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Physiologically based pharmacokinetic predictions of tramadol exposure throughout pediatric life: an analysis of the different clearance contributors with emphasis on CYP2D6 maturation

Huybrecht T'jollyn, Jan Snoeys, An Vermeulen UGent, Robin Michelet UGent, Filip Cuykens, Geert Mannens, Achiel Van Peer, Pieter Annaert, Karel Allegaert, Jan Van Bocxlaer UGent, et al. (2015) AAPS JOURNAL. 17(6). p.1376-1387
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
ontogeny, clearance, pbpk, pediatric, tramadol, DRUG-DRUG INTERACTION, IN-VITRO, 1ST MONTHS, ONTOGENY, BIOAVAILABILITY, COMMUNICATION, FORMULATIONS, DISPOSITION, METABOLISM, TRANSPORTERS
journal title
AAPS JOURNAL
AAPS J.
volume
17
issue
6
pages
1376 - 1387
Web of Science type
Article
Web of Science id
000364104100006
JCR category
PHARMACOLOGY & PHARMACY
JCR impact factor
3.819 (2015)
JCR rank
49/253 (2015)
JCR quartile
1 (2015)
ISSN
1550-7416
DOI
10.1208/s12248-015-9803-z
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
6971142
handle
http://hdl.handle.net/1854/LU-6971142
date created
2015-10-30 10:33:23
date last changed
2016-12-19 15:46:55
@article{6971142,
  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{\textregistered} 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{\textregistered} 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.},
  author       = {T'jollyn, Huybrecht and Snoeys, Jan and Vermeulen, An and Michelet, Robin and Cuykens, Filip and Mannens, Geert and Van Peer, Achiel and Annaert, Pieter and Allegaert, Karel and Van Bocxlaer, Jan and Boussery, Koen},
  issn         = {1550-7416},
  journal      = {AAPS JOURNAL},
  keyword      = {ontogeny,clearance,pbpk,pediatric,tramadol,DRUG-DRUG INTERACTION,IN-VITRO,1ST MONTHS,ONTOGENY,BIOAVAILABILITY,COMMUNICATION,FORMULATIONS,DISPOSITION,METABOLISM,TRANSPORTERS},
  language     = {eng},
  number       = {6},
  pages        = {1376--1387},
  title        = {Physiologically based pharmacokinetic predictions of tramadol exposure throughout pediatric life: an analysis of the different clearance contributors with emphasis on CYP2D6 maturation},
  url          = {http://dx.doi.org/10.1208/s12248-015-9803-z},
  volume       = {17},
  year         = {2015},
}

Chicago
T’jollyn, Huybrecht, Jan Snoeys, An Vermeulen, Robin Michelet, Filip Cuykens, Geert Mannens, Achiel Van Peer, et al. 2015. “Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: An Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation.” Aaps Journal 17 (6): 1376–1387.
APA
T’jollyn, H., Snoeys, J., Vermeulen, A., Michelet, R., Cuykens, F., Mannens, G., Van Peer, A., et al. (2015). Physiologically based pharmacokinetic predictions of tramadol exposure throughout pediatric life: an analysis of the different clearance contributors with emphasis on CYP2D6 maturation. AAPS JOURNAL, 17(6), 1376–1387.
Vancouver
1.
T’jollyn H, Snoeys J, Vermeulen A, Michelet R, Cuykens F, Mannens G, et al. Physiologically based pharmacokinetic predictions of tramadol exposure throughout pediatric life: an analysis of the different clearance contributors with emphasis on CYP2D6 maturation. AAPS JOURNAL. 2015;17(6):1376–87.
MLA
T’jollyn, Huybrecht, Jan Snoeys, An Vermeulen, et al. “Physiologically Based Pharmacokinetic Predictions of Tramadol Exposure Throughout Pediatric Life: An Analysis of the Different Clearance Contributors with Emphasis on CYP2D6 Maturation.” AAPS JOURNAL 17.6 (2015): 1376–1387. Print.