Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients

Giaccone, M.; Bartoli, A.; Gatti, G.; Marchiselli, Roberto; Pisani, Francesco; Latella, M.A.; Perucca, Emilio

doi:10.1046/j.1365-2125.1996.03601.x

Cited by 32 publications

(13 citation statements)

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“…According to the study protocol, 12 subjects had to complete both treatments, a sample size that in previous studies with similar design was adequate in demonstrating induction of metabolism of low‐clearance substrates (14–18). The study was approved by the Ethics Committee of the University of Pavia.…”

Section: Methodsmentioning

confidence: 99%

Pharmacokinetic and Metabolic Investigation of Topiramate Disposition in Healthy Subjects in the Absence and in the Presence of Enzyme Induction by Carbamazepine

Britzi

Perucca

Soback³

et al. 2005

Epilepsia

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Summary:Purpose: To characterize the metabolic profile of topiramate (TPM) in humans and to assess the influence of enzyme induction by carbamazepine (CBZ) on the pharmacokinetics and metabolic profile of TPM.Methods: Twelve healthy subjects received a single oral dose of TPM (200 mg) on two randomized occasions. On one occasion, TPM was administered alone, and on the other, it was given on day 18 of a 24-day treatment with CBZ (maintenance dosage, 600 mg/day). Blood and urine samples were collected for ≥72 h after dosing. TPM and its metabolites were assayed in plasma and urine by a specific liquid chromatography-mass spectroscopy (LC-MS) method.Results: Mean TPM oral clearance (CL/F) increased from 1.2 L/h (control) to 2.2 L/h after CBZ treatment. Mean TPM halflife decreased from 29 h to 19 h. TPM was excreted extensively in urine both under noninduced (56%) and CBZ-induced conditions (40%). 2,3-O-Des-isopropylidene-TPM (2,3-diol-TPM) was identified as the most prominent urinary metabolite, with a recovery accounting for 3.2% and 7.9% of the TPM dose under noninduced and induced conditions, respectively. Corresponding recovery values for 10-hydroxy-TPM (10-OH-TPM) were 1.2% and 1.8%, respectively. The control AUC metabolite /AUC drug ratio for 2,3-diol-TPM and 10-OH-TPM were 1.5% and 0.6%, and they increased by threefold and twofold, respectively, after CBZ treatment.Conclusions: TPM remains appreciably excreted unchanged in urine (41%) under CBZ-induced conditions, even though TPM CL/F increased by twofold. Although 2,3-diol-TPM and 10-OH-TPM were measured in unconjugated form, the significant increases in their AUC and urinary excretion are consistent with the twofold increase in TPM clearance. Key Words: Topiramate-CarbamazepinePharmacokinetics-Metabolism-Drug interaction-Enzyme induction-Healthy subjects.Topiramate (TPM) is a broad-spectrum secondgeneration antiepileptic drug (AED), which is approved for adjunctive therapy or monotherapy or both in >95 countries worldwide (1-4). It also is approved for use as migraine prophylaxis and is under evaluation as a potential treatment in a variety of other neurologic and psychiatric disorders (3).The pharmacokinetics of TPM has been investigated mostly under noninduced conditions and is characterized by linearity over the 100-to 800-mg/day dose range, a low oral clearance (22-36 ml/min), largely accounted for by renal clearance of unchanged drug (10-20 ml/min), and a relatively long half-life (19-25 h) (5-7). The absolute bioavailability of TPM is 81-95%, and it is not affected by food (8). Although TPM is not extensively metabolized when administered in monotherapy (fraction metabolized, <30%) (5,9), when TPM is administered with enzyme-inducing AEDs such as phenytoin and carbamazepine (CBZ), its oral clearance increases up to twofold, and its half-life is reduced by ∼50% (10-12). The magnitude of increase in total clearance implies that the formation clearance of metabolites produced via inducible pathways (P-450 oxidation or glucuronide conjugation or both) ca...

