Dose Adjustments of Lacosamide Not Needed in Patients With Partial-Onset Seizures on Antiepileptic Therapy: Presented at ACCP

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Title: Dose Adjustments of Lacosamide Not Needed in Patients With Partial-Onset Seizures on Antiepileptic Therapy: Presented at ACCP
URL: http://www.pslgroup.com/dg/22C9F2.htm
Doctor's Guide
September 17, 2008

By Crina Frincu-Mallos, PhD

PHILADELPHIA -- September 17, 2008 -- Due to the modest effect of cytochrome P450 (CYP450)-inducer antiepileptic drugs on lacosamide exposure, coadministration of these agents is not expected to impact the efficacy of lacosamide, researchers reported here at the American College of Clinical Pharmacology (ACCP) 37th Annual Meeting.

In addition, the patient's body weight and gender do not appear to have a significant impact on exposure to lacosamide, which is currently being tested as adjunctive therapy for patients with partial-onset seizures. Therefore, dose adjustments based on these parameters are not necessary, according to Bernd Nickel, PhD, UCB Pharma, Monheim am Rhein, Germany, and colleagues.

Dr. Nickel presented the data from 2 phase 3, double-blind, multicentre, randomised, parallel group, placebo-controlled trials in a poster session on September 14.

Dr. Nickel and colleagues sought to identify covariates with potential to influence the pharmacokinetics of lacosamide, possibly resulting in dosing recommendations, in a cohort of 287 men and 278 women.

At baseline, patients' were a mean of 38 years old (range, 16-71 years), mean weight was 79 kg (range, 39-188 kg), body mass index (BMI) was 27 kg/m² (range, 14-67 kg/m²), and mean creatinine clearance was 120 mL/min (range, 56-150 mL/min).

They were randomised to oral lacosamide doses of 200, 400, or 600 mg/day, all given twice daily.

The researchers analysed a total of 2,370 lacosamide plasma concentrations, using a nonlinear mixed-effect modelling, explained Dr. Nickel.

Possible covariates examined were age, gender, body weight, BMI, ethnicity, and concomitant antiepileptic drug (AED) category with regard to CYP450 (ie, neutral, inducer, or inhibitor of CYP450), as well as creatinine clearance.

From the overall cohort, 34.2% of patients received CYP450-inhibitor AEDs concomitantly with lacosamide, 30.4% received CYP450-inducer AEDs, 14.7% received CYP450-neutral AEDs, and 20.7% received CYP450-inhibitor plus inducer AEDs.

Lacosamide plasma concentrations were effectively described by a one-compartment model with low residual variability, said Dr. Nickel.

Gender was identified as a covariate on the apparent volume of distribution (V/f). Gender, weight, and CYP450-inducer AEDs were identified as covariates of the apparent total body clearance (CL/f). The effects of gender and weight amounted to <15% in lacosamide exposure. Therefore, the researchers dropped these covariates from the final model.

In the absence of AED inducers, the typical population values were estimated to be 64.8 L for V/f and 1.97 L/hour for CL/f.

When assessed as a class, AED inducers increased the CL/f by approximately 36%, explained Dr. Nickel. When looking at individual CYP-inducers, the investigators observed that coadministration of carbamazepine or phenytoin (both CYP450-inducers) resulted in an approximate decrease of 20% in the area under the curve at steady state, whereas coadministration of phenobarbital yielded an approximate 30% decrease.

Based on these data, the investigators concluded that since body weight and gender had limited influence of lacosamide exposure, dose adjustments based on these parameters are not necessary.

Funding was provided by UCB Pharma, Monheim am Rhein, Germany.

[Presentation title: Population Pharmacokinetics of Lacosamide in Subjects With Partial-Onset Seizures: Results From Two Phase III Trials. Abstract #131]

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