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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

(2015) AAPS JOURNAL. 17(6). p.1376-1387
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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.
Keywords
ontogeny, clearance, pbpk, pediatric, tramadol, DRUG-DRUG INTERACTION, IN-VITRO, 1ST MONTHS, ONTOGENY, BIOAVAILABILITY, COMMUNICATION, FORMULATIONS, DISPOSITION, METABOLISM, TRANSPORTERS

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Citation

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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.
@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},
}

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