Valproic Acid‐Ethosuximide Interaction: A Pharmacokinetic Study

Pisani, Francesco; Narbone, M. C.; Trunfio, C.; Fazio, A.; Rosa, G. La; Oteri, G.; Perri, R. Di

doi:10.1111/j.1528-1157.1984.tb04180.x

Cited by 35 publications

(11 citation statements)

References 12 publications

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“…Different investigators have examined the effect of valproic acid on the pharmacokinetics of ethosuximide with equivocal results: an increase, [172] a decrease [ 174,175] or no modification [ 176.177] of ethosuximide clearance have been all reported. The magnitude of the effect, if any, appears to be clinically negligible, since the ethosuximide dosage does not need to be adjusted.…”

Section: Ethosuximide Interactionsmentioning

confidence: 98%

Pharmacokinetic Interactions Between Antiepileptic Drugs

Riva¹,

Albani²,

Contin³

et al. 1996

Clinical Pharmacokinetics

150

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Antiepileptic drug interactions represent a common clinical problem which has been compounded by the introduction of many new compounds in recent years. Most pharmacokinetic interactions involve the modification of drug metabolism; the propensity of antiepileptic drugs to interact depends on their metabolic characteristics and action on drug metabolic enzymes. Phenobarbital, phenytoin, primidone and carbamazepine are potent inducers of cytochrome P450 (CYP), epoxide hydrolase and uridine diphosphate glucuronosyltransferase (UDPGT) enzyme systems; oxcarbazepine is a weak inducer of CYP enzymes, probably acting on a few specific isoforms only. All stimulate the rate of metabolism and the clearance of the drugs which are catabolised by the induced enzymes. Valproic acid (valproate sodium) inhibits to different extents many hepatic enzyme system activities involved in drug metabolism and is able to significantly displace drugs from plasma albumin. Felbamate is an inhibitor of some specific CYP isoforms and mitochondrial beta-oxidation, whereas it is a weak inducer of other enzyme systems. Topiramate is an inducer of specific CYP isoforms and an inhibitor of other isoforms. Ethosuximide, vigabatrin, lamotrigine, gabapentin and possibly zonisamide and tiagabine have no significant effect on hepatic drug metabolism. Apart from vigabatrin and gabapentin, which are mainly eliminated unchanged by the renal route, all other antiepileptic drugs are metabolised wholly or in part by hepatic enzymes and their disposition may be altered by metabolic changes. Some interactions are clinically unremarkable and some need only careful clinical monitoring, but others require prompt dosage adjustment. From a practical point of view, if valproic acid is added to lamotrigine or phenobarbital therapy, or if felbamate is added to phenobarbital, phenytoin or valproic acid therapy, a significant rise in plasma concentrations of the first drug is expected with a corresponding increase in clinical effects. In these cases a concomitant reduction of the dosage of the first drug is recommended to avoid toxicity. Conversely, if a strong inducer is added to carbamazepine, lamotrigine, valproic acid or ethosuximide monotherapy, a significant decrease in their plasma concentrations is expected within days or weeks, with a possible reduction in efficacy. In these cases a dosage increase of the first drug may be required.

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Section: Ethosuximide Interactionsmentioning

confidence: 98%

Pharmacokinetic Interactions Between Antiepileptic Drugs

Riva¹,

Albani²,

Contin³

et al. 1996

Clinical Pharmacokinetics

150

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“…In contrast, serum ethosuximide concentrations are increased by isoniazid (van Wieringen & Vrijlandt, 1983). Valproic acid exerts a variable effect, with ethosuximide clearance being reported to be increased, decreased, or unchanged following addition of valproic acid (Mattson & Cramer, 1980; Bauer et al, 1982; Pisani et al, 1984; Bourgeois, 1988; Tanaka, 1999).…”

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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“…Because ethosuximide is frequently combined with valproic acid, the possibility of a pharmacokinetic interaction between the two AEDs has been extensively investigated. The interaction is bidirectional, in that plasma valproic acid concentrations are reduced by ethosuximide, while valproic acid has been reported to both increase and decrease plasma ethosuximide concentrations (14). Perhaps the most clinically significant interaction with ethosuximide relates to the enhancement of ethosuximide metabolism by enzyme‐inducing AEDs, resulting in lower plasma ethosuximide concentrations (15).…”

Section: Ethosuximidementioning

confidence: 99%

Properties of Antiepileptic Drugs in the Treatment of Idiopathic Generalized Epilepsies

Patsalos¹

2005

Epilepsia

109

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Although valproate is considered to be the drug of first choice for the treatment of idiopathic generalized epilepsies (IGEs), other antiepileptic drugs (AEDs), both old (etho-suximide, clobazam, and clonazepam) and new (lamotrigine, levetiracetam, topiramate, and zonisamide) are also available. These AEDs do not appear to have a common mechanism of action in that both inhibitory gamma-aminobutyric acid (GABA; e.g., clobazam, clonazepam, and valproate) and excitatory glu-tamate (e.g., lamotrigine and topiramate) mechanisms are involved. Ethosuximide primarily acts by blocking T-type voltage-gated calcium channels in thalamic neurones while topiramate and zonisamide have multiple mechanisms of action. In contrast, levetiracetam is unique in that it may act via a specific binding site in the brain. In terms of their pharmacokinetic characteristics, all eight AEDs are rapidly absorbed after oral ingestion with peak blood concentration being achieved within 1-4 hours. Bioavailability is 100% with the exception clonazepam (90%) and topiramate (81-95%). Plasma protein binding is variable with valproate (90%), clobazam (85%) and clonazepam (86%) showing substantial binding, lamotrigine (55%) and zonisamide (50%) intermediate binding, and levetiracetam (0%), ethosuximide (0%) and topiramate (10%) being minimally bound. However, the binding by zonisamide is complicated by its binding to erythrocytes as well as albumin. All AEDs, with the exception of lamotrigine and levetiracetam, undergo elimination as a result of extensive metabolism by hepatic cytochrome P450 enzymes, which are highly amenable to induction and inhibition by other drugs and therefore susceptible to pharmacokinetic interactions. Lamotrigine metabolism is via hepatic glu-curonidation, a process that is also susceptible to induction and inhibition by concurrent drugs. Levetiracetam is minimally metabolized (by hydrolysis in blood), is excreted predominantly unchanged in urine, and to date has not been associated with any clinically significant pharmacokinetic interactions. Using a semiquantitative pharmacokinetic rating system, based on 16 pharmacokinetic characteristics, a direct comparison between AEDs is possible. Thus valproic acid, regarded as the drug of first choice in the treatment of IGEs, rates lowest with respect to favorable pharmacokinetic characteristics, mostly because of its nonlinear pharmacokinetics, extensive hepatic metabolism, and its high propensity to interact both with other AEDs and non-AEDs. Levetiracetam rates highest with topiramate in second place.

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Valproic Acid‐Ethosuximide Interaction: A Pharmacokinetic Study

Cited by 35 publications

References 12 publications

Pharmacokinetic Interactions Between Antiepileptic Drugs

Pharmacokinetic Interactions Between Antiepileptic Drugs

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

Properties of Antiepileptic Drugs in the Treatment of Idiopathic Generalized Epilepsies

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