Individualized dosing of tyrosine kinase inhibitors: are we there yet?

Wit, Djoeke de; Guchelaar, Henk‐Jan; Hartigh, Jan den; Gelderblom, Hans; Erp, Nielka P. van

doi:10.1016/j.drudis.2014.09.007

Cited by 76 publications

(68 citation statements)

References 250 publications

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“…There is large interpatient variability in plasma imatinib concentrations for a given dose, with variable imatinib metabolism a likely major contributor (Bouchet et al, 2013;de Wit et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Impact ofCYP2C8*3polymorphism onin vitrometabolism of imatinib to N-desmethyl imatinib

2015

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1. Imatinib is metabolized to N-desmethyl imatinib by CYPs 3A4 and 2C8. The effect of CYP2C8*3 genotype on N-desmethyl imatinib formation was unknown. 2. We examined imatinib N-demethylation in human liver microsomes (HLMs) genotyped for CYP2C8*3, in CYP2C8*3/*3 pooled HLMs and in recombinant CYP2C8 and CYP3A4 enzymes. Effects of CYP-selective inhibitors on N-demethylation were also determined. 3. A single-enzyme Michaelis-Menten model with autoinhibition best fitted CYP2C8*1/*1 HLM (n = 5) and recombinant CYP2C8 kinetic data (median ± SD Ki = 139 ± 61 µM and 149 µM, respectively). Recombinant CYP3A4 showed two-site enzyme kinetics with no autoinhibition. Three of four CYP2C8*1/*3 HLMs showed single-enzyme kinetics with no autoinhibition. Binding affinity was higher in CYP2C8*1/*3 than CYP2C8*1/*1 HLM (median ± SD Km = 6 ± 2 versus 11 ± 2 µM, P=0.04). CYP2C8*3/*3 (pooled HLM) also showed high binding affinity (Km = 4 µM) and single-enzyme weak autoinhibition (Ki = 449 µM) kinetics. CYP2C8 inhibitors reduced HLM N-demethylation by 47-75%, compared to 0-30% for CYP3A4 inhibitors. 4. In conclusion, CYP2C8*3 is a gain-of-function polymorphism for imatinib N-demethylation, which appears to be mainly mediated by CYP2C8 and not CYP3A4 in vitro in HLM.

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Section: Introductionmentioning

confidence: 99%

Impact ofCYP2C8*3polymorphism onin vitrometabolism of imatinib to N-desmethyl imatinib

2015

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“…; Figure 2A shows the extent to which variations occurred between patients. Variations in axitinib exposure (expressed as coefficient of variation of up to 94%) have been previously reported; this variability in exposure is not unique to axitinib and similar variations can also be demonstrated with all other oral mRCC drugs [21,22].…”

Section: Interpatient Variability In Axitinib Exposurementioning

confidence: 93%

“…As can be expected, these factors are not the same in every patient, and there can also be differences in the impact of metabolic processes on exposure in an individual patient ( Figure 1) [21,22]. For example, absorption, distribution, metabolism and elimination (ADME) all influence drug exposure [4].…”

Section: Interpatient Variability In Axitinib Exposurementioning

confidence: 99%

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Individualized Dosing with Axitinib: Rationale and Practical Guidance

