Influence of cirrhosis on lamotrigine pharmacokinetics

Abstract

Aims Lamotrigine, an antiepileptic drug, is cleared from the systemic circulation mainly by glucuronidation. The possibility of changes in the pharmacokinetics of lamotrigine in plasma owing to hepatic dysfunction has been evaluated. Methods Thirty‐six subjects, including 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers received a single 100 mg dose of lamotrgine. Blood samples were taken for 7 days in all subjects, except nine with severe cirrhosis, who had a 29 day blood sampling period. Results The pharmacokinetics of lamotrigine were comparable between the patients with moderate cirrhosis (corresponding to Child‐Pugh grade A) and the healthy subjects. Plasma oral clearance mean ratios (90% confidence interval) in patients with severe cirrhosis without or with ascites (corresponding, respectively, to Child‐Pugh grade B and C) to healthy subjects were, respectively, 60% (44%, 83%) and 36% (25%, 52%). Plasma half‐life mean ratios (90% confidence interval) in these two patient groups to healthy subjects were, respectively, 204% (149%, 278%) and 287% (202%, 408%). Conclusions Lamotrigine administered as a single oral dose of 100 mg was well tolerated in all groups. Initial, escalation and maintenance doses should generally be reduced by approximately 50 or 75% in patients with Child‐Pugh Grade B or C cirrhosis. Escalation and maintenance doses should be adjusted according to clinical response.

Effect of Mild and Moderate Hepatic Impairment on the Pharmacokinetics and Safety of Carisbamate

“…These results were consistent with those reported for other drugs that are metabolized by direct glucuronidation, such as morphine, zidovudine, lamotrigine, oxazepam, diflunisal, and mycophenolate mofetil. [11][12][13][14][15][16] Carisbamate displayed a greater binding affinity for albumin in comparison with α1-AGP, a finding that is consistent with observations in previous in vitro studies (data on file). The unbound plasma carisbamate fractions in this study were similar across the 3 hepatic function groups (ranging from 60.9%-61.7%), indicating that hepatic impairment did not alter the percentage of carisbamate binding to the plasma proteins.…”

Lamotrigine in the treatment of bipolar disorder

“…Pharmacokinetic studies using single doses in subjects with renal failure indicate that lamotrigine pharmacokinetics are minimally affected, but plasma concentrations of the major glucuronide metabolite increase almost eight-fold due to reduced renal clearance [26,27]. A single-dose pharmacokinetic study of 24 patients with various degrees of liver cirrhosis and 12 healthy volunteers, showed a reduction in lamotrigine clearance in proportion to the severity of illness in patients with cirrhosis [28]. Lamotrigine clearance increases during pregnancy, peaking at 32 weeks.…”

Solubility of Lamotrigine, Diazepam, Clonazepam, and Phenobarbital in Propylene Glycol + Water Mixtures at 298.15 K

“…6 The experimentally obtained values of log P for lamotrigine (LTG), diazepam (DZP), clonazepam (CZP), and phenobarbital (PB) employed in this work were 1.19, 7 2.99, 8 2.41, 9 and 1.47, 8 respectively. …”