title: Population Pharmacokinetic Modeling of Armodafinil and Its Major Metabolites.
abstract: Population pharmacokinetic models for armodafinil and its major metabolites, R-modafinil acid and modafinil sulfone, were developed, and selected covariates were investigated. Data from 583 healthy subjects and patients with bipolar I disorder in 11 phase 1-3 studies (8027 concentrations) of armodafinil, given as single or multiple once-daily doses (50- to 400-mg tablet or capsule), were pooled. A previously developed 1-compartment model with first-order absorption without covariate effects was initially applied to pooled phase 1 and 2 data. After covariate analysis, the phase 3 data were pooled with the phase 1 and 2 data set and the model was refined again using a second backward elimination step. Population modeling was performed with NONMEM version 7 with the first-order conditional estimation method. Estimated armodafinil apparent oral clearance (CL/F), volume of distribution (Vc/F), and absorption t½were 2.01 L/h, 45 L, and 0.226 hours, respectively. Armodafinil CL/F and Vc/F increased with weight; predicted steady-state area under the curve was 16.4% higher and 29.1% lower in a patient weighing 50 or 150 kg, respectively, relative to a 70-kg patient. Female participants had 10.2% lower armodafinil Vc/F compared with male participants. Age, race (white vs nonwhite), health status (healthy vs bipolar I disorder), liver function, and renal function were not statistically significant predictors of armodafinil pharmacokinetics. CL/F and Vc/F for R-modafinil acid and modafinil sulfone were 16.7 L/h and 8.95 L and 6.82 L/h and 12.4 L, respectively. Weight did not affect exposure of either metabolite. These population pharmacokinetic models were from the largest population of adults reported to date and provide a robust characterization of the pharmacokinetics of armodafinil, R-modafinil acid, and modafinil sulfone in adults.
authors.affiliation: Cognigen Corporation, Buffalo, NY, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Willavize
authors.affiliation: Cognigen Corporation, Buffalo, NY, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Fiedler-Kelly
authors.affiliation: Cognigen Corporation, Buffalo, NY, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ludwig
authors.affiliation: Teva Pharmaceuticals, Frazer, PA, USA.
authors.forename: Lingling
authors.initials: L
authors.lastname: Guan
mesh_terms: D000328:Adult; D019540:Area Under Curve; D001559:Benzhydryl Compounds / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation; D001714:Bipolar Disorder / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics*; D018491:Dopamine Agonists / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005006:Ethnicity; D005260:Female; D006207:Half-Life; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077408:Modafinil; D015233:Models, Statistical; D011153:Population; D012727:Sex Characteristics
chemical_list: D001559:Benzhydryl Compounds; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D000077408:Modafinil
keywords: R-modafinil acid; armodafinil; modafinil; modafinil sulfone; modeling; population pharmacokinetics