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Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

Curator: Larry H Bernstein, MD, FCAP

Introduction
This is the second part of a series on toxicities of therapeutic medications, the first being on the impact on drug development of early phase failure to identify toxicities that are found in late stage trials and result in withdrawal.  This portion will go into details of identifying the effects clinically and give some examples.  In the future, the design of therapies, the identification of high probability successful genomic targets, and more accurate patient selection will transform the approach to development, clinical trials, and clinical use of pharmaceuticals in patients.

Cardiotoxicity and Cardiomyopathy

refer to: What are cardiotoxicity and cardiomyopathy?

The Scott Hamilton Cares Initiative
Cardiotoxicity is a condition of heart muscle functional impairment from toxicity as an
  • adverse secondary effect of taking an essential medication, or
  • as a result of interactions between prescribed medications that result in heart damage,
  • usually dose and time related.
If severe, the adverse effect of chemotherapy may lead to cardiomyopathy.  While cardiomyopathy might be a result of treatments, such as chemotherapeutic medications, it may also caused by a group of diseases or disorders, leading to
  • damaged myocardiocytes, and the injury leads to
  • insufficient cardiac output, referred to as
  • heart failure.
Cardiomyopathy has many causes, singly or in combination:
  • viruses – such as,
    • coxsackie B,
    • human immunodeficiency virus (HIV)
  • systemic inflammatory disorder
    • systemic lupus erythematosis
  • Amyloidosis – amyloid protein deposits in the myocardium alone, and/or other organs
  • Infection –
    • bacterial (tetanus),
    • parasitic (Chaga’s disease)
    • Rheumatic fever
  •  high blood pressure
  • Chronic or long-term alcohol use (B vitamin deficiency)
  • Endocrine disease, such as hyperthyroidism
  • Thiamine and Vitamin B deficiency
  • Radiation therapy
  • Medications – anthracyclines.

Anthracyclines may be used to treat leukemia, lymphoma, multiple myeloma, breast cancer, and sarcoma. A commonly used anthracycline is called doxorubicin (Adriamycin®).

  • cardiomyopathy may also result from genetic defects
  • illegal drugs and toxic substances, cocaine, may also produce serious myocardial damage

With certain drugs, such as doxorubicin, there is a dose at which these cardiotoxic effects on the heart may occur.
An echocardiogram, or a radionuclide ventriculography scan, is performed

  • prior to initiating a cardiotoxic medication
  • to determine baseline cardiac function., and
  • repeated at intervals to monitor heart function while receiving cardiotoxic medications.

The ejection fraction (EF) is a percentage of blood pumped out into the body during each heartbeat. An EF of 50%-75% is considered normal.

  • The lower the ejection fraction, the more severe the heart failure may be.
This may determine if the cardiotoxic drug has caused cardiomyopathy.

Symptoms of cardiomyopathy:

  • fatigue
  •  shortness of breath
  •  fever and aching of the joints,
      • all characteristic of a flu-like illness.
  • Or, sudden heart failure or sudden cardiac death without any prior symptoms.
    • swollen feet and ankles
    • distended neck veins
    • tachycardia
    • dyspnea while reclining

Diagnosis:

  • history & physical examination
  • laboratory tests
  • EKG
  • Chest x-ray
  • Echocardiography
  • Cardiac cath
  • Angiography

Treatment:

  • Dexraoxane HCL –  doxorubicin
  • ACE inhibitors
  • Beta-blockers
  • Diuretics
  • Digoxin

 Biomolecular Screening for Drug Toxicity

Multiparameter In Vitro Assessment of Compound Effects on Cardiomyocyte Physiology Using iPSC Cells

O Sirenko, C Crittenden, N Callamaras, J Hesley, Yen-Wen Chen, et al.
 A sufficient percentage of drugs fail in clinical studies due to cardiac toxicity that the development of new, sensitive in vitro assays that can evaluate potential adverse effects on cardiomyocytes is needed. Cell-based models are more clinically relevant than those used in practice. Human-induced pluripotent stem cell–derived cardiomyocytes are especially attractive because
  • they express ion channels and
  • demonstrate spontaneous mechanical and electrical activity
    • similar to adult cardiomyocytes.
This study introduces techniques for measuring the impact of pharmacologic compounds on the beating rate of cardiomyocytes with ImageXpress Micro and FLIPR Tetra systems. The assays employ
calcium-sensitive dyes to monitor changes in Ca2+ fluxes
  • synchronous with cell beating,
This method allows monitoring of the
  • beat rate
  • amplitude, and
  • other parameters.
The system detects
  • concentration-dependent atypical patterns caused by
  • hERG inhibitors and other ion channel blockers.
In addition,
  • both positive and negative chronotropic effects on cardiac rate can be observed and
  • IC50 values determined.
This methodology is well suited for safety testing and can be used to estimate efficacy and dosing of drug candidates prior to clinical studies.
J Biomol Screen Jan 2013;18(1): 39-53  http://dx.doi.org/10.1177/1087057112457590

Estimating the risk of drug-induced proarrhythmia using human induced pluripotent stem cell-derived cardiomyocytes.

