Effects of age and sex on the disposition of retigabine.
BACKGROUND
The novel antiepileptic drug retigabine is the first selective M-current potassium channel opener for KCNQ2/3 and KCNQ3/5 channels. Retigabine undergoes phase II metabolism (N-glucuronidation, acetylation) exclusively and renal excretion.


OBJECTIVE
Our objective was to evaluate the effects of age and sex on the pharmacokinetics of retigabine.


METHODS
Healthy young (age range, 18-40 years) and elderly (age range, 66-81 years) white subjects (12 men and 12 women in each group) received a single 200-mg oral dose of retigabine. After dosing, blood was collected over a 72-hour period to determine plasma concentrations of retigabine and its acetylated metabolite, AWD21-360. Pharmacokinetics was compared for age group and sex by ANOVA.


RESULTS
In young men, retigabine was rapidly absorbed, with the maximum concentration occurring within 2 hours, and was eliminated with an apparent clearance of 0.67 L x h(-1) x kg(-1) and a mean terminal half-life of 8.5 hours. Subjects were similarly exposed to AWD21-360. Compared with young men, young women had higher retigabine maximum concentration (56%) and exposure (20%) but similar clearance (0.68 L x h(-1) x kg(-1)); these differences were related to differences in body weight. Although maximum concentration was similar in elderly subjects, retigabine elimination was slower (30% lower apparent clearance normalized for weight), resulting in higher exposure (42%) and a longer half-life (30%). Because phase II metabolism is scarcely affected by age, these differences may be related to the known decline of renal function with age.


CONCLUSIONS
Although there are no substantial sex-related differences in the disposition of retigabine, a relevant decrease in clearance resulting in higher exposure occurs in elderly patients. The results suggest that decline of renal function with age may account for some of the observed changes.
Hermann
Robert
R
Clinical Research and Development, VIATRIS GmbH & Co KG, and Clinphase, Frankfurt/Main, Germany. robert.hermann@viatris.de
Ferron
Geraldine M
GM
Erb
Katharina
K
Knebel
Norbert
N
Ruus
Peter
P
Paul
Jeffrey
J
Richards
Lyette
L
Cnota
Hans-Peter
HP
Troy
Steven
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D000927:Anticonvulsants / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics*; D003404:Creatinine / Q000097:blood; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D010655:Phenylenediamines / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values; D012727:Sex Characteristics
D000927:Anticonvulsants; D002219:Carbamates; D010655:Phenylenediamines; C101866:ezogabine; D003404:Creatinine