title: Impact of impaired renal function on the pharmacokinetics of the antiepileptic drug lacosamide.
abstract: OBJECTIVE
  The antiepileptic drug lacosamide is eliminated predominantly via the kidneys. Therefore, an evaluation of the impact of renal impairment on its pharmacokinetic profile is an important component of its safety assessment. The objective of this study was to evaluate the pharmacokinetic profile of lacosamide among individuals with renal impairment (mild, moderate, or severe) and among patients with end-stage renal disease (ESRD), including those on hemodialysis.
  
  
  METHODS
  This was an open-label, Phase I trial. The pharmacokinetics of a single oral 100-mg lacosamide dose were evaluated in five groups of participants: healthy controls, patients with mild, moderate, or severe renal impairment, and patients with ESRD (with and without hemodialysis).
  
  
  RESULTS
  Forty participants completed the trial, eight in each group. In healthy volunteers, renal clearance accounted for approximately 30 % of total body clearance [geometric mean 0.5897 l/h (coefficient of variation 37.9 %) vs 2.13 l/h (20.8 %)]. With severe renal impairment, renal clearance was approximately 11 % of total body clearance [0.1428 l/h (31.8 %) vs 1.34 l/h (26.9 %)]. Terminal half-life and systemic exposure were increased with renal impairment, while total body clearance, renal clearance, and urinary excretion were decreased. Strong positive correlations between creatinine clearance, renal clearance, and urinary excretion were observed. Among patients with ESRD, approximately 50 % of lacosamide was cleared from systemic circulation by 4-h hemodialysis. In patients with essentially no renal clearance, nonrenal clearance was still present (1.1 l/h). Lacosamide was well tolerated by healthy volunteers and patients.
  
  
  CONCLUSIONS
  In patients with mild-to-moderate renal impairment, lacosamide dose adjustment is not necessary, because total body clearance decreased by only approximately 20 %. Dose adjustment, however, is required for patients with severe renal impairment. Hemodialysis removes approximately 50 % of lacosamide from plasma; therefore, dose supplementation following hemodialysis should be considered.
authors.affiliation: UCB Pharma, Global Biostatistics, Alfred-Nobel-Strasse 10, 40789, Monheim am Rhein, Germany, Willi.Cawello@ucb.com.
authors.forename: Willi
authors.initials: W
authors.lastname: Cawello
authors.forename: Uwe
authors.initials: U
authors.lastname: Fuhr
authors.forename: Ursula
authors.initials: U
authors.lastname: Hering
authors.forename: Haidar
authors.initials: H
authors.lastname: Maatouk
authors.forename: Atef
authors.initials: A
authors.lastname: Halabi
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000378:metabolism*
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D000078334:Lacosamide