Jamie T. Gilman

A placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children

Objective: To compare the safety and efficacy of add-on lamotrigine and placebo in the treatment of children and adolescents with partial seizures. Background: Add-on and monotherapy lamotrigine is safe and effective in adults with partial seizures, and reports of preliminary uncontrolled trials suggest similar benefits in children. Methods: We studied 201 children with diagnoses of partial seizures of any subtype currently receiving stable conventional regimens of antiepileptic therapy at 40 study sites in the United States and France. After a baseline observation period (to confirm that more than four seizures occurred in each of two consecutive 4-week periods), patients were randomized to add-on lamotrigine or placebo therapy. A 6-week dose-escalation period was followed by a 12-week maintenance period. Results: Compared with placebo, lamotrigine significantly reduced the frequency of all partial seizures and the frequency of secondarily generalized partial seizures in these treatment-resistant patients. The most commonly reported adverse events in the lamotrigine-treated patients were vomiting, somnolence, and infection; the frequency of these and other adverse events was similar to that in the placebo-treated group, with the exception of ataxia, dizziness, tremor, and nausea, which were more frequent in the lamotrigine-treated group. The frequency of withdrawals for adverse events was similar between groups. Two patients were hospitalized for skin rash, which resolved after discontinuation of lamotrigine therapy. Conclusions: Lamotrigine was effective for the adjunctive treatment of partial seizures in children and demonstrated an acceptable safety profile.

Carbamazepine toxicity resulting from generic substitution

Generic substitution is practiced widely in both hospital and community settings. There have been several reports of reduced serum concentrations and seizure exacerbation following generic substitution of Tegretol. We describe the first 2 cases of carbamazepine toxicity resulting from the substitution of Tegretol with Epitol. Two 6-year-old children experienced increases in the maximum serum carbamazepine concentration, one of 22% and one of 41%. Both became asymptomatic when their serum concentrations were lowered and had no residual effects.

Medical intractability in children evaluated for epilepsy surgery

We assessed the value of therapeutic reevaluation and additional pharmacotherapy in medically intractable children referred for epilepsy surgery. In 21 children with antiepileptic drug treatment omissions, correcting the omission was ineffective in 19 (90%). Two children (10%), both of whom had structural lesions, achieved significant seizure control with high-dose carbamazepine monotherapy. Therapeutic reevaluation is indicated in all medically intractable children prior to epilepsy surgery.

Lamotrigine: an Anhepileptic Agent for the Treatment of Partial Seizures

Objective: To review the current literature on lamotrigine and its use as an antiepileptic drug (AED). Data Sources: MEDLINE and bibliographic literature searches pertaining to lamotrigine were performed. Additionally, Burroughs Wellcome provided a comprehensive bibliography, data on file, and investigators brochure. Data Selection: The selection of reported data for this review includes both controlled and uncontrolled studies as well as case reports and unreported data from both European and US trials. Data Synthesis: Lamotrigine is effective as an adjunctive agent in the treatment of complex and simple partial seizures with or without secondary generalization. Anecdotal reports suggest that the spectrum of activity may include other seizure types, but controlled studies substantiating these reports are needed. Lamotrigine has a favorable pharmacokinetic profile, including a long half-life, low serum protein binding, and lack of mixed-function oxidase enzyme induction. It is likely that the drug induces metabolism through the glucuronidation pathway, although probably not to a clinically significant extent. Concurrent use of enzyme-inducing AEDs increase lamotrigines clearance, whereas valproic acid decreases it. Adverse effects are primarily central nervous system-related, with dizziness, diplopia, ataxia, and somnolence reported in at least 10% of the patients treated. The incidence of these effects is higher in patients treated concomitantly with carbamazepine and may represent a pharmacodynamic interaction. The occurrence of rash may limit lamotrigines use and was the most common cause for discontinuation in clinical trials (2.3%). The incidence of rash is higher in patients comedicated with valproic acid. Conclusions: Lamotrigine appears to be a safe and effective new AED for patients with refractory partial seizures when used as an adjunctive agent. It has a favorable pharmacokinetic profile allowing for once- or twice-daily dosing and adverse effects appear mild and transient. Additional studies are required to confirm efficacy in other seizure types.

