Juan A. Armijo

Clinical Side Effects of Phenobarbital, Primidone, Phenytoin, Carbamazepine, and Valproate During Monotherapy in Children

Summary: The rate of onset of side effects was examined in 392 pediatric outpatients who received long‐term monotherapy with phenobarbital (PB), primidone (PRM), phenytoin (PHT), carbamazepine (CBZ), or valproate (VPA) for epilepsy or febrile convulsions. The severity of side effects (based on need to alter treatment), the nature of each drugs most common side effects, and the doses and plasma levels of occurrence were recorded. Our results show that usually accepted therapeutic ranges are well tolerated. Indeed, although some form of side effect occurred in 50% of patients, treatment had to be changed in only 18% and the drug had to be stopped in only 7%. In decreasing order, the rates for side effects were PHT (71%) > PB (64%) > CBZ (43%) > VPA (43%) > PRM (29%). Serious side effects requiring withdrawal of treatment occurred at the following rates: PHT (10%) > VPA (8%) > PRM (8%) > PB (4%) > CBZ (3%). Among our patients, the best tolerated antiepileptic drug (AED) was CBZ, and the least tolerated was PHT. Behavioral disorders were most common with PB, neurologic disorders with PHT, digestive tract disorders with VPA, and gingival hyperplasia and hirsutism with PHT. Behavioral disorders involving excitement seen with PB and PRM occurred most commonly at low plasma levels. Behavioral disorders involving depression seen with PB and VPA, those involving excitement seen with PHT and VPA, and digestive disorders seen with VPA occurred particularly when plasma levels were high.

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.

Genetic factors associated with drug-resistance of epilepsy: Relevance of stratification by patient age and aetiology of epilepsy

Epilepsy drug-resistance may depend on the metabolism of antiepileptic drugs (AEDs), transport to the epileptic focus and/or target sensitivity. Furthermore, drug response depends on multiple characteristics of the patient, the epilepsy, and the antiepileptic drugs used. We have investigated the association between polymorphisms related to antiepileptic drug metabolism (CYP2C9, CYP2C19, and UGT), transport (ABCB1), and targets (SCN1A) both in a crude analysis and after adjusting by clinical factors associated with drug-resistance, and stratifying by patient age or aetiology of epilepsy. Caucasian outpatients (N=289), children (N=80) and adolescent-adults (N=209), with idiopathic (N=69), cryptogenic (N=97) or symptomatic epilepsies (N=123) were selected when they had either drug-resistance (with at least four seizures over the previous year after treatment with more than three appropriate AEDs at appropriate doses) or drug responsiveness (without seizures for at least a year). Samples were genotyped by allelic discrimination using TaqMan probes. No significant association between polymorphisms and drug-resistance was found either in the crude analysis or in the adjusted analysis. However, adults with the ABCB1_3435TT or 2677TT genotypes had a lower risk of drug-resistance than those with the CC or the GG genotypes. Furthermore, patients with symptomatic epilepsies with the ABCB1_3435CT or TT genotypes had a lower risk of drug-resistance than those with the CC genotype. An opposite but insignificant tendency was found in children and in idiopathic epilepsies. Although replication studies will be needed to confirm our results, they suggest that stratification by patient age and by the aetiology of epilepsy could contribute to unmask the association between ABCB1 polymorphisms and drug-resistance of epilepsy.

Nimodipine-enhanced opiate analgesia in cancer patients requiring morphine dose escalation : a double-blind, placebo-controlled study

&NA; The ability of nimodipine, a dihydropyridine calcium antagonist, to reduce the daily dose of oral morphine in cancer patients who had developed dose escalation, was tested in 54 patients under randomized, double‐blind, placebo‐controlled conditions. We selected patients that required at least two successive increments of morphine to maintain pain relief. A possible pharmacokinetic interaction between nimodipine and morphine was also studied in 14 patients by assaying steady‐state serum levels of morphine and its 3‐ and 6‐glucuronides. A total of 30 patients completed the study, 14 and 16 in the nimodipine and placebo groups, respectively. Nimodipine controlled the escalation of the morphine dose in 9 patients (65%), and placebo in 4 (28%), the difference being statistically significant (P=0.03). The dose of morphine was reduced from 313±52 to 174±33 mg/day (P<0.001) in the nimodipine group, and from 254±26 to 218±19 mg/day (not significant) in the placebo group. The percentages of reduction in the daily dose of morphine also showed significant differences between both groups (P=0.02). One week after introducing nimodipine or placebo, while the dose of morphine remained similar to that of the pre‐test week, the serum levels of morphine and its glucuronides were not modified significantly. We conclude that the introduction of nimodipine in patients chronically treated with morphine may be a safe alternative to reduce the daily requirements of the opioid. It is suggested that interference with Ca2+‐related events may attenuate the development and/or expression of tolerance to morphine in a clinically relevant way.

