. Comedication explained 70% of the LTG-CDR variability, patient age 24%, and UGT2B7_−161C>T 12%. In contrast, a significant association between LTG-CDR and this polymorphism was not found in the bivariate study when age and comedication groups were not considered. A significant association between UGT2B7_372A>G and LTG-CDR was not found in the bivariate or the multivariate studies. UGT2B7_−161C>T polymorphism is significantly associated with LTG-CDR when comedication with other antiepileptic drugs and patient age are taken into account in a multivariate analysis.

Effectiveness and Toxicity of Phenobarbital, Primidone, and Sodium Valproate in the Prevention of Febrile Convulsions, Controlled by Plasma Levels

Summary: The effectiveness and toxicity of phenobarbital (PB), primidone (PRM), and sodium valproate (VPA), used exclusively in monotherapy, were compared in 95 children affected with febrile convulsions. Treatment was restricted to either complicated or simple febrile convulsions with risk factors. The effectiveness and toxicity of each drug were related to the daily dose and the steady‐state plasma levels. PB (4.8 ± 0.7 mg/kg/day) achieved plasma levels of 16.4 ± 2.8 μg/ml and prevented febrile convulsions in 80% of the patients. Side effects were observed in 76.7% of the patients, a change in dose being required only in 13.3%. PRM (17.8 mg/kg/day) yielded PB plasma levels of 14.1 ± 3.7 μg/ml and was effective in 88.2% of the patients. The incidence of side effects was 53%, but no change in treatment was required. VPA (35.2 ± 5.9 mg/kg/day) achieved plasma levels of 57.2 ± 15.3 μg/ml (measured before the first dose in the morning) and was effective in 91.7% of the patients. Side effects were detected in 45% (significantly lower than after PB, p < 0.01), and required a change in treatment in 14.3%. No differences in doses and plasma levels were found between patients with or without recurrence of febrile convulsions and with or without side effects; an exception was the higher doses of VPA administered to patients who showed side effects. It is concluded that PRM and VPA were at least as effective and well tolerated as PB. Because the plasma levels of the three drugs were near the lower limit of the therapeutic range, it remains to be elucidated whether higher doses may increase the benefit without adding unacceptable toxicity.

Topiramate serum concentration-to-dose ratio : influence of age and concomitant antiepileptic drugs and monitoring implications

The influence of age and concomitant antiepileptic drugs (AEDs) on the trough steady-state serum concentration of topiramate, normalized to 1 mg/kg body weight or concentration-to-dose ratio (TPM-CDR), was assessed using multivariate methods in samples from 94 epileptic patients (38 under 11 years and 56 over 11 years of age), most of whom were outpatients receiving either just TPM (n = 20) or TPM in combination with other AEDs (n = 74). Analysis of the covariance showed that the age of the patients was influential (P < 0.001) and also showed a difference in TPM-CDR between the non-inducers group (TPM or TPM + lamotrigine or valproate) and the inducers group (TPM + carbamazepine, phenobarbital, or phenytoin) (P < 0.001). The TPM-CDR was 0.4 ± 0.1 in patients under 11 years with inducers (n = 7), 0.8 ± 0.3 in patients over 11 years with inducers (n = 32), 1.1 ± 0.4 in patients under 11 years with noninducers (n = 30), and 1.8 ± 0.6 in patients over 11 years with noninducers (n = 21). A two-way analysis of the variance showed differences between patients under 11 years and those over 11 years (P < 0.001), and between the noninducers and inducers groups (P < 0.001). TPM-CDR was nearly 50% lower in patients under 11 years than in patients over 11 years, and in patients with TPM + inducers than in patients with TPM or TPM + noninducers, in both children and adults. To achieve the same serum concentration of TPM, children will need double the daily dose per kilogram of TPM required by adults, and both children and adults taking enzyme-inducing AEDs will require double the dose needed by those who do not take them.

10-Hydroxycarbazepine serum concentration-to-oxcarbazepine dose ratio: influence of age and concomitant antiepileptic drugs.

