title: Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: an Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation.
abstract: This paper focuses on the retrospective evaluation of physiologically based pharmacokinetic (PBPK) techniques used to mechanistically predict clearance throughout pediatric life. An intravenous tramadol retrograde PBPK model was set up in Simcyp® using adult clearance values, qualified for CYP2D6, CYP3A4, CYP2B6, and renal contributions. Subsequently, the model was evaluated for mechanistic prediction of total, CYP2D6-related, and renal clearance predictions in very early life. In two in vitro pediatric human liver microsomal (HLM) batches (1 and 3 months), O-desmethyltramadol and N-desmethyltramadol formation rates were compared with CYP2D6 and CYP3A4 activity, respectively. O-desmethyltramadol formation was mediated only by CYP2D6, while N-desmethyltramadol was mediated in part by CYP3A4. Additionally, the clearance maturation of the PBPK model predictions was compared to two in vivo maturation models (Hill and exponential) based on plasma concentration data, and to clearance estimations from a WinNonlin® fit of plasma concentration and urinary excretion data. Maturation of renal and CYP2D6 clearance is captured well in the PBPK model predictions, but total tramadol clearance is underpredicted. The most pronounced underprediction of total and CYP2D6-mediated clearance was observed in the age range of 2-13 years. In conclusion, the PBPK technique showed to be a powerful mechanistic tool capable of predicting maturation of CYP2D6 and renal tramadol clearance in early infancy, although some underprediction occurs between 2 and 13 years for total and CYP2D6-mediated tramadol clearance.
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium. huybrecht.tjollyn@ugent.be.
authors.forename: Huybrecht
authors.initials: H
authors.lastname: T'jollyn
authors.affiliation: Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Vermeulen
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium.
authors.forename: Robin
authors.initials: R
authors.lastname: Michelet
authors.affiliation: Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: Filip
authors.initials: F
authors.lastname: Cuyckens
authors.affiliation: Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Mannens
authors.affiliation: Janssen Research & Development, Division of Janssen Pharmaceutica NV, Turnhoutseweg 30, B-2340, Beerse, Belgium.
authors.forename: Achiel
authors.initials: A
authors.lastname: Van Peer
authors.affiliation: Drug Delivery & Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O&N2, Herestraat, 49-box 921, B-3000, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Annaert
authors.affiliation: Department of Development and Regeneration, KU Leuven and Neonatal Intensive Care Unit, University Hospitals Leuven, B-3000, Leuven, Belgium.
authors.forename: Karel
authors.initials: K
authors.lastname: Allegaert
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Van Bocxlaer
authors.affiliation: Laboratory of Medical Biochemistry and Clinical Analysis, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Boussery
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D005544:Forecasting; D006801:Humans; D007223:Infant; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D012189:Retrospective Studies; D014147:Tramadol / Q000493:pharmacokinetics*
chemical_list: D000701:Analgesics, Opioid; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6
keywords: PBPK; clearance; ontogeny; pediatric; tramadol