Kinase inhibitor pharmacokinetics: comprehensive summary and roadmap for addressing inter-individual variability in exposure

Andrew Rowland, Madelé van Dyk, Arduino A. Mangoni, John O. Miners, Ross A. McKinnon, Michael D. Wiese, Angela Rowland, Ganessan Kichenadasse, Howard Gurney, Michael J. Sorich

Research output: Contribution to journalReview articleResearchpeer-review

Abstract

Introduction: Small molecule protein kinase inhibitors (KIs) are a class of drugs with complex and unconventional physiochemical and pharmacokinetic characteristics. Cytochrome P450 mediated metabolism and transporter-mediated uptake and efflux are important processes that determine KI disposition and exposure. Areas covered: We provide an overview of KI pharmacology, with a comprehensive summary of KI physiochemical and pharmacokinetic properties and description of the major sources of variability in KI pharmacokinetics focusing on common pathways involved in determining exposure. We also consider the strategies proposed to optimize KI dosing, appraise the current evidence for their use and analyze the challenges and knowledge gaps for KI dose optimization. Expert opinion: A number of strategies to optimize KI dosing have been proposed, but evidence underpinning their use is limited. The major challenge for optimized KI dosing is the development of high-quality evidence to demonstrate a significant improvement in therapeutic outcomes and /or reduction in adverse events through appropriately designed trials in a setting where the limited KI prescribing restricts capacity to undertake prospective randomized studies. If precision KI dosing can facilitate a fraction of the reported observational benefits, then substantial gains in patient outcomes will be derived in a cost-effective manner.

LanguageEnglish
Pages31-49
Number of pages19
JournalExpert Opinion on Drug Metabolism and Toxicology
Volume13
Issue number1
DOIs
Publication statusPublished - 2017
Externally publishedYes

Fingerprint

Pharmacokinetics
Phosphotransferases
Expert Testimony
Protein Kinase Inhibitors
Metabolism
Cytochrome P-450 Enzyme System
Prospective Studies
Pharmacology
Costs and Cost Analysis
Molecules

Keywords

  • cytochromes P450
  • inter-individual variability
  • optimised dosing
  • P-glycoprotein
  • pharmacogenetics
  • pharmacokinetics
  • precision medicine
  • small molecule kinase inhibitor
  • therapeutic drug monitoring
  • toxicity guided dosing

Cite this

Rowland, Andrew ; van Dyk, Madelé ; Mangoni, Arduino A. ; Miners, John O. ; McKinnon, Ross A. ; Wiese, Michael D. ; Rowland, Angela ; Kichenadasse, Ganessan ; Gurney, Howard ; Sorich, Michael J. / Kinase inhibitor pharmacokinetics : comprehensive summary and roadmap for addressing inter-individual variability in exposure. In: Expert Opinion on Drug Metabolism and Toxicology. 2017 ; Vol. 13, No. 1. pp. 31-49.
@article{0250455e74aa46b09fc5b18157eb7f13,
title = "Kinase inhibitor pharmacokinetics: comprehensive summary and roadmap for addressing inter-individual variability in exposure",
abstract = "Introduction: Small molecule protein kinase inhibitors (KIs) are a class of drugs with complex and unconventional physiochemical and pharmacokinetic characteristics. Cytochrome P450 mediated metabolism and transporter-mediated uptake and efflux are important processes that determine KI disposition and exposure. Areas covered: We provide an overview of KI pharmacology, with a comprehensive summary of KI physiochemical and pharmacokinetic properties and description of the major sources of variability in KI pharmacokinetics focusing on common pathways involved in determining exposure. We also consider the strategies proposed to optimize KI dosing, appraise the current evidence for their use and analyze the challenges and knowledge gaps for KI dose optimization. Expert opinion: A number of strategies to optimize KI dosing have been proposed, but evidence underpinning their use is limited. The major challenge for optimized KI dosing is the development of high-quality evidence to demonstrate a significant improvement in therapeutic outcomes and /or reduction in adverse events through appropriately designed trials in a setting where the limited KI prescribing restricts capacity to undertake prospective randomized studies. If precision KI dosing can facilitate a fraction of the reported observational benefits, then substantial gains in patient outcomes will be derived in a cost-effective manner.",
keywords = "cytochromes P450, inter-individual variability, optimised dosing, P-glycoprotein, pharmacogenetics, pharmacokinetics, precision medicine, small molecule kinase inhibitor, therapeutic drug monitoring, toxicity guided dosing",
author = "Andrew Rowland and {van Dyk}, Madel{\'e} and Mangoni, {Arduino A.} and Miners, {John O.} and McKinnon, {Ross A.} and Wiese, {Michael D.} and Angela Rowland and Ganessan Kichenadasse and Howard Gurney and Sorich, {Michael J.}",
year = "2017",
doi = "10.1080/17425255.2016.1229303",
language = "English",
volume = "13",
pages = "31--49",
journal = "Expert Opinion on Drug Metabolism and Toxicology",
issn = "1742-5255",
publisher = "Informa Healthcare",
number = "1",

}

Rowland, A, van Dyk, M, Mangoni, AA, Miners, JO, McKinnon, RA, Wiese, MD, Rowland, A, Kichenadasse, G, Gurney, H & Sorich, MJ 2017, 'Kinase inhibitor pharmacokinetics: comprehensive summary and roadmap for addressing inter-individual variability in exposure', Expert Opinion on Drug Metabolism and Toxicology, vol. 13, no. 1, pp. 31-49. https://doi.org/10.1080/17425255.2016.1229303

Kinase inhibitor pharmacokinetics : comprehensive summary and roadmap for addressing inter-individual variability in exposure. / Rowland, Andrew; van Dyk, Madelé; Mangoni, Arduino A.; Miners, John O.; McKinnon, Ross A.; Wiese, Michael D.; Rowland, Angela; Kichenadasse, Ganessan; Gurney, Howard; Sorich, Michael J.

In: Expert Opinion on Drug Metabolism and Toxicology, Vol. 13, No. 1, 2017, p. 31-49.

Research output: Contribution to journalReview articleResearchpeer-review

TY - JOUR

T1 - Kinase inhibitor pharmacokinetics

T2 - Expert Opinion on Drug Metabolism and Toxicology

AU - Rowland, Andrew

AU - van Dyk, Madelé

AU - Mangoni, Arduino A.

AU - Miners, John O.

AU - McKinnon, Ross A.

AU - Wiese, Michael D.

AU - Rowland, Angela

AU - Kichenadasse, Ganessan

AU - Gurney, Howard

AU - Sorich, Michael J.

PY - 2017

Y1 - 2017

N2 - Introduction: Small molecule protein kinase inhibitors (KIs) are a class of drugs with complex and unconventional physiochemical and pharmacokinetic characteristics. Cytochrome P450 mediated metabolism and transporter-mediated uptake and efflux are important processes that determine KI disposition and exposure. Areas covered: We provide an overview of KI pharmacology, with a comprehensive summary of KI physiochemical and pharmacokinetic properties and description of the major sources of variability in KI pharmacokinetics focusing on common pathways involved in determining exposure. We also consider the strategies proposed to optimize KI dosing, appraise the current evidence for their use and analyze the challenges and knowledge gaps for KI dose optimization. Expert opinion: A number of strategies to optimize KI dosing have been proposed, but evidence underpinning their use is limited. The major challenge for optimized KI dosing is the development of high-quality evidence to demonstrate a significant improvement in therapeutic outcomes and /or reduction in adverse events through appropriately designed trials in a setting where the limited KI prescribing restricts capacity to undertake prospective randomized studies. If precision KI dosing can facilitate a fraction of the reported observational benefits, then substantial gains in patient outcomes will be derived in a cost-effective manner.

AB - Introduction: Small molecule protein kinase inhibitors (KIs) are a class of drugs with complex and unconventional physiochemical and pharmacokinetic characteristics. Cytochrome P450 mediated metabolism and transporter-mediated uptake and efflux are important processes that determine KI disposition and exposure. Areas covered: We provide an overview of KI pharmacology, with a comprehensive summary of KI physiochemical and pharmacokinetic properties and description of the major sources of variability in KI pharmacokinetics focusing on common pathways involved in determining exposure. We also consider the strategies proposed to optimize KI dosing, appraise the current evidence for their use and analyze the challenges and knowledge gaps for KI dose optimization. Expert opinion: A number of strategies to optimize KI dosing have been proposed, but evidence underpinning their use is limited. The major challenge for optimized KI dosing is the development of high-quality evidence to demonstrate a significant improvement in therapeutic outcomes and /or reduction in adverse events through appropriately designed trials in a setting where the limited KI prescribing restricts capacity to undertake prospective randomized studies. If precision KI dosing can facilitate a fraction of the reported observational benefits, then substantial gains in patient outcomes will be derived in a cost-effective manner.

KW - cytochromes P450

KW - inter-individual variability

KW - optimised dosing

KW - P-glycoprotein

KW - pharmacogenetics

KW - pharmacokinetics

KW - precision medicine

KW - small molecule kinase inhibitor

KW - therapeutic drug monitoring

KW - toxicity guided dosing

UR - http://www.scopus.com/inward/record.url?scp=85003510918&partnerID=8YFLogxK

U2 - 10.1080/17425255.2016.1229303

DO - 10.1080/17425255.2016.1229303

M3 - Review article

VL - 13

SP - 31

EP - 49

JO - Expert Opinion on Drug Metabolism and Toxicology

JF - Expert Opinion on Drug Metabolism and Toxicology

SN - 1742-5255

IS - 1

ER -