L Guo, RMC Abrams, JE Babiarz, JD Cohen, S Kameoka, et al.
 Early prediction of drug-induced toxicity is needed in the pharmaceutical and biotechnology industries to decrease late-stage drug attrition.
  • Cardiotoxicity accounts for about one third of safety-based withdrawn pharmaceuticals.
This study reports a high-throughput functional assay,  detailing a model that accurately detects
  • drug-induced cardiac abnormalities.
It employs
  • induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
  • Using 96-well plates with interdigitated electrode arrays  detect
    • assess impedance,
    • the rhythmic, synchronous contractions of the iPSC-CMs
Treatment of the iPSC-CMs with 28 different compounds with known cardiac effects resulted in
  • compound-specific changes in the beat rate and/or
  • the amplitude of the impedance measurement.
Changes in impedance for the compounds tested were comparable with the results from a related technology,
  • electric field potential assessment obtained from microelectrode arrays.
Using the results from the set of compounds,
  • an index of drug-induced arrhythmias was calculated,
  • which enabled the determination of a drug’s proarrhythmic potential.
This system of interrogating human cardiac function in vitro opens new opportunities for predicting cardiac toxicity and studying cardiac biology.
Toxicol Sci. Sep 2011; 123 (1):281-9  21693436

Determination of the Human Cardiomyocyte mRNA and miRNA Differentiation Network by Fine-Scale Profiling.

JE Babiarz, M Ravon, S Sridhar, P Ravindran, B Swanson,  et al.
This study is a detailed comparison of the mRNA and miRNA transcriptomes
  • across differentiating human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and
  • biopsies from fetal, adult, and hypertensive human hearts
Gene ontology analysis of the mRNA expression levels of the hiPSCs differentiating into cardiomyocytes
revealed 3 distinct groups of genes:
  • pluripotent specific,
  • transitional cardiac specification, and
  • mature cardiomyocyte specific.
Hierarchical clustering of the mRNA data revealed that the transcriptome of hiPSC cardiomyocytes
  • stabilizes 20 days after initiation of differentiation.
But analysis of cells continuously cultured for 120 days indicated that
  • the cardiomyocytes continued to mature toward a more adult-like gene expression pattern.
Analysis of cardiomyocyte-specific miRNAs (miR-1, miR-133a/b, and miR-208a/b) revealed
  • an miRNA pattern indicative of stem cell to cardiomyocyte specification.
A biostatistitical approach integrated the miRNA and mRNA expression profiles revealing a
  • cardiomyocyte differentiation miRNA network and
  • identified putative mRNAs targeted by multiple miRNAs.
Together, these data reveal the
miRNA network in human heart development and
  • support the notion that overlapping miRNA networks
  • re-enforce transcriptional control during developmental specification.
Stem Cells Dev. 2012 Jul 20;21 (11):1956-65  22050602

Comparative Gene Expression Profiling in Human Induced Pluripotent Stem Cell Derived Cardiocytes and Human and Cynomolgus Heart Tissue.

D Puppala, LP Collis, SZ Sun, V Bonato, X Chen, B Anson, et al.  Compound Safety Prediction.
Cardiotoxicity is one of the leading causes of drug attrition. Current in vitro models insufficiently predict cardiotoxicity.  The authors describe
  • the gene expression profile of human induced pluripotent stem cell derived cardiocytes (iCC)
  • post-thaw over a period of 42 days in culture and
  • compare this profile to human fetal and adult as well as
  • adult cynomolgus nonhuman primate (NHP: Macaca fascicularis) heart tissue.
The results indicate that iCC express relevant cardiac markers such as
  • ion channels (SCN5A, KCNJ2, CACNA1C, KCNQ1 and KCNH2),
  • tissue specific structural markers (MYH6, MYLPF, MYBPC3, DES, TNNT2 and TNNI3),
  • transcription factors (NKX2.5, GATA4 and GATA6), and
  • lack the expression of stem cell markers (FOXD3, GBX2, NANOG, POU5F1, SOX2, and ZFP42).

A functional evaluation of contractility of the iCC showed

  • functional and pharmacological correlations with myocytes isolated from adult NHP hearts.
The results suggest that stem cell derived cardiocytes may represent
  • a novel in vitro model to study human cardiac toxicity with potential ex vivo and in vivo translation.
Toxicol Sci. Sep 14 2012;:   22982684

Characterization of Human Induced Pluripotent Stem Cell Derived Cardiomyocytes:
Bioenergetics and Utilization in Safety Screening.

