Vatalanib population pharmacokinetics in patients with myelodysplastic syndrome: <scp>CALGB</scp> 10105 (<scp>A</scp>lliance)

Owzar, Kouros; Gupta, Pankaj; Larson, Richard A.; Mulkey, Flora; Miller, Antonius A.; Lewis, Lionel D.; Hurd, David D.; Vij, Ravi; Ratain, Mark J.; Murry, Daryl J.

doi:10.1111/bcp.12427

Cited by 7 publications

(4 citation statements)

References 30 publications

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“…In washed platelets, dasatinib, sunitinib, pazopanib, cabozantinib, and vatalanib prominently inhibited collagen-induced aggregation, while in PRP, this response was unaffected (cabozantinib and pazopanib) or required a higher concentration of the TKI to achieve inhibition (dasatinib, sunitinib, and vatalanib). For pazopanib, sunitinib, and dasatinib, this is in line with previously reported findings [ 28 , 30 , 56 ] and can be explained by high plasma-binding [ 34 , 57 , 58 , 59 ]. Indeed, in patients undergoing TKI treatment, the bioavailability of the drug is considered to be influenced by plasma binding, with implications for drug toxicity and response [ 60 ].…”

Section: Discussionsupporting

confidence: 92%

Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment

Tullemans

Veninga

Fernández

et al. 2021

IJMS

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Current antiplatelet drugs for the treatment of arterial thrombosis often coincide with increased bleeding risk. Several tyrosine kinase inhibitors (TKIs) for cancer treatment inhibit platelet function, with minor reported bleeding symptoms. The aim of this study was to compare the antiplatelet properties of eight TKIs to explore their possible repurposing as antiplatelet drugs. Samples of whole blood, platelet-rich plasma (PRP), or isolated platelets from healthy donors were treated with TKI or the vehicle. Measurements of platelet aggregation, activation, intracellular calcium mobilization, and whole-blood thrombus formation under flow were performed. Dasatinib and sunitinib dose-dependently reduced collagen-induced aggregation in PRP and washed platelets; pazopanib, cabozantinib, and vatalanib inhibited this response in washed platelets only; and fostamatinib, axitinib, and lapatinib showed no/limited effects. Fostamatinib reduced thrombus formation by approximately 50% on collagen and other substrates. Pazopanib, sunitinib, dasatinib, axitinib, and vatalanib mildly reduced thrombus formation on collagen by 10–50%. Intracellular calcium responses in isolated platelets were inhibited by dasatinib (>90%), fostamatinib (57%), sunitinib (77%), and pazopanib (82%). Upon glycoprotein-VI receptor stimulation, fostamatinib, cabozantinib, and vatalanib decreased highly activated platelet populations by approximately 15%, while increasing resting populations by 39%. In conclusion, the TKIs with the highest affinities for platelet-expressed molecular targets most strongly inhibited platelet functions. Dasatinib, fostamatinib, sunitinib, and pazopanib interfered in early collagen receptor-induced molecular-signaling compared with cabozantinib and vatalanib. Fostamatinib, sunitinib, pazopanib, and vatalanib may be promising for future evaluation as antiplatelet drugs.

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Section: Discussionsupporting

confidence: 92%

Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment

Tullemans

Veninga

Fernández

et al. 2021

IJMS

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“…). However, similar to midostaurin, both masitinib and vatalanib are also CYP3A4 inducers . While no interaction studies have been published for masitinib and trametinib, one study reports that co‐administration of vatalanib and paclitaxel, a CYP2C8 and CYP3A4 substrate, increased paclitaxel clearance by 30‐80% in patients .…”

Section: Discussionmentioning

confidence: 99%

In Vitro Screening of Six Protein Kinase Inhibitors for Time‐Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug–Drug Interactions