Valproic acid efficacy, toxicity, and pharmacokinetics in neonates with intractable seizures

Six neonates with prolonged, intractable seizures were treated with valproic acid (VPA). Each patient had received maximum doses of phenobarbital (>40 μg/ml), and five patients received at least two additional anticonvulsants, without success. Seizure activity was controlled in five of six (83%) cases. In four cases, all other anticonvulsants could be withdrawn, and seizures were controlled on VPA monotherapy. VPA was discontinued in three patients because of VPA-induced hyperammonemia. VPA pharmacokinetic measurements were as follows: for total VPA, volume of distribution (V) = 0.40 l/kg (range, 0.36 to 0.47 l/kg), serum clearance (Cl) = 14.4 ml/h/kg (5.5 to 18.2 ml/h/kg), half-life (T½) = 26.4 hours (8.6 to 48.5); for unbound VPA, V = 2.02 l/kg (1.14 to 2.44 l/kg), Cl = 108.9 ml/h/kg (42.0 to 252.0 ml/h/kg). T½ = 17.6 hours (6.7 to 34.2). VPA free fraction ranged from 11.3 to 31.6% (mean, 19.2%).

Therapeutic drug monitoring in the neonate and paediatric age group. Problems and clinical pharmacokinetic implications.

Therapeutic drug monitoring should encompass not only serum concentration monitoring but also assessments of organ and clinical functions. This is especially important in children, in whom receptor drug concentration or sensitivity may be different from that seen in the adult population. Therapeutic end-points should be identified and serum drug concentrations adjusted to meet these goals. This is further complicated by the added impact of pharmacokinetic idiosyncrasies displayed by children, coupled with the routine pitfalls of therapeutic drug monitoring seen in any patient population. Neonates and infants present the additional challenge of having a set of mechanisms whose degree of maturation sometimes changes on a day-to-day basis with alarming rapidity. It is this phenomenon which makes the definition of pharmacokinetic parameters following a single dose so unreliable and potentially hazardous. Therapy should be based not only on the capacity of the infant to eliminate and respond to a particular agent, but also on the understanding of the dynamic changes that will occur on an ongoing maturational basis. A basic familiarity with the patient population under study is essential in obtaining relevant data for pharmacokinetic analysis. Special consideration in children should focus on potential problems with drug administration, drug absorption, metabolite patterns, changing drug disposition, idiosyncratic reactions, receptor sensitivity and chronopharmacokinetics. As with other patient populations, serum drug concentration monitoring is only a small part of the clinical scenario, the whole of which must be the basis for therapeutic decisions and pharmacodynamic titration.

Vigabatrin: A Novel Therapy for Seizure Disorders

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and adverse effects of vigabatrin and its role in the management of seizure disorders. METHODS: A MEDLINE search of English-language literature from January 1993 through January 1999 was conducted using vigabatrin as a search term to identify pertinent studies and review articles. Additional studies were identified from the bibliographies of reviewed literature. The manufacturer provided postmarketing surveillance data. Priority was given to randomized, double-blind, placebo-controlled studies. FINDINGS: Vigabatrin is a selective and irreversible inhibitor of γ-aminobutyric acid transaminase. In controlled clinical trials of vigabatrin add-on therapy in patients with uncontrolled partial seizures, 24–67% of patients achieved a ≤50% reduction in seizure frequency. Data from two comparative trials with carbamazepine monotherapy indicate that vigabatrin monotherapy reduces the frequency of partial seizures in patients with newly diagnosed epilepsy. Vigabatrin also controls infantile spasms, particularly those associated with tuberous sclerosis. Vigabatrin is more effective in patients with partial seizures than in those with generalized seizures. The drug is generally well tolerated. Headache and drowsiness were the most common adverse effects observed in controlled clinical trials; visual field defects, psychiatric reactions, and hyperactivity also have been reported. There are no known clinically significant drug interactions. CONCLUSIONS: Vigabatrin improves seizure control as add-on therapy for refractory partial seizures and may produce therapeutic benefits in the treatment of infantile spasms. Vigabatrin is generally well tolerated, with a convenient administration schedule, a lack of known significant drug interactions, and no need for routine monitoring of plasma concentrations.