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.

Gamma-vinyl GABA (vigabatrin): relationship between dosage, plasma concentrations, platelet GABA-transaminase inhibition, and seizure reduction in epileptic children.

Summary: The relationship between vigabatrin γ‐vinyl GABA (GVG, vigabatrin) daily dosage or steady‐state plasma concentrations (CSS), platelet GABA‐transaminase (GABA‐T) inhibition, and seizure reduction were studied in 16 children with refractory epilepsy. After 2 months of observation and 1 month of single‐blind add‐on placebo, a fixed GVG dosage was added for 2 months. The dosage was then adjusted in two 2‐month periods each, based on the patients clinical response. In the fixed‐dose period, GVG dosages of 56.8 mg/kg/day and CSS of 8.1 mg/L reduced GABA‐T activity from 13.9 to 5.1 pmol/min/mg protein (p < 0.001) and that of seizures from 51.4 to 22.3 seizures per month (p < 0.01). Seizure reduction was correlated with dosage (r= 0.83, p < 0.001), but not with CSS or with platelet GABA‐T inhibition. After the GVG dose‐adjustment periods, in which dosages of 84.4 mg/kg/day and CSS of 10.6 mg/L were reached, only a slight reduction was observed in both GABA‐T activity (from 5.1 to 4.9 pmol/min/mg protein) and seizures (from 22.3 to 18.1 seizures per month). In GVG‐responsive patients (excluding placebo‐sensitive and GVG‐resistant patients), a greater reduction of seizures was achieved (from 17.0 to 7.1 seizures per month, p < 0.05), which was not accompanied by greater inhibition of GABA‐T. GVG treatment in children should be started with a dosage of 50 mg/kg/day, increased to 75 or even 100 mg/kg/day when a partial response is observed. If seizures do not improve or if they become worse, the patient should be considered resistant and GVG should be discontinued.

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.

Dose-Response Study of Vigabatrin in Children With Refractory Epilepsy

Twenty children aged 2 months to 18 years were included in a dose-response study of vigabatrin as add-on therapy to preexisting antiepileptic drugs (up to two per patient). All children had severe refractory epilepsy: partial seizures with or without secondary generalization in 19, and myoclonic seizures in one. After a 2-month observation period and a 1-month add-on placebo period, a fixed dose of add-on vigabatrin was given for 2 months: 1, 1.5, or 2 g/day, according to body weight (mean dose, 60 mg/kg/day). Three patients (15%) became seizure free, and nine (45%) showed a 50% to 99% reduction in seizure frequency. In the 17 patients whose seizures were not totally suppressed, vigabatrin dose was increased for a further 2 months, and in 7 patients who still showed less than 50% reduction in seizure frequency, vigabatrin dose was increased again. Efficacy appeared unchanged by these higher doses. During a 9-month follow-up phase, no tolerance to the effects of vigabatrin was observed, with three children seizure free and 13 (65%) reporting a 50% to 99% reduction in seizure frequency. During the study, adverse effects were recorded in three children (15%), namely drowsiness, constipation, fatigue, and apathy. These effects were generally transient, being observed during the dose-modification phase and disappearing either spontaneously or on reduction of vigabatrin dose. Clinical and laboratory tolerability to vigabatrin appeared to be very good, with no patients having withdrawn from the study because of side effects. A slight reduction in red blood cell count and hemoglobin levels was noted but was of doubtful clinical significance. There was also a slight, nonsignificant decrease in phenytoin plasma levels. In conclusion, vigabatrin is an effective and well-tolerated therapy in children with refractory epilepsy at the dose of 60 mg/kg/day. Higher doses do not appear to bring any further significant benefit. (J Child Neurol 1991;6(Suppl):2S45-2S51).