title: Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (CES1) Variants.
abstract: The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d-MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two-compartment disposition model with absorption transit compartments. Novel effects of rs115629050 and CES1 diplotypes, as well as previously reported effects of rs71647871 and body weight, were included in the final model. Assessment of the independent and combined effect of CES1 covariates identified several specific risk factors that may result in severely increased d-MPH plasma exposure.
authors.affiliation: Roskilde University Hospital, Unit of Clinical Pharmacology, Roskilde, Denmark.
authors.forename: Y K
authors.initials: YK
authors.lastname: Lyauk
authors.affiliation: Bispebjerg University Hospital, Department of Clinical Pharmacology, Roskilde, Denmark.
authors.forename: C
authors.initials: C
authors.lastname: Stage
authors.affiliation: Clinical Pharmacology, Department of Public Health, University of Southern Denmark, Odense, Denmark.|The Hospital Pharmacy, Hospital of South Jutland, Esbjerg, Denmark.
authors.forename: T K
authors.initials: TK
authors.lastname: Bergmann
authors.affiliation: Mental Health Centre Sct. Hans, Institute for Biological Psychiatry, Roskilde, Denmark.
authors.forename: L
authors.initials: L
authors.lastname: Ferrero-Milliani
authors.affiliation: Mental Health Centre Sct. Hans, Institute for Biological Psychiatry, Roskilde, Denmark.
authors.forename: D
authors.initials: D
authors.lastname: Bjerre
authors.affiliation: University of Copenhagen, Department of Forensic Medicine, Copenhagen, Denmark.
authors.forename: R
authors.initials: R
authors.lastname: Thomsen
authors.affiliation: Bispebjerg University Hospital, Department of Clinical Pharmacology, Copenhagen, Denmark.
authors.forename: K P
authors.initials: KP
authors.lastname: Dalhoff
authors.affiliation: Mental Health Centre Sct. Hans, Institute for Biological Psychiatry, Roskilde, Denmark.
authors.forename: H B
authors.initials: HB
authors.lastname: Rasmussen
authors.affiliation: Roskilde University Hospital, Unit of Clinical Pharmacology, Roskilde, Denmark.
authors.forename: G
authors.initials: G
authors.lastname: Jürgens
mesh_terms: D000328:Adult; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D003198:Computer Simulation; D014644:Genetic Variation; D006801:Humans; D008774:Methylphenidate / Q000493:pharmacokinetics*; D008954:Models, Biological
chemical_list: D008774:Methylphenidate; D002265:Carboxylic Ester Hydrolases