Pharmacokinetic evaluation of novel sustained‐release dosage forms of valproic acid in humans

Bialer, Meir; Friedman, Michael; Dubrovsky, Joseph; Abramsky, Oded

doi:10.1002/bdd.2510060406

Cited by 23 publications

(4 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…12 After oral administration of 900 mg valpromide (tablet or solution), no or very low plasma valpromide concentrations could be detected in humans, but valproate was consistently detected in plasma. 13 The absorption rate of valproate after oral administration of valpromide enteric-coated tablet is slower than after oral administration of valproate sodium enteric-coated tablets, but similar after oral administration of sustained release forms of valproate sodium 14 After a therapeutic dose, serum valproate levels peak at 6 ]/10 hours following valpromide ingestion, whereas serum valproate levels peak at 2 ]/ 4 hours following ingestion of valproate sodium regular-release forms. 15 The delayed increase of serum valproate levels in our three cases is consistent with the pharmacokinetic profile of valpromide.…”

Section: Discussionmentioning

confidence: 99%

Delayed toxicity following acute ingestion of valpromide

Payen¹,

Frantz²,

Martin

et al. 2004

Hum Exp Toxicol

View full text Add to dashboard Cite

As valpromide is a prodrug of valproic acid (valproate), the clinical presentation of overdoses with either valpromide or valproate sodium is generally considered similar. Whereas plasma peak levels and signs of central nervous system depression occur within a few hours after the acute ingestion of regular-release forms of valproate sodium, delayed toxicity and time to peak levels following valpromide ingestion can be seen as shown by the three reported cases. They were initially considered as mild because patients presented with no or only moderate symptoms and serum valproate levels were below or at therapeutic levels on admission more than 3 hours post-ingestion in two of the three patients. Serum valproate levels were not monitored until marked deterioration more than 10 hours after ingestion. At the time of deterioration, serum valproate was at toxic level in the three reported cases. Therefore, large intake of valpromide should be closely monitored because no or moderate symptoms together with low plasma levels in the first few hours after ingestion do not exclude a subsequent severe intoxication. Despite the usual favourable outcome and the poor correlation between plasma levels and toxic symptoms, patients should not be discharged until plasma levels are documented to remain at low levels for at least 10 hours after the ingestion of valpromide and the patient asymptomatic.

show abstract

Section: Discussionmentioning

confidence: 99%

Delayed toxicity following acute ingestion of valpromide

Payen¹,

Frantz²,

Martin

et al. 2004

Hum Exp Toxicol

View full text Add to dashboard Cite

show abstract

“…The first published report concerned 5 new sustained release valproic acid formulations, administered to 6 healthy volunteers in comparison with a standard tablet and an intravenous preparation (Bialer et al 1985). Three of the formulations exhibited prolonged and uniform absorption rates and yielded serum concentrations which were sustained within the therapeutic range (50 to 100 mg!…”

Section: Valproic Acidmentioning

confidence: 98%

Pharmacokinetic Evaluation of Sustained Release Formulations of Antiepileptic Drugs

Bialer

1992

Clinical Pharmacokinetics

Self Cite

View full text Add to dashboard Cite

Epilepsy is a chronic disease that requires long term therapy, and most of the established antiepileptic drugs (the exception is phenobarbital) must be administered several times daily. This results in compliance problems and fluctuations in plasma concentrations which may lead to subtherapeutic and potentially toxic levels. Development of sustained release formulations of the existing antiepileptic agents may improve antiepileptic therapy. At present, only the following 4 major drugs are used for the treatment of epilepsy: phenobarbital, phenytoin, carbamazepine and valproic acid. Of these, only the latter 2 are suitable candidates for sustained release formulations. This review, therefore, focuses on the evaluation and clinical implications of sustained release formulations of valproic acid and carbamazepine.

show abstract

“…The biotransformation was complete in the case of the ethyl, trichloroethyl, propyl, butyl and hexyl derivatives of valproate, but was only partial in the case of the isobutyl, isoamyl and valproyl derivatives. Due to the rapid conversion of the prodrugs to the parent drug, the valproate plasma levels obtained after administration of the prodrugs peaked 6-26 rain after dosing, and did not yield a sustained release profile in vivo [28]. Of the eight monoesters of valproate only propylvalproate demonstrated anticonvulsant activity.…”

Section: Monoester Prodrugs Of Valproic Acidmentioning

confidence: 99%

Can we develop improved derivatives of valproic acid?

et al. 1994

Self Cite

View full text Add to dashboard Cite

Valproic acid is one of the major antiepileptic drugs. In animal models, valproate showed less anticonvulsant potency than the other three established antiepileptic drugs: phenobarbital, phenytoin and carbamazepine. In addition, two major side-effects, teratogenicity and hepatotoxicity, have been associated with valproate therapy. Due to the above and the shortage of new antiepileptic drugs there is a substantial need to develop improved derivatives of valproate. This paper analyses three kinds of valproate derivatives: valpromide, the primary amide of valproate, and its analogues; monoester prodrugs of valproate and an active metabolite of valproate, 2-n-propyl-2-pentenoate. The comparative evaluation was carried out by pharmacokinetic and pharmacodynamic analyses in animals. From the data accumulated so far, we can conclude that 2-n-propyl-2-pentenoate and/or a valpromide isomer, which does not undergo amide-acid biotransformation and preferably is not an epoxide hydrolase inhibitor, may prove to be improved derivatives of the parent compound valproic acid.

show abstract

Pharmacokinetic evaluation of novel sustained‐release dosage forms of valproic acid in humans

Cited by 23 publications

References 12 publications

Delayed toxicity following acute ingestion of valpromide

Delayed toxicity following acute ingestion of valpromide

Pharmacokinetic Evaluation of Sustained Release Formulations of Antiepileptic Drugs

Can we develop improved derivatives of valproic acid?

Contact Info

Product

Resources

About