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Hypertension as a predictive factor of Sunitinib activity

Posted: Sun Dec 18, 2016 7:49 am
by D.ap
Hypertension as a predictive factor of Sunitinib activity
Authors

Sunitinib malate is a new reference standard for the treatment of metastatic renal cell carcinoma (mRCC) [1, 2]. Clinical or biological markers of activity and toxicity are warranted due to large variations in treatment response, as well as side effects. Hypertension is a major toxicity observed after most antiangiogenic treatments and is a potential signal of drug exposure. We aimed to retrospectively analyze a putative correlation between sunitinib activity and hypertension.
Early and intensive antihypertensive therapy with the goal of maintaining the sunitinib® use may improve response rate in those patients
http://m.annonc.oxfordjournals.org/cont ... 2F6%2F1117

Re: Hypertension as a predictive factor of Sunitinib activity

Posted: Sun Dec 18, 2016 7:59 am
by D.ap
Blockade of Platelet-Derived Growth Factor Receptor-Beta by CDP860, a Humanized, PEGylated di-Fab', Leads to Fluid Accumulation and Is Associated With Increased Tumor Vascularized Volume

Conclusion


These observations suggest that inhibition of PDGFR-β might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.

http://ascopubs.org/doi/abs/10.1200/jco.2005.01.032

Hypertension management in
patients with renal cell cancer
treated with anti-angiogenic
agents

7. SUMMARY
Hypertension is a common adverse effect of
vegf-i treatment. The incidence of this adverse
event needs clarification, although it appears that
almost all patients have some increase in bp, and
a significant percentage develop hypertension
according to standard hypertension guidelines.
Although a short-term increase in bp will generally
not be associated with cardiovascular damage,
the need for antihypertensive therapy depends on
the degree of the increase in bp, the underlying
cardiovascular status of the patient, and other
associated risk factors. In general, vegf-i dose
reductions, vegf-i schedule changes, and treatment
discontinuations are rarely necessary in the
management of hypertension. Nearly all patients
developing hypertension are well controlled with
1 or 2 antihypertensive medications.


https://www.ncbi.nlm.nih.gov/pmc/articl ... 19-202.pdf

Challenges Associated with Tyrosine Kinase Inhibitor Therapy for Metastatic Thyroid Cancer

Posted: Sun Dec 18, 2016 10:55 am
by D.ap
Herein lies a thought with drug interactions when treating side effects like perceived high BP
With any cancer being treated, but article talks about metastic thyroid cancer.


1. Drug-Drug Interactions

Cytochrome P450 enzymes, expressed primarily in the liver, play a primary role in the metabolism of many drugs. Sunitinib, sorafenib, pazopanib, and vandetanib are all metabolized by cytochrome P450 3A4 (CYP3A4). Of the four drugs, sorafenib appears to be the least susceptible to CYP3A4 inducers or inhibitors, although the package labeling warns against concomitant use of CYP3A4 inducers [8]. Concomitant use of CYP3A4 inducers may decrease the plasma concentration of the TKI, resulting in decreased efficacy, while inhibitors may increase the plasma concentration, resulting in toxicity. Itraconazole, a potent inhibitor of CYP3A4, does not appear to affect the metabolism of vandetanib [9]. Table 2 lists the more common, clinically significant drugs metabolized via the CYP3A4 enzyme system.


The medical history should include a thorough review of medications which may affect the metabolism of the TKI. Concomitant drugs which are metabolized via CYP3A4 should be avoided or substituted for another drug. If a CYP3A4 inhibitor drug cannot be eliminated, a dose reduction in the TKI should be considered. Patients should also be monitored for increasing side effects if a CYP3A4 inhibitor is coadministered.

Table 2: Clinically significant CYP3A4 inducers, inhibitors, and substrates.
CYP3A4 inducersCYP3A4 inhibitorsCYP3A4 substrates
DexamethasoneCalcium channel blockers: amiodarone, verapamilStatins: atorvastatin, lovastatin, and simvastatin (not pravastatin) (not rosuvastatin)
Anticonvulsants: phenytoin, carbamazepineAzole antifungals: itraconazole, voriconazole, and ketoconazoleCalcium channel blockers: amlodipine, diltiazem, felodipine, nifedipine, and verapamil
Phenobarbital
RifampinMacrolide antibiotics: erythromycin, and clarithromycin (not azithromycin)
St. John’s wort
HIV antivirals: nonnucleoside reverse transcriptase inhibitors: efavirenz, and nevirapineHIV antivirals: protease inhibitors: indinavir, nelfinavir, and ritonavir

https://www.hindawi.com/journals/jtr/2011/985780/

Re: Hypertension as a predictive factor of Sunitinib activity

Posted: Sun Dec 18, 2016 11:14 am
by D.ap
I know that this is not the only possible reason that TKI's are not only working for a but a fraction of our friends and families, however there has not been a lot of focus with the re-evaluating of treating the patient with BP meds as far as I can see.
I'm a BP patient myself and I've been educated just enough to know that there all a lot of choices to the doctor and patient when it comes to lowering BP. Lifestyle is one

I hope there comes a time that we don't have to worry about this topic and cancer. :P

Love to all

Re: Hypertension as a predictive factor of Sunitinib activity

Posted: Fri Apr 28, 2017 7:58 am
by Cusuch
Angiogenesis is the target of several agents in the treatment of malignancies, including renal cell carcinoma (RCC). There is a real need for surrogate biomarkers that can predict selection of patients who may benefit from antiangiogenic therapies, prediction of disease outcome and which may improve the knowledge regarding mechanism of action of these treatments. Tyrosine kinase inhibitors (TKI) have proven efficacy in metastatic RCC (mRCC). However, the molecular mechanisms underlying the clinical response to these drugs remain unclear.

Re: Hypertension as a predictive factor of Sunitinib activity

Posted: Fri Apr 28, 2017 7:33 pm
by D.ap
Hi Cusuch

Thanks for the thought
My expertise is mom first , avid reader and I'm not pretending to know it all
Your " surrogate" reference threw me
Genomic testing?
Kinomes?

Please elaborate when able
Debbie

Re: Hypertension as a predictive factor of Sunitinib activity

Posted: Fri Apr 28, 2017 8:02 pm
by D.ap

25 Years of Small Molecular Weight Kinase Inhibitors: Potentials and Limit


From a pharmological veiw 2015

http://molpharm.aspetjournals.org/conte ... 6.full.pdf