Clinical Pharmacokinetics of Tyrosine Kinase Inhibitors

Abstract

The treatment of many malignancies has been improved in recent years by the introduction of molecular targeted therapies. These drugs interact preferentially with specific targets that are mutated and/or overexpressed in malignant cells. A group of such targets are the tyrosine kinases, against which a number of inhibitors (tyrosine kinase inhibitors, TKIs) have been developed. Imatinib, a TKI with targets that include the breakpoint cluster region-Abelson (bcr-abl) fusion protein kinase and mast/stem cell growth factor receptor kinase (c-Kit), was the first clinically successful drug of this type and revolutionized the treatment and prognosis of chronic myeloid leukemia and gastrointestinal stromal tumors. This success paved the way for the development of other TKIs for the treatment of a range of hematological malignancies and solid tumors. To date, 14 TKIs have been approved for clinical use and many more are under investigation. All these agents are given orally and are substrates of a range of drug transporters and metabolizing enzymes. In addition, some TKIs are capable of inhibiting their own transporters and metabolizing enzymes, making their disposition and metabolism at steady-state unpredictable. A given dose can therefore give rise to markedly different plasma concentrations in different patients, favoring the selection of resistant clones in the case of subtherapeutic exposure, and increasing the risk of toxicity if dosage is excessive. The aim of this review was to summarize current knowledge of the clinical pharmacokinetics and known adverse effects of the TKIs that are available for clinical use and to provide practical guidance on the implications of these data in patient management, in particular with respect to therapeutic drug monitoring.

Therapeutic drug monitoring and tyrosine kinase inhibitors

“…PAULINE HERVIOU [1][2][3] , EMILIE THIVAT [3][4][5] , DAMIEN RICHARD 1,2 , LUCIE ROCHE 1,2 , JOYCE DOHOU 3-5, MÉLANIE POUGET 3,5,6 physiological (age), pathological (renal or liver failure) and environmental (food) (4). These factors are important role in the pharmacokinetics of a molecule, since at the same dosage, the plasma concentration of a drug can differ from patient to patient, leading to variations in the therapeutic responses obtained, as well as the occurrence of adverse effects (4).…”

“…The limited use of TDM may also be due to certain analytical difficulties, either technical or faced during the interpretation of the results, such as the presence of an active metabolite, and determination of the free vs. tumor concentration of the drug (2). Tyrosine kinase inhibitors (TKIs) are a class of targeted therapy used in the treatment of malignant diseases (5,6). The most well known TKI is imatinib, which is used in patients with chronic myeloid leukemia (CML) (5,6).…”

Simple Determination of Plasma Ponatinib Concentration Using HPLC

“…Some TKIs have a narrow therapeutic range, and they are known to have large interindividual variations according to the acidity of gastric absorption, possible detoxification based on the polymorphisms in genes of metabolic enzymes, and drug-drug interactions. 5,6) Currently, ponatinib is the only effective TKI for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia with the acquired T315I-mutant BCR-ABL, which shows absolute resistance to other TKIs. [7][8][9] Ponatinib is known to be associated with frequent adverse events that either may be controllable events (rash: 25.7%, increased lipase: 31.4%, and hypertension: 37.1%) or severe vascular adverse events.…”

Individualized Dosing with Axitinib: Rationale and Practical Guidance

“…However, most tyrosine kinase inhibitors (TKIs) demonstrate high interpatient variability in drug exposure (depending on oral bioavailability and first-pass liver metabolism of drugs); therefore, the subsequent therapeutic effect and toxicity for the same administered dose may vary [6]. As a result, fixed dosing may result in suboptimal efficacy for some patients or excessive toxicity in others [7]. In addition, higher-than-needed doses may be excessive if therapeutic effects are already achieved at lower doses.…”

“…Approximately 30-60% of orally administered axitinib is eliminated in the feces, with a further 23% eliminated renally [13]. Variability between patients in each of the four ADME processes has a direct impact on drug exposure and helps to explain why giving a fixed standard dose of a drug to all patients will not always produce either the same anticancer effect or the same side effects [7,21]. In addition, most drug-metabolizing enzymes are polymorphic; therefore, a patient's response to treatment can be affected by genetic variation [21].…”