A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats: Pooled Analysis of Published Data

Jing Tao Lu, Ying Cai, Feng Chen, Wei Wei Jia, Zhe Yi Hu, Yuan Sheng Zhao

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background and Objective: Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug’s therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats. Methods: Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data. Results: The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug–metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected. Conclusion: The developed PBPK model can be regarded as the first step towards a PBPK–pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event.

Original languageEnglish (US)
Pages (from-to)689-703
Number of pages15
JournalEuropean Journal of Drug Metabolism and Pharmacokinetics
Volume41
Issue number6
DOIs
StatePublished - Dec 1 2016

Fingerprint

Amiodarone
Pharmacokinetics
Toxic Actions
Drug and Narcotic Control
Tissue Distribution
Atrial Fibrillation
Fats
desethylamiodarone
Therapeutics
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats : Pooled Analysis of Published Data. / Lu, Jing Tao; Cai, Ying; Chen, Feng; Jia, Wei Wei; Hu, Zhe Yi; Zhao, Yuan Sheng.

In: European Journal of Drug Metabolism and Pharmacokinetics, Vol. 41, No. 6, 01.12.2016, p. 689-703.

Research output: Contribution to journalArticle

@article{f47692e2740f4a44880221e5086ebd71,
title = "A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats: Pooled Analysis of Published Data",
abstract = "Background and Objective: Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug’s therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats. Methods: Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data. Results: The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug–metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected. Conclusion: The developed PBPK model can be regarded as the first step towards a PBPK–pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event.",
author = "Lu, {Jing Tao} and Ying Cai and Feng Chen and Jia, {Wei Wei} and Hu, {Zhe Yi} and Zhao, {Yuan Sheng}",
year = "2016",
month = "12",
day = "1",
doi = "10.1007/s13318-015-0295-0",
language = "English (US)",
volume = "41",
pages = "689--703",
journal = "European Journal of Drug Metabolism and Pharmacokinetics",
issn = "0378-7966",
publisher = "Springer Paris",
number = "6",

}

TY - JOUR

T1 - A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats

T2 - Pooled Analysis of Published Data

AU - Lu, Jing Tao

AU - Cai, Ying

AU - Chen, Feng

AU - Jia, Wei Wei

AU - Hu, Zhe Yi

AU - Zhao, Yuan Sheng

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Background and Objective: Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug’s therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats. Methods: Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data. Results: The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug–metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected. Conclusion: The developed PBPK model can be regarded as the first step towards a PBPK–pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event.

AB - Background and Objective: Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug’s therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats. Methods: Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data. Results: The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug–metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected. Conclusion: The developed PBPK model can be regarded as the first step towards a PBPK–pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event.

UR - http://www.scopus.com/inward/record.url?scp=84938819374&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938819374&partnerID=8YFLogxK

U2 - 10.1007/s13318-015-0295-0

DO - 10.1007/s13318-015-0295-0

M3 - Article

AN - SCOPUS:84938819374

VL - 41

SP - 689

EP - 703

JO - European Journal of Drug Metabolism and Pharmacokinetics

JF - European Journal of Drug Metabolism and Pharmacokinetics

SN - 0378-7966

IS - 6

ER -