title: Characterization of Atomoxetine Biotransformation and Implications for Development of PBPK Models for Dose Individualization in Children.
abstract: Atomoxetine (ATX) is a second-line nonstimulant medication used to control symptoms of attention deficit hyperactivity disorder (ADHD). Inconsistent therapeutic efficacy has been reported with ATX, which may be related to variable CYP2D6-mediated drug clearance. We characterized ATX metabolism in a panel of human liver samples as a basis for a bottom-up PBPK model to aid in ATX exposure prediction and control. Km, Vmax, and Clint values in pooled human liver microsomes (HLMs) were 2.4 µM, 479 pmol/min/mg protein, and 202 µl/min/mg protein, respectively. Mean population values of kinetic parameters are not adequate to describe variability in a population, given that Km, Vmax, and Clint values from single-donor HLMs ranged from 0.93 to 79.2 µM, 20.0 to 1600 pmol/min/mg protein, and 0.3 to 936 µl/min/mg protein. All kinetic parameters were calculated from 4-hydroxyatomoxetine (4-OH-ATX) formation. CYP2E1 and CYP3A contributed to 4-OH-ATX formation in livers with CYP2D6 intermediate and poor metabolizer status. In HLMs with lower CYP2D6 activity levels, 2-hydroxymethylatomoxetine (2-CH2OH-ATX) formation became a more predominant pathway of metabolism, which appeared to be catalyzed by CYP2B6. ATX biotransformation at clinically relevant plasma concentrations was characterized in a panel of pediatric HLM (n = 116) samples by evaluating primary metabolites. Competing pathways of ATX metabolism [N-desmethylatomoxetine (NDM-ATX) and 2-CH2OH-ATX formation] had increasing importance in livers with lesser CYP2D6 activity, but, overall ATX clearance was still compromised. Modeling ATX exposure to individualize therapy would require comprehensive knowledge of factors that affect CYP2D6 activity as well as an understanding of competing pathways, particularly for individuals with lower CYP2D6 activity.
authors.affiliation: Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation (J.C.D., L.V.H., R.E.P., A.G., J.S.L.), Department of Pediatrics, Children's Mercy Hospital (L.V.H., R.E.P., A.G., J.S.L.), University of Kansas Medical Center (J.S.L.), and Department of Pharmacology (A.G., R.E.P., J.S.L.), University of Missouri-Kansas City, Kansas City, Missouri jdinh@cmh.edu.
authors.forename: Jean C
authors.initials: JC
authors.lastname: Dinh
authors.affiliation: Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation (J.C.D., L.V.H., R.E.P., A.G., J.S.L.), Department of Pediatrics, Children's Mercy Hospital (L.V.H., R.E.P., A.G., J.S.L.), University of Kansas Medical Center (J.S.L.), and Department of Pharmacology (A.G., R.E.P., J.S.L.), University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: Robin E
authors.initials: RE
authors.lastname: Pearce
authors.affiliation: Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation (J.C.D., L.V.H., R.E.P., A.G., J.S.L.), Department of Pediatrics, Children's Mercy Hospital (L.V.H., R.E.P., A.G., J.S.L.), University of Kansas Medical Center (J.S.L.), and Department of Pharmacology (A.G., R.E.P., J.S.L.), University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: Leon
authors.initials: L
authors.lastname: Van Haandel
authors.affiliation: Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation (J.C.D., L.V.H., R.E.P., A.G., J.S.L.), Department of Pediatrics, Children's Mercy Hospital (L.V.H., R.E.P., A.G., J.S.L.), University of Kansas Medical Center (J.S.L.), and Department of Pharmacology (A.G., R.E.P., J.S.L.), University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: Andrea
authors.initials: A
authors.lastname: Gaedigk
authors.affiliation: Division of Clinical Pharmacology, Toxicology, and Therapeutic Innovation (J.C.D., L.V.H., R.E.P., A.G., J.S.L.), Department of Pediatrics, Children's Mercy Hospital (L.V.H., R.E.P., A.G., J.S.L.), University of Kansas Medical Center (J.S.L.), and Department of Pharmacology (A.G., R.E.P., J.S.L.), University of Missouri-Kansas City, Kansas City, Missouri.
authors.forename: J Steven
authors.initials: JS
authors.lastname: Leeder
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000069445:Atomoxetine Hydrochloride / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D001289:Attention Deficit Disorder with Hyperactivity / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D001711:Biotransformation; D000697:Central Nervous System Stimulants / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D002648:Child; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D054796:Drug Dosage Calculations; D005838:Genotype; D006801:Humans; D006900:Hydroxylation; D007223:Infant; D007527:Isoenzymes; D008745:Methylation; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D008954:Models, Biological; D010636:Phenols / Q000493:pharmacokinetics; D010641:Phenotype; D011437:Propylamines / Q000493:pharmacokinetics; D013379:Substrate Specificity; D055815:Young Adult
chemical_list: D000697:Central Nervous System Stimulants; D007527:Isoenzymes; D010636:Phenols; D011437:Propylamines; D000069445:Atomoxetine Hydrochloride; C454679:4-hydroxyatomoxetine; D003577:Cytochrome P-450 Enzyme System