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Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors

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Abstract

Scientists have identified the impact of angiogenesis on tumor growth and survival. Among other efficient drugs, several small-molecule tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR) have been developed and have already been integrated into the treatment of various advanced malignancies. This review provides a compilation of current knowledge on the pharmacokinetic aspects of all VEGFR–TKIs already approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) and of those still under investigation. Additional information on substance metabolism, potential for drug–drug interactions (DDIs), and the need for dose adaptation in patients with predominant renal and/or hepatic impairment has been included. All TKIs introduced in this review were administered orally, allowing for easy drug handling for healthcare professionals and patients. For almost all substances, the maximum plasma concentrations were reached within a short period of time. The majority of the substances showed a high plasma protein binding and their excretion occurred via the feces and, to a lesser extent, via the urine. In most cases, dose adaptation in patients with mild to moderate renal or hepatic impairment is not recommended. Cytochrome P450 (CYP) 3A4 was found to play a crucial role in the drug metabolic processes of many compounds. In order to prevent unwanted DDIs, co-administration of VEGFR TKIs together with CYP3A4 inhibitors or inducers should be avoided. Throughout all TKIs, the data indicate high inter-individual variability. The causes of this are still unclear and require further research to allow for individualization of treatment regimens.

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Abbreviations

AML:

Acute myeloid leukemia

AUC:

Area under the plasma concentration-time curve

BCRP:

Breast cancer resistance protein

C max :

Peak plasma concentration

CL/F :

Apparent total clearance

CML:

Chronic myeloid leukemia

CNS:

Central nervous system

CRC:

Colorectal carcinoma

CSF-1R:

Colony stimulating factor receptor Type 1

CYP:

Cytochrome P450

DDI:

Drug–drug interaction

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

FGF:

Fibroblast growth factor

FGFR:

Fibroblast growth factor receptor

FLT3:

Fms-like tyrosine kinase-3

GIST:

Gastrointestinal stromal cancer

HCC:

Hepatocellular cancer

HGF:

Hepatocyte growth factor

HRPC:

Hormone refractory prostate cancer

IPF:

Idiopathic pulmonary fibrosis

InsR:

Insulin receptor

MDS:

Myelodysplastic syndrome

MTC:

Medullary thyroid cancer

MTD:

Maximum-tolerated dose

mTOR:

Mammalian target of rapamycin

NIH:

National Institute of Health

NSCLC:

Non-small cell lung cancer

PDGFR:

Platelet derived growth factor receptor

Pgp:

P-glycoprotein

pNET:

Pancreatic neuroendocrine tumors

PK:

Pharmacokinetics

PLGF:

Placenta growth factor

Raf kinases:

Rapid accelerated fibrosarcoma kinases

RCC:

Renal cell carcinoma

RTK:

Receptor tyrosine kinase

SCF:

Stem cell factor

SmPC:

Summary of product characteristics

T max :

Time to reach the peak plasma concentration (C max)

T 1/2 :

Half-life time needed for a drug concentration to reach half of its original value

TKI:

Tyrosine kinase inhibitor

UGT:

UDP-glucuronyltransferase

UI:

Under investigation

V d/F :

Apparent volume of distribution

VEGF:

Vascular endothelial growth factor

VEGFR:

Vascular endothelial growth factor receptor

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  1. Department of Clinical Pharmacology, Medical University of Vienna, Währinger-Gürtel 18-20, 1090, Vienna, Austria

    Beatrix Wulkersdorfer & Markus Zeitlinger

  2. Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria

    Monika Schmid

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Wulkersdorfer, B., Zeitlinger, M. & Schmid, M. Pharmacokinetic Aspects of Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors. Clin Pharmacokinet 55, 47–77 (2016). https://doi.org/10.1007/s40262-015-0302-2

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