Pharmacokinetics and Drug Disposition
Clinical Pharmacology & Therapeutics (2005) 77, 529–541; doi: 10.1016/j.clpt.2005.02.003
Pharmacokinetics of Levetiracetam in Patients with Moderate to Severe Liver Cirrhosis (Child-Pugh Classes A, B, and C): Characterization by Dynamic Liver Function Tests*
Jürgen Brockmöller MD1, Torben Thomsen MD1, Marcus Wittstock PhD1, René Coupez1, Herbert Lochs MD1 and Ivar Roots MD1
1Abteilung für Klinische Pharmakologie, Universität Göttingen, Göttingen; Pharm PlanNet Contract Research GmbH, Mönchengladbach; UCB SA, Brussels; Klinik für Gastroenterologie and Institut für Klinische Pharmakologie, Universitätsklinikum Charité, Campus Berlin Mitte, Berlin.
Correspondence: Ivar Roots, MD, Institut für Klinische Pharmakologie, Universitätsklinikum Charité, D-10098 Berlin, Germany. E-mail: ivar.roots@charite.de
*The study was supported by UCB SA, which manufactures levetiracetam.
Received 7 September 2004; Accepted 11 February 2005.
Abstract
Background: Levetiracetam is an antiepileptic drug approved for use as adjunctive therapy in adults with partial-onset seizures. We sought to investigate possible changes in the pharmacokinetics of levetiracetam and its metabolite ucb L057 in patients with liver cirrhosis, who may require dose adjustments.
Methods: A single dose of levetiracetam was administered to 5 healthy subjects and to patients with Child-Pugh class A (n = 5), B (n = 6), or C (n = 5) alcohol-induced cirrhosis. The pharmacokinetics of levetiracetam and ucb L057 was measured and correlated with biochemical liver function parameters, with creatinine clearance, and with kinetics of caffeine, lidocaine, and D-sorbitol as probes for specific liver functions.
Results: Dynamic liver function tests revealed a deterioration of liver function. The pharmacokinetics of levetiracetam and its metabolite did not differ between healthy subjects and those with class A or B cirrhosis. However, in patients with class C cirrhosis, levetiracetam total clearance was reduced by 57% (90% confidence interval [CI], 43%-67%; P < .001). The geometric mean ratio of the area under the plasma concentration-time curve for levetiracetam, Child-Pugh class C versus control, was 2.41 (90% CI, 1.80–3.23), and the geometric mean of the half-life ratio was 2.27 (90% CI, 1.74–2.97). This was explained by the deterioration of renal function in patients with severe hepatic disease.
Conclusions: In pharmacokinetic studies of hepatic impairment, including all classes of cirrhosis may be more revealing than including only selected classes of liver failure. No dose adjustment of levetiracetam is necessary in patients with mild to moderate liver impairment; however, patients with severe cirrhosis should initially receive only half of the commonly recommended dose.