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Section: Methodsmentioning

confidence: 99%

Pharmacokinetic and Metabolic Investigation of Topiramate Disposition in Healthy Subjects in the Absence and in the Presence of Enzyme Induction by Carbamazepine

Britzi

Perucca

Soback³

et al. 2005

Epilepsia

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“…The clearance of ethosuximide is increased in epileptic patients who are co-medicated with enzyme-inducing anticonvulsant drugs, resulting in lower plasma levels of ethosuximide. Giaccone et al (1996) have shown that the rate of ethosuximide metabolism in patients receiving phenobarbital, phenytoin, or carbamazepine is higher than that in control subjects. In order to evaluate the combination of ethosuximide and valproate experimentally, this combination has been studied in mice to define their pharmacodynamic interactions and the efficacy-toxicity ratio.…”

Section: Pharmacokineticsmentioning

confidence: 97%

Ethosuximide: From Bench to Bedside

2007

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Ethosuximide, 2-ethyl-2-methylsuccinimide, has been used extensively for "petit mal" seizures and it is a valuable agent in studies of absence epilepsy. In the treatment of epilepsy, ethosuximide has a narrow therapeutic profile. It is the drug of choice in the monotherapy or combination therapy of children with generalized absence (petit mal) epilepsy. Commonly observed side effects of ethosuximide are dose dependent and involve the gastrointestinal tract and central nervous system. Ethosuximide has been associated with a wide variety of idiosyncratic reactions and with hematopoietic adverse effects. Typical absence seizures are generated as a result of complex interactions between the thalamus and the cerebral cortex. This thalamocortical circuitry is under the control of several specific inhibitory and excitatory systems arising from the forebrain and brainstem. Corticothalamic rhythms are believed to be involved in the generation of spike-and-wave discharges that are the characteristic electroencephalographic signs of absence seizures. The spontaneous pacemaker oscillatory activity of thalamocortical circuitry involves low threshold T-type Ca2+ currents in the thalamus, and ethosuximide is presumed to reduce these low threshold T-type Ca2+ currents in thalamic neurons. Ethosuximide also decreases the persistent Na+ and Ca2+ -activated K+ currents in thalamic and layer V cortical pyramidal neurons. In addition, there is evidence that in a genetic absence epilepsy rat model ethosuximide reduces cortical gamma-aminobutyric acid (GABA) levels. Also, elevated glutamate levels in the primary motor cortex of rats with absence epilepsy (but not in normal animals) are reduced by ethosuximide.

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“…Enzyme‐inducing AEDs and rifampicin enhance the metabolism of ethosuximide, resulting in lower serum concentrations (Giaccone et al, 1996; Riva et al, 1996; Tanaka, 1999). In contrast, serum ethosuximide concentrations are increased by isoniazid (van Wieringen & Vrijlandt, 1983).…”

Section: Relevance Of Tdm For Individual Aedsmentioning

confidence: 99%

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies

et al. 2008

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SUMMARYAlthough no randomized studies have demonstrated a positive impact of therapeutic drug monitoring (TDM) on clinical outcome in epilepsy, evidence from nonrandomized studies and everyday clinical experience does indicate that measuring serum concentrations of old and new generation antiepileptic drugs (AEDs) can have a valuable role in guiding patient management provided that concentrations are measured with a clear indication and are interpreted critically, taking into account the whole clinical context. Situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential causes for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (e.g., children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (e.g., in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.

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Effect of enzyme inducing anticonvulsants on ethosuximide pharmacokinetics in epileptic patients

Cited by 32 publications

References 10 publications

Pharmacokinetic and Metabolic Investigation of Topiramate Disposition in Healthy Subjects in the Absence and in the Presence of Enzyme Induction by Carbamazepine

Pharmacokinetic and Metabolic Investigation of Topiramate Disposition in Healthy Subjects in the Absence and in the Presence of Enzyme Induction by Carbamazepine

Ethosuximide: From Bench to Bedside

Antiepileptic drugs—best practice guidelines for therapeutic drug monitoring: A position paper by the subcommission on therapeutic drug monitoring, ILAE Commission on Therapeutic Strategies

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