Levetiracetam

Levetiracetam in Hepatic Dysfunction

Levetiracetam

Is the S-enantiomer of etiracetam, Approved for use as adjunctive

therapy in adults with partial-onset seizures

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Epilepsy co-morbid with Hepatic Dysfunction and role of AEDs

Patients with epilepsy may suffer from hepatic diseases that modify the metabolism of antiepileptic drugs

Seizures may occur in renal and hepatic disease, caused by the dysfunction itself, by its treatment, or by treatment of comorbidities

Loss of hepatocytes and disruption of liver blood flow alter the metabolism of AEDs

Some factors increases free AED levels:- Hypoalbuminemia, Lower albumin binding affinity, and impaired metabolism by cytochrome P450 (CYP450) and

glucosyltranferase enzymes Low protein-bound AEDs with little liver metabolism, i.e.,

gabapentin, topiramate, vigabatrin, and Levetiracetam, are most suitable for treatment

Reference: Glenda Lacerda et.al;Optimizing therapy of seizures in patients with renal or hepatic dysfunction; NEUROLOGY 2006;67(Suppl 4):S28–S33

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Pharmacokinetics of Levetiracetam

Major Route of excretion is urine (almost 95%) Protein Binding: <10% (Not significant) Less than 2% metabolism is by liver, so no dose adjustment

required In a study, it was found:

Pharmacokinetics of Levetiracetam was not significantly different between healthy subjects and subjects in Child-Pugh classes A and B

In group with severe (class C) cirrhosis, the total clearance was reduced to 43% of that observed in healthy subject groups

Renal clearance was reduced in the Child-Pugh class C group to 34% of that in healthy group

No dose adjustment is necessary in patients with mild to moderate liver impairment. However, in those classified as Child-Pugh class C, careful monitoring and a dosage reduction of about 50% would be advisable

Reference: Brockmöller J; PK of levetiracetam in hepatically impaired subjects; Clin Pharmacol Ther. 2005 Jun; 77(6):529-41

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Comparative study of pharmacokinetic parameters of Levetiracetam

Reference: Brockmöller J; PK of levetiracetam in hepatically impaired subjects; Clin Pharmacol Ther. 2005 Jun; 77(6):529-41

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Benefits of Using Levetiracetam

Levetiracetam has no identified effect on CYP450 NO DRUG – DRUG INTERACTION Exhibits linear pharmacokinetics and steady-state is

reached after 2 days of a twice-a-day administration One report describes successful use of

Levetiracetam as monotherapy after failure of Phenytoin in liver graft recipients

Levetiracetam does not induce hepatic metabolism

Reference: Glenda Lacerda et.al;Optimizing therapy of seizures in patients with renal or hepatic dysfunction; NEUROLOGY 2006;67(Suppl 4):S28–S33

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To sum up….. Levetiracetam is a preferred AED in cases

of epilepsy co-morbid with liver dysfunction

No dose adjustment is necessary in patients with mild to moderate liver impairment

In those classified as Child-Pugh class C, careful monitoring and a dosage reduction of about 50% would be advisable

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Levetiracetam

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