Clinical pharmacokinetics of tyrosine kinase inhibitors
Abstract
In the recent years, eight tyrosine kinase inhibitors (TKIs) have been approved for cancer treatment and numerous are under investigation. These drugs are rationally designed to target specific tyrosine kinases that are mutated and/or over-expressed in cancer tissues. Post marketing study commitments have been made upon (accelerated) approval such as additional pharmacokinetic studies in patients with renal- or hepatic impairment, in children, additional interactions studies and studies on the relative or absolute bioavailability. Therefore, much information will emerge on the pharmacokinetic behavior of these drugs after their approval. In the present manuscript, the pharmacokinetic characteristics; absorption, distribution, metabolism and excretion (ADME), of the available TKIs are reviewed. Results from additional studies on the effect of drug transporters and drug-drug interactions have been incorporated. Overall, the TKIs reach their maximum plasma levels relatively fast; have an unknown absolute bioavailability, are extensively distributed and highly protein bound. The drugs are primarily metabolized by cytochrome P450 (CYP) 3A4 with other CYP-enzymes playing a secondary role. They are predominantly excreted with the feces and only a minor fraction is eliminated with the urine. All TKIs appear to be transported by the efflux ATP binding-cassette transports B1 and G2. Additionally these drugs can inhibit some of their own metabolizing enzymes and transporters making steady-state metabolism and drug-drug interactions both complex and unpredictable. By understanding the pharmacokinetic profile of these drugs and their similarities, factors that influence drug exposure will be better recognized and this knowledge may be used to limit sub- or supra-therapeutic drug exposure.
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Tyrosine kinase inhibitors, which are mostly metabolized by cytochrome P450, are among the majority of anticancer medications whose metabolism is blocked by CYP3A4 inhibition.
“Tyrosine kinase inhibitors, which are mostly metabolized by cytochrome P450, are among the majority of anticancer medications whose metabolism is blocked by CYP3A4 inhibition.32”
From Itraconazole as a repurposed anti-cancer agent: focusing on synthesis, mechanisms of action and therapeutic insights (2026) · cites this paper as [32]
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- Authors
- van Erp, N. P., Gelderblom, H., & Guchelaar, H.-J.
- Affiliations
- Leiden University Medical Center (NL)
- Venue
- Cancer Treatment Reviews
- Publisher
- Elsevier BV
- Published
- 2009-12
- Volume
- 35
- Issue
- 8
- Pages
- 692-706
- ISSN
- 0305-7372 (ISSN-L)
- OpenAlex
- W2012978969
- Cited by
- 503
- References
- 10
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 16 · 2023: 27 · 2022: 19 · 2021: 27 · 2020: 27 · 2019: 22 · 2018: 23 · 2017: 46 · 2016: 35 · 2015: 32 · 2014: 48 · 2013: 52 · 2012: 35
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Treatment Reviews (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Keywords
- tyrosine kinase inhibitors, clinical pharmacokinetics, ADME, drug-drug interactions, drug transporters, P-glycoprotein, TAP1, CYP3A4, enzyme inhibition, bioavailability, renal dysfunction, liver dysfunction, pediatric pharmacokinetics, cancer therapy
- MeSH terms
- Imatinib Mesylate, Erlotinib Hydrochloride, Dasatinib, Gefitinib, Sorafenib, Sunitinib, Lapatinib, Administration, Oral, Antineoplastic Agents, Benzamides, Benzenesulfonates, Biological Availability, Cytochrome P-450 Enzyme System, Drug Interactions, Humans, Indoles, Intestinal Absorption, Niacinamide, Phenylurea Compounds, Piperazines, Protein-Tyrosine Kinases, Pyridines, Pyrimidines, Pyrroles, Quinazolines, Thiazoles, Tissue Distribution, Protein Kinase Inhibitors
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