Scopus list of publications for February 11, 2024
CYP2D6 Phenotype Influences Pharmacokinetic Parameters of Venlafaxine: Results from a Population Pharmacokinetic Model in Older Adults with Depression
(2024) Clinical Pharmacology and Therapeutics, .
Men, X.a b , Taylor, Z.L.c d , Marshe, V.S.e , Blumberger, D.M.b f , Karp, J.F.g , Kennedy, J.L.b f , Lenze, E.J.h , Reynolds, C.F., IIIi , Stefan, C.b j , Mulsant, B.H.b f , Ramsey, L.B.c d k , Müller, D.J.a b f
a Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada
b Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
c Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
d Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
e Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
f Department of Psychiatry, University of Toronto, Toronto, ON, Canada
g Department of Psychiatry, The University of Arizona College of Medicine, Tucson, AZ, United States
h Department of Psychiatry, Washington University, St. Louis, MO, United States
i Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
j Clinical Laboratory and Diagnostic Services, Centre for Addiction and Mental Health, Toronto, ON, Canada
k Division of Research in Patient Services, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
Abstract
In this study, we aimed to improve upon a published population pharmacokinetic (PK) model for venlafaxine (VEN) in the treatment of depression in older adults, then investigate whether CYP2D6 metabolizer status affected model-estimated PK parameters of VEN and its active metabolite O-desmethylvenlafaxine. The model included 325 participants from a clinical trial in which older adults with depression were treated with open-label VEN (maximum 300 mg/day) for 12 weeks and plasma levels of VEN and O-desmethylvenlafaxine were assessed at weeks 4 and 12. We fitted a nonlinear mixed-effect PK model using NONMEM to estimate PK parameters for VEN and O-desmethylvenlafaxine adjusted for CYP2D6 metabolizer status and age. At both lower doses (up to 150 mg/day) and higher doses (up to 300 mg/day), CYP2D6 metabolizers impacted PK model-estimated VEN clearance, VEN exposure, and active moiety (VEN + O-desmethylvenlafaxine) exposure. Specifically, compared with CYP2D6 normal metabolizers, (i) CYP2D6 ultra-rapid metabolizers had higher VEN clearance; (ii) CYP2D6 intermediate metabolizers had lower VEN clearance; (iii) CYP2D6 poor metabolizers had lower VEN clearance, higher VEN exposure, and higher active moiety exposure. Overall, our study showed that including a pharmacogenetic factor in a population PK model could increase model fit, and this improved model demonstrated how CYP2D6 metabolizer status affected VEN-related PK parameters, highlighting the importance of genetic factors in personalized medicine. © 2024 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMH
Brain and Behavior Research FoundationBBRF
American Foundation for Suicide PreventionAFSP
Merck
Centers for Medicare and Medicaid ServicesCMS
Patient-Centered Outcomes Research InstitutePCORI
National Center for Advancing Translational SciencesNCATS
Fondation Brain Canada
Campbell Family Mental Health Research Institute
Centre for Addiction and Mental Health FoundationCAMH
Commonwealth of Pennsylvania
Canadian Institutes of Health ResearchIRSC
Canada Foundation for InnovationCFI
University of TorontoU of T
Université Pierre et Marie CurieUPMC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus