Quantifying the relationship between inhibition of VEGF receptor 2, drug-induced blood pressure elevation and hypertension

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Abstract

<div class="section"> <a class="named-anchor" id="bph14103-sec-0001">  </a> <h5 class="section-title" id="d1023309e273">Background and Purpose</h5> <p id="d1023309e275">Several anti‐angiogenic cancer drugs that inhibit VEGF receptor (VEGFR) signalling for efficacy are associated with a 15–60% incidence of hypertension. Tyrosine kinase inhibitors (TKIs) that have off‐target activity at VEGFR‐2 may also cause blood pressure elevation as an undesirable side effect. Therefore, the ability to translate VEGFR‐2 off‐target potency into blood pressure elevation would be useful in development of novel TKIs. Here, we have sought to quantify the relationship between VEGFR‐2 inhibition and blood pressure elevation for a range of kinase inhibitors. </p> </div><div class="section"> <a class="named-anchor" id="bph14103-sec-0002">  </a> <h5 class="section-title" id="d1023309e278">Experimental Approach</h5> <p id="d1023309e280">Porcine aortic endothelial cells overexpressing VEGFR‐2 (PAE) were used to determine IC <sub>50</sub> for VEGFR‐2 phosphorylation. These IC <sub>50</sub> values were compared with published reports of exposure attained during clinical use and the corresponding incidence of all‐grade hypertension. Unbound average plasma concentration (C <sub>av,u</sub>) was selected to be the most appropriate pharmacokinetic parameter. The pharmacokinetic‐pharmacodynamic (PKPD) relationship for blood pressure elevation was investigated for selected kinase inhibitors, using data derived either from clinical papers or from rat telemetry experiments. </p> </div><div class="section"> <a class="named-anchor" id="bph14103-sec-0003">  </a> <h5 class="section-title" id="d1023309e292">Key Results</h5> <p id="d1023309e294">All‐grade hypertension was predominantly observed when the C <sub>av,u</sub> was >0.1‐fold of the VEGFR‐2 (PAE) IC <sub>50</sub>. Furthermore, based on the PKPD analysis, an exposure‐dependent blood pressure elevation >1 mmHg was observed only when the C <sub>av,u</sub> was >0.1‐fold of the VEGFR‐2 (PAE) IC <sub>50</sub>. </p> </div><div class="section"> <a class="named-anchor" id="bph14103-sec-0004">  </a> <h5 class="section-title" id="d1023309e309">Conclusions and Implications</h5> <p id="d1023309e311">Taken together, these data show that the risk of blood pressure elevation is proportional to the amount of VEGFR‐2 inhibition, and a margin of >10‐fold between VEGFR‐2 IC <sub>50</sub> and C <sub>av,u</sub> appears to confer a minimal risk of hypertension. </p> </div>

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Relationship between exposure to sunitinib and efficacy and tolerability endpoints in patients with cancer: results of a pharmacokinetic/pharmacodynamic meta-analysis.

George Demetri, B Poland, Murilo Bello … (2010)

In this pharmacokinetic/pharmacodynamic meta-analysis, we investigated relationships between clinical endpoints and sunitinib exposure in patients with advanced solid tumors, including patients with gastrointestinal stromal tumor (GIST) and metastatic renal cell carcinoma (mRCC). Pharmacodynamic data were available for 639 patients of whom 443 had pharmacokinetic data. Sunitinib doses ranged from 25 to 150 mg QD or QOD. Models to express endpoint values and/or changes from baseline by the highest-correlating exposure measures were developed in S-PLUS or NONMEM using fixed- and mixed-effects modeling. Tentative relationships were identified between (1) steady-state AUC of total drug (sunitinib + its active metabolite SU12662) and time to tumor progression (TTP), overall survival (OS), with AUC significantly associated with longer TTP and OS in patients with GIST and mRCC, and incidence, but not severity, of fatigue; (2) steady-state AUC of sunitinib and response probability, with AUC significantly associated with objective response in patients with mRCC and stable disease in patients with both mRCC and GIST (with no such correlations in patients with solid tumors); (3) dose and tumor size reductions; (4) total drug concentration and diastolic blood pressure (DBP), with a typical patient on sunitinib 50 mg QD (the recommended dose) predicted to experience a maximum DBP increase of 8 mmHg; and (5) cumulative AUC of total drug and absolute neutrophil count (ANC), with ANC reductions occurring predominantly after one treatment cycle. The results of this meta-analysis indicate that increased exposure to sunitinib is associated with improved clinical outcomes (longer TTP, longer OS, greater chance of antitumor response), as well as some increased risk of adverse effects. A sunitinib 50-mg starting dose seems reasonable, providing clinical benefit with acceptably low risk of adverse events.

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Molecular conformations, interactions, and properties associated with drug efficiency and clinical performance among VEGFR TK inhibitors.

Dana M. McTigue, H. Chen, Douglas B. Murray … (2012)

Analyses of compounds in clinical development have shown that ligand efficient-molecules with privileged physical properties and low dose are less likely to fail in the various stages of clinical testing, have fewer postapproval withdrawals, and are less likely to receive black box safety warnings. However, detailed side-by-side examination of molecular interactions and properties within single drug classes are lacking. As a class, VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) have changed the landscape of how cancer is treated, particularly in clear cell renal cell carcinoma, which is molecularly linked to the VEGF signaling axis. Despite the clear role of the molecular target, member molecules of this validated drug class exhibit distinct clinical efficacy and safety profiles in comparable renal cell carcinoma clinical studies. The first head-to-head randomized phase III comparative study between active VEGFR TKIs has confirmed significant differences in clinical performance [Rini BI, et al. (2011) Lancet 378:193-1939]. To elucidate how fundamental drug potency-efficiency is achieved and impacts differentiation within the VEGFR TKI class, we determined potencies, time dependence, selectivities, and X-ray structures of the drug-kinase complexes using a VEGFR2 TK construct inclusive of the important juxtamembrane domain. Collectively, the studies elucidate unique drug-kinase interactions that are dependent on distinct juxtamembrane domain conformations, resulting in significant potency and ligand efficiency differences. The identified structural trends are consistent with in vitro measurements, which translate well to clinical performance, underscoring a principle that may be broadly applicable to prospective drug design for optimal in vivo performance.

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THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Catalytic receptors

Stephen Ph Alexander, Doriano Fabbro, Eamonn Kelly … (2017)

The Concise Guide to PHARMACOLOGY 2017/18 provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide represents approximately 400 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13876/full. Catalytic receptors are one of the eight major pharmacological targets into which the Guide is divided, with the others being: G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, nuclear hormone receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.