Autism and Associated Behavioral Disorders: Pharmacotherapeutic Intervention

Objective: To review the literature on autism and pervasive developmental disorders (PDDs) as well as their respective pharmacotherapies. Data sources: An Index Medicus, MEDLINE, and bibliographic search of the literature pertaining to autism, PDDs, and respective treatments. Study selection: Because of the paucity of literature on the treatment of autism and PDDs, the selection of reported data for this review included both controlled and uncontrolled studies, as well as case reports and any other information reported in the literature on the treatment of these disorders. Data synthesis: Autism and PDDs are severe developmental disabilities defined by behavioral criteria. These disorders are lifelong in nature and present in varying severity of clinical manifestations. Behavioral manifestations of patients with autism include core deficits in social interaction, communication, and imaginative activities, with a restricted repertoire of activities and interests. The present understanding of the neurochemical basis of the disorder is limited. The role of pharmacotherapy in the management of autism and PDDs is to ameliorate behavioral symptoms that interfere with the patients ability to participate in educational, social, work, and family systems. Agents that have shown positive clinical effects in the treatment of children with autism and PDDs are reviewed in this article. Conclusions: Autism is a complex developmental disorder representing a heterogeneous group of individuals with similar symptomatologies and multiple biologic etiologies. Present pharmacotherapeutic intervention seeks to resolve behavioral symptoms. Treatment of autism and PDDs requires appropriate delineation of the behaviors and neurobiologic disorders associated with each patient. No single therapeutic agent, or combination thereof, is appropriate for the treatment of all children and adults with autism or PDDs.

Pharmacokinetics of Lamotrigine in Children in the Absence of other Antiepileptic Drugs

We evaluated the pharmacokinetics of lamotrigine in 12 children with epilepsy who were receiving no other antiepileptic drugs. Each patient received a single oral dose of lamotrigine 2 mg/kg. Plasma concentrations of the drug were measured up to 48 hours after dosing. Pharmacokinetic parameters were calculated using noncompartmental methods. After rapid absorption, the lamotrigine concentration declined monoexponentially. Oral clearance was 0.64 ± 0.26 ml/min/kg. The apparent volume of distribution was 1.50 ± 0.51 L/kg. Weight‐normalized clearance and volume were higher in children than in adults. The mean half‐life was 32 hours, similar to that in adults. Should similar plasma lamotrigine concentrations in adults and children be desirable, children will likely require higher weight‐normalized doses at the same dosing frequency.

Long-Term Tolerability and Efficacy of Lamotrigine in Pediatric Patients With Epilepsy:

Accumulating data suggest that the antiepilepsy drug lamotrigine, which has been available for adult use for more than a decade, also confers broad-spectrum, well-tolerated control of epilepsy in children. The current study—the open-label continuation phase of several short-term clinical trials—was conducted to assess the long-term tolerability and efficacy of lamotrigine as open-label adjunctive therapy or monotherapy in pediatric patients for a variety of seizure types and syndromes including partial seizures, absence seizures, and Lennox-Gastaut syndrome. Clinic visits occurred every 24 weeks throughout the treatment period. A total of 252 patients under 16 years of age were enrolled in the study. The numbers of patients exposed to at least 48 weeks, 96 weeks, and 144 weeks of treatment with lamotrigine were 185 (73.4%), 119 (47.2%), and 60 (23.8%), respectively, for an average duration of exposure of 96.7 weeks. The most common adverse events considered by the investigator to be drug related were dizziness (9.1%), somnolence (7.9%), nausea (6.3%), vomiting (5.2%), and headache (5.2%). The most common serious adverse events (regardless of suspected cause) included pneumonia (3.0%) and infection (1.9%). Investigators judged that the overall clinical status of three-fourths of the patients had improved at treatment weeks 48 and 96 relative to prelamotrigine clinical status. Lamotrigine administered as monotherapy or adjunctive therapy for an average of 2 years (96.7 weeks) was well tolerated and effective in pediatric patients with partial or generalized epilepsy. These results complement and extend the large body of data demonstrating the tolerability and efficacy of lamotrigine with short- and long-term use in adults. (J Child Neurol 2002;17:278-285).