et al. 2017

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Axitinib is a potent, selective, vascular endothelial growth factor receptor inhibitor with demonstrated efficacy as second-line treatment for metastatic renal cell carcinoma. Analyses of axitinib drug exposures have demonstrated high interpatient variability in patients receiving the 5 mg twice-daily (b.i.d.) starting dose. Clinical criteria can be used to assess whether individual patients may benefit further from dose modifications, based on their safety and tolerability data. This review provides practical guidance on the 'flexible dosing' method, to help physicians identify who would benefit from dose escalations, dose reductions or continuation with manageable toxicity at the 5 mg b.i.d. dose. This flexible approach allows patients to achieve the best possible outcomes without compromising safety. Rationale for individualized dosingBefore the development of molecular targeted therapy, most available anticancer drugs, with hormone therapies and immunotherapies being notable exceptions, were chemotherapy agents: chemicals aimed at having a cytotoxic effect on cancer cells [1,2]. These drugs were dosed according to a patient's weight or body surface area, based on the observation that patients with a greater body size generally have a greater volume of distribution and require higher doses than smaller patients to reach equal drug concentrations [3]. It was thought this approach would deliver consistent systemic drug exposure, thereby optimizing treatment outcomes. This dosing approach was also chosen based on a lack of a better option at that time. However, it was known that multiple factors beyond patient size (including age, sex, renal function, hepatic function, concomitant medication, disease state and genetics) could have an impact on the actual concentration of a drug in an individual's bloodstream [4]. Consequently, there remains high variability between patients (interpatient variability) in systemic drug concentrations, even when normalized for weight/body surface area [5].When molecular targeted agents were first introduced for use in metastatic renal cell carcinoma (mRCC), these drugs were recommended at a fixed dose, based on an assumption that the maximum tolerated fixed dose would result in the best efficacy and that this same high dose would be appropriate for all patients. 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.

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“…It is reported that the max concnetrations in patients after 28 days of sunitinib administration with doses of 50 mg, 75 mg and 100 mg is about 180 nM, 354 nM and 406/499.4 nM, respectively (Faivre et al 2006). Prior studies have shown that sunitinib potently inhibited angiogenesis and tumor growth by blocking multiple receptor tyrosine kinases, including VEGFR, PDGFR, c-kit, and other receptors (de Wit et al 2015). As high concentration may reduce the specificity of sunitinib, sunitinib may affect different signaling pathways in treating different diseases.…”

Section: Discussionmentioning

confidence: 99%

Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

Huang

Wang

Yuan

et al. 2016

Tohoku J. Exp. Med.

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Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease, characterized by excessive accumulation of fibroblasts, extensive deposition of extracellular matrix, and destruction of alveolar architecture. IPF is associated with an epithelial-dependent fibroblast-activated process, termed the epithelial-to-mesenchymal transition (EMT). However, there is still a lack of strategies to target EMT for the treatment of IPF. Sunitinib, a small-molecule multi-targeted tyrosine kinase inhibitor, targets multiple kinases that may play an important role in developing pulmonary fibrosis. Here, we explored the therapeutic potential of sunitinib using a mouse model of pulmonary fibrosis. Mice received intratracheal instillation of bleomycin (BLM). Then, the mice were intragastrically administrated with sunitinib or normal saline until the end of the experiment. Distinguished destruction of pulmonary architecture, conspicuous proliferation of fibroblasts and extensive deposition of collagen fibers were found in BLM mice. Sunitinib attenuated the pulmonary fibrosis and inhibited the accumulation of fibroblasts in the lung of BLM mice. To investigate if the inhibition of fibroblast accumulation in the lung by sunitinib was associated with EMT, we used human bronchial epithelial cells (HBEs) and W138 human lung fibroblasts. Sunitinib suppressed the degree of EMT induced by TGF-β, a profibrotic factor, in HBEs and the proliferation of WI38 fibroblasts. Moreover, sunitinib reduced the degree of phosphorylation of serine residues on Smad2/3 that was induced by TGF-β in HBEs. As EMT and accumulation of fibroblasts are critical for the development of pulmonary fibrosis, targeting multiple pro-fibrosis signaling pathways with sunitinib may be a novel strategy to treat pulmonary fibrosis.

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Individualized dosing of tyrosine kinase inhibitors: are we there yet?

Cited by 76 publications

References 250 publications

Impact ofCYP2C8*3polymorphism onin vitrometabolism of imatinib to N-desmethyl imatinib

Impact ofCYP2C8*3polymorphism onin vitrometabolism of imatinib to N-desmethyl imatinib

Individualized Dosing with Axitinib: Rationale and Practical Guidance

Sunitinib, a Small-Molecule Kinase Inhibitor, Attenuates Bleomycin-Induced Pulmonary Fibrosis in Mice

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