P Rana, B Anson, S Engle, Y Will.   Compound Safety Prediction. Pfizer Global R&D, Groton CT.
Cardiotoxicity remains the number one reason for drug withdrawal from the market and FDA issued black box warnings; thus
  • demonstrating the need for more predictive preclinical safety screening,
  • especially early in the drug discovery process.
Whereas hERG screening has become routine to mitigate proarrhythmic risk,
  • the development of in vitro assays predicting additional on- and off-target biochemical toxicities
  • will benefit from cellular models exhibiting true cardiomyocyte characteristics
    • such as, native tissue-like mitochondrial activity.
An hypothesis was tested  for using human stem cell derived tissue cells by using a combination of
  • flux analysis,
  • gene and protein expression, and
  • toxicity-profiling techniques
    • to characterize mitochondrial function
    • in induced pluripotent stem cell (iPSC)-derived human cardiomyocytes
      • in the presence of differing carbon sources
      • over extended periods in cell culture.
Functional analyses demonstrate that iPSC-derived cardiomyocytes:
1) are capable of utilizing anaerobic or aerobic respiration depending upon the available carbon substrate,
2) are bioenergetically closest to adult heart tissue cells when cultured in galactose or galactose supplemented with fatty acids, and
3) show a dose dependent toxicity profile to a variety of kinase inhibitors with known clinical cardiac liabilities.
Furthermore, gene and protein expression analyses revealed that in comparison to adult cardiac tissue,
  • iPSCs-derived cardiomyocytes possess a qualitatively similar expression pattern of mitochondrial genes,
  • an up-regulation of apoptotic and antioxidant genes, and
  • a mitochondrial transcription pattern that is similar across different carbon substrates
  • despite showing changes in protein levels and functional bioenergetic adaptation.
Toxicol Sci. 2012 Jul 27;:   22843568

Decreasing cardiac chamber sizes and associated heart dysfunction in COPD – role of hyperinflation.

H Watz, B Waschki, T Meyer, G Kretschmar, A Kirsten, M Claussen, H Magnussen
This study examined the relationship of
  • lung function with heart size and heart dysfunction and
  • associated consequences for 6-minute walk distance (6MWD)
    • in patients with COPD of different severity.
METHODS:   138 patients with COPD (GOLD I-IV)
  • the size of all cardiac chambers,
  • left ventricular diastolic dysfunction (relaxation and filling), and
  • global right ventricular dysfunction (Tei-index)
    • were measured by echocardiography .
  • lung function (spirometry, bodyplethysmography, diffusion capacity) and
  • 6MWD …. were measured.
RESULTS: Size of all cardiac chambers decreased with GOLD stages. Overall,
moderate relationships existed between
  • variables of lung function and cardiac chamber sizes.
  • Static hyperinflation (inspiratory-to-total lung capacity ratio [IC/TLC],
  • functional residual capacity, and residual volume)
showed stronger associations with
  • cardiac chamber sizes than
  • airway obstruction or diffusion capacity.
IC/TLC ratio correlated best with cardiac chamber sizes and was
  • an independent predictor of cardiac chamber sizes
    • after adjustment for body surface area.
Patients with an IC/TLC ratio <!–= 0.25 had a significantly–>
  • impaired left ventricular diastolic filling pattern and
  • a significantly impaired Tei-index
    • compared to patients with an IC/TLC ratio > 0.25.
An impaired left ventricular diastolic filling pattern was independently associated with
  • a reduced 6MWD.
An increasing severity of COPD is associated with a decreasing heart size.
Hyperinflation in patients with COPD might have an important role with respect to
  • heart size and
  • cardiac dysfunction
Chest. Feb 26 2010;:   20190002  Cit:4

Cardiovascular Events After Clarithromycin Use in Lower Respiratory Tract Infections
Analysis of Two Prospective Cohort Studies

S Schembri, PA Williamson, PM Short, A Singanayagam, A Akram, et al. British Medical Journal
Acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia are common causes of admission to a hospital.
Antibiotics, including clarithromycin, are commonly prescribed during acute exacerbations of chronic obstructive pulmonary disease, especially
  • in the presence of increased breathlessness,
  • sputum volume, and
  • purulence.
 Use of macrolide antibiotics in community acquired pneumonia has been consistently associated with improved short term mortality in observational studies,
and national and international guidelines therefore recommend their use in combination with β lactams for patients admitted to hospital.

Widespread use of macrolide antibiotics has been accompanied by concerns about adverse effects on cardiovascular morbidity and mortality.
A retrospective study of erythromycin use in 1,249,943 patients identified an increase in deaths from cardiovascular disease.
Azithromycin was shown to have a similar association with increased cardiovascular deaths

  • during the time of administration.

CLARICOR (Effect of Clarithromycin on Mortality and Morbidity in Patients with Ischemic Heart Disease trial) was a double blind, placebo controlled trial
showing that a two week course of clarithromycin administered to patients with coronary heart disease 

  • increased cardiovascular and all cause mortality
The increased mortality rate (clear of pulmonary infection)
  • persisted for three years after discontinuation of the drug.

A recent meta-analysis of 17 trials of antibiotics in coronary heart disease showed

  • increased long term mortality after macrolides, primarily due
  • to increased deaths from cardiovascular disease.

However, no studies have examined the long term effect of clarithromycin on cardiovascular events and mortality in patients

  • after acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia.

Therefore, this prospective cohort study was undertaken to examine the association of clarithromycin with cardiovascular events

  • in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia.

Population.

  • 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease
  • and 1631 patients admitted with community acquired pneumonia.

Main