Population pharmacokinetic study of memantine: effects of clinical and genetic factors.
OBJECTIVE
Memantine, a frequently prescribed anti-dementia drug, is mainly eliminated unchanged by the kidneys, partly via tubular secretion. Considerable inter-individual variability in plasma concentrations has been reported. We aimed to investigate clinical and genetic factors influencing memantine disposition.


METHODS
A population pharmacokinetic study was performed including data from 108 patients recruited in a naturalistic setting. Patients were genotyped for common polymorphisms in renal cation transporters (SLC22A1/2/5, SLC47A1, ABCB1) and nuclear receptors (NR1I2, NR1I3, RXR, PPAR) involved in transporter expression.


RESULTS
The average clearance was 5.2 L/h with a 27 % inter-individual variability (percentage coefficient of variation). Glomerular filtration rate (p = 0.007) and sex (p = 0.001) markedly influenced memantine clearance. NR1I2 rs1523130 was identified as the unique significant genetic covariate for memantine clearance (p = 0.006), with carriers of the NR1I2 rs1523130 CT/TT genotypes presenting a 16 % slower memantine elimination than carriers of the CC genotype.


CONCLUSIONS
The better understanding of inter-individual variability of memantine disposition might be beneficial in the context of individual dose optimization.
Unit of Pharmacogenetics and Clinical Psychopharmacology, Centre for Psychiatric Neuroscience, Department of Psychiatry, Hospital of Cery, University Hospital Lausanne, 1008 Prilly-Lausanne, Switzerland.
Muriel
M
Noetzli
Monia
M
Guidi
Karsten
K
Ebbing
Stephan
S
Eyer
Laurence
L
Wilhelm
Agnès
A
Michon
Valérie
V
Thomazic
Abdel-Messieh
AM
Alnawaqil
Sophie
S
Maurer
Serge
S
Zumbach
Panteleimon
P
Giannakopoulos
Armin
A
von Gunten
Chantal
C
Csajka
Chin B
CB
Eap
D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics; D000090702:Constitutive Androstane Receptor; D003704:Dementia / Q000188:drug therapy / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008559:Memantine / Q000097:blood / Q000493:pharmacokinetics*; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D008954:Models, Biological; D011110:Polymorphism, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics
D002352:Carrier Proteins; D000090702:Constitutive Androstane Receptor; D018691:Excitatory Amino Acid Antagonists; D026901:Membrane Transport Proteins; C000716327:NR1I3 protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D008559:Memantine