Filppula

Mustonen

Backman

2018

Basic Clin Pharma Tox

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Several protein kinase inhibitors have been reported to affect cytochrome P450 (CYP) 3A by time-dependent inhibition. Herein, we tested a set of six kinase inhibitors for time-dependent inhibition of CYP2C8 and CYP3A4 in human liver microsomes. Dovitinib, midostaurin and nintedanib exhibited an increased inhibition of CYP3A4 after a 30-min. pre-incubation with NADPH, as compared to no pre-incubation (IC shift >1.5). Masitinib, trametinib and vatalanib did not affect CYP2C8 or CYP3A4 by time-dependent inhibition (IC shift <1.5). The inhibitory mechanism of CYP3A4 by midostaurin and nintedanib, but not by dovitinib, was consistent with irreversible mechanism-based inhibition. The maximal inactivation rate (k ) and inhibitor concentration that supports half-maximal rate of inactivation (K ) values of midostaurin and nintedanib were 0.052 1/min. and 2.72 μM, and 0.025 1/min. and 17.3 μM, respectively. According to static predictions, inactivation of CYP3A4 by nintedanib was unlikely to cause drug-drug interactions with clinically used doses of nintedanib, whereas midostaurin was predicted to increase the plasma exposure to CYP3A4-dependent substrates several fold. Furthermore, based on reversible inhibition, masitinib and vatalanib were predicted to increase the plasma exposure to sensitive CYP2C8 and CYP3A4 substrates by ≥2-fold. In summary, our data identify midostaurin and nintedanib as time-dependent inhibitors of CYP3A4 and detect a risk of drug-drug interactions between vatalanib and CYP2C8 substrates, and between masitinib, midostaurin and vatalanib and CYP3A4 substrates. The liability of kinase inhibitors to affect CYP enzymes by time-dependent inhibition may have long-term consequences, in terms of drug-drug interactions and toxicities.

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“…Our actual findings, however, do not support this assumption: treatment with sunitinib (the tested RTKI with the lowest IC50 value against PDGFRβ, 18) significantly decreased the pericyte coverage of tumor capillaries (as assessed by desmin expression). Notably, because all the five investigated RTKIs are highly bound to plasma proteins 48-51, it is also unlikely that their distinctive intratumoral distributions are due to their different plasma protein-binding profile.…”

Section: Discussionmentioning

confidence: 99%

Limited Tumor Tissue Drug Penetration Contributes to Primary Resistance against Angiogenesis Inhibitors

Török¹,

Rezeli²,

Kelemen³

et al. 2017

Theranostics

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Resistance mechanisms against antiangiogenic drugs are unclear. Here, we correlated the antitumor and antivascular properties of five different antiangiogenic receptor tyrosine kinase inhibitors (RTKIs) (motesanib, pazopanib, sorafenib, sunitinib, vatalanib) with their intratumoral distribution data obtained by matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI). In the first mouse model, only sunitinib exhibited broad-spectrum antivascular and antitumor activities by simultaneously suppressing vascular endothelial growth factor receptor-2 (VEGFR2) and desmin expression, and by increasing intratumoral hypoxia and inhibiting both tumor growth and vascularisation significantly. Importantly, the highest and most homogeneous intratumoral drug concentrations have been found in sunitinib-treated animals. In another animal model, where - in contrast to the first model - vatalanib was detectable at homogeneously high intratumoral concentrations, the drug significantly reduced tumor growth and angiogenesis. In conclusion, the tumor tissue penetration and thus the antiangiogenic and antitumor potential of antiangiogenic RTKIs vary among the tumor models and our study demonstrates the potential of MALDI-MSI to predict the efficacy of unlabelled small molecule antiangiogenic drugs in malignant tissue. Our approach is thus a major technical and preclinical advance demonstrating that primary resistance to angiogenesis inhibitors involves limited tumor tissue drug penetration. We also conclude that MALDI-MSI may significantly contribute to the improvement of antivascular cancer therapies.

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Vatalanib population pharmacokinetics in patients with myelodysplastic syndrome: CALGB 10105 (Alliance)

Cited by 7 publications

References 30 publications

Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment

Multiparameter Evaluation of the Platelet-Inhibitory Effects of Tyrosine Kinase Inhibitors Used for Cancer Treatment

In Vitro Screening of Six Protein Kinase Inhibitors for Time‐Dependent Inhibition of CYP2C8 and CYP3A4: Possible Implications with regard to Drug–Drug Interactions

Limited Tumor Tissue Drug Penetration Contributes to Primary Resistance against Angiogenesis Inhibitors

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