This study was done to evaluate the association between patient age and the concomitant use of enzyme-inducing antiepileptic drugs (AEDs) and oxcarbazepine (OXC) concentration-to-dose ratio (CDR) by a multivariate analysis. The influence of patient age and concomitant AEDs on the trough steady-state serum concentration of 10-hydroxycarbazepine (OHC) normalized to 1 mg/kg body weight of OXC or concentration-to-dose ratio (OHC-OXC-CDR) was assessed by analysis of covariance. Samples were collected from 106 patients (90% outpatients), aged 1-80, who were receiving OXC either alone (n = 41) or in combination with other AEDs (n = 65). The average OHC-OXC CDR was 0.70 ± 0.26 (mean ± SD). Analysis of covariance showed that patient age was influential (P < 0.001) and that there was a difference between the noninducers group (OXC or OXC + lamotrigine, topiramate, or valproate) and the inducers group (OXC + phenobarbital or phenytoin) (P < 0.001). The OHC-OXC CDR increased with age (r2 = 0.14, P < 0.001) and was approximately 48% lower in children aged 6 or less than in patients over 45, and approximately 32% lower in the inducers group than in patients receiving OXC alone. The correlation between OHC-OXC CDR and the age of the patients concerned with OXC alone was r2 = 0.48, P < 0.001. In the noninducers group the OHC-OXC CDR was 0.59 ± 0.24 in patients aged 11 or less (n = 16), and 0.81 ± 0.23 in patients over 11 years (n = 62). In the inducers group it was 0.25 ± 0.11 in patients aged 11 or less (n = 3) and 0.57 ± 0.18 in patients over the age of 11 (n = 25). The OHC-OXC CDR increased with patient age and decreased in the presence of enzyme-inducing AEDs in epileptic patients chronically treated with OXC. These influences may be clinically relevant, and, therefore, patient age and the presence of inducers should be considered in estimating either compliance or the OXC dose needed to achieve a desired OHC concentration.

Coadministration of vigabatrin and valproate in children with refractory epilepsy.

The effects of adding vigabatrin (GVG) to the antiepileptic regimens of 16 children with refractory epilepsy have been studied. One-half of the regimens included sodium valproate (VPA). Parameters studied were seizure reduction, platelet GABA-T activity, and steady-state plasma concentrations (CSS) of GVG and VPA. Add-on GVG reduced the seizure frequency both in patients receiving VPA (from 42.9 to 4.5 seizures/month, p < 0.01) and in those without VPA (from 60.0 to 31.7 seizures/month, p < 0.05). GVG also reduced GABA-T activity in both groups (from 19.4 to 5.4, p < 0.001 and from 8.3 to 4.5 pmol/min/mg of protein, p < 0.05, respectively). Seizure reduction and GABA-T inhibition were greater in patients taking VPA than in those who were not. In patients receiving VPA, no significant changes were observed in VPA CSS values before and after the addition of GVG. On the other hand, no differences were found in GVG CSS values between patients with and without VPA. It is concluded that the coadministration of GVG to valproate reduces the frequency of seizures in refractory epileptic children and does not affect the steady-state plasma concentrations of either drug. Therefore, their association could be useful in clinical practice.

Early-onset absence epilepsy: Clinical and electroencephalographic features in three children

To describe the clinical and electroencephalographic features of three infants diagnosed as having early-onset absence seizures. Two males and one female, aged 21-29 months were seen in our neuropaediatric outpatient clinic because of daily episodes of motor arrest and loss of contact. Neurological examination and mental development was considered normal in all of them. Two out three had first-degree relatives with seizures with onset in the childhood and favourable evolution in the adulthood. A video-electroencephalogram was requested. Ictal EEG revealed a normal background and generalised spike-and-wave complexes at 3-3.5 Hz accompanied by disruption of ongoing activity in keeping with absence seizures. The duration of seizures ranged from 2 to 10s. One child (patient 2) experienced rhythmic myoclonic jerks in upper limbs and head as those described in myoclonic absences. Clinical and electroencephalographic follow-up ranged from 8 months to 4 years. Two children were on treatment with valproate and in the case of the patient 3, the combination of valproate and ethosuximide was necessary. Control of absence seizures was achieved in all our cases. Absence seizures should be considered as a possible cause of transient impairment of consciousness even among infants minor than 3 years of age. A video-electroencephalogram is the method of choice in the diagnostic evaluation and syndromic classification of these paroxysmal events.

Poor correlation between single-dose data and steady-state kinetics for phenobarbitone, primidone, carbamazepine and sodium valproate in children during monotherapy. Possible reasons for the lack of correlation.

SummaryAn investigation was performed to determine the relationship between the serum drug concentration/dose ratio at 24 hours following a first dose and that at steady-state for phenobarbitone, primidone (as phenobarbitone and as primidone), carbamazepine and sodium valproate, in order to assess the utility of this method in clinical practice. The drugs were given as monotherapy to 63 children for the treatment of epilepsy or febrile convulsions.The correlation between concentration/dose ratios, instead of between serum concentrations, was investigated with the aim of allowing the use of variable doses. The correlation coefficients were: r = 0.30 for phenobarbitone; r = 0.05 for phenobarbitone derived from primidone; r = 0.38 for primidone; r = 0.19 for carbamazepine; and r = 0.52 for sodium valproate. None of these correlation coefficients differed statistically from 0.These low correlation coefficients contrast with the acceptable results found by other authors for other drugs, indicating that several factors may have a greater influence on this correlation than earlier investigations suggest. The poor correlation obtained emphasises the need for clinical verification of mathematical models based on theoretical considerations which do not always apply in practice.