Clinical pharmacokinetics of tyrosine kinase inhibitors.
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.
van Erp
Nielka P
NP
Departments of Clinical Pharmacy and Toxicology, University Medical Center, 2333 ZA Leiden, The Netherlands. p.h.van_erp@lumc.nl
Gelderblom
Hans
H
Guchelaar
Henk-Jan
HJ
D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D001549:Benzamides; D001557:Benzenesulfonates / Q000493:pharmacokinetics; D001682:Biological Availability; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000069439:Dasatinib; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D000077341:Lapatinib; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D010879:Piperazines / Q000493:pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000493:pharmacokinetics; D011758:Pyrroles / Q000493:pharmacokinetics; D011799:Quinazolines / Q000493:pharmacokinetics; D000077157:Sorafenib; D000077210:Sunitinib; D013844:Thiazoles / Q000493:pharmacokinetics; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D001549:Benzamides; D001557:Benzenesulfonates; D007211:Indoles; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D011799:Quinazolines; D013844:Thiazoles; D000077341:Lapatinib; D009536:Niacinamide; D000068877:Imatinib Mesylate; D003577:Cytochrome P-450 Enzyme System; D000077157:Sorafenib; D000069347:Erlotinib Hydrochloride; D011505:Protein-Tyrosine Kinases; C498826:nilotinib; D000069439:Dasatinib; D000077156:Gefitinib; D000077210:Sunitinib