TY - JOUR
T1 - Kinase inhibitor pharmacokinetics: comprehensive summary and roadmap for addressing interindividual variability in exposure
AU - Rowland, Andrew
AU - Van Dyk, Madele
AU - Mangoni, Arduino
AU - Miners, John
AU - McKinnon, Ross
AU - Wiese, Michael
AU - Rowland, Evaggelia
AU - Kichenadasse, Ganessan
AU - Gurney, Howard
AU - Sorich, Michael
PY - 2017/1/2
Y1 - 2017/1/2
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
SN - 1742-5255
VL - 13
SP - 31
EP - 49
JO - Expert Opinion on Drug Metabolism and Toxicology
JF - Expert Opinion on Drug Metabolism and Toxicology
IS - 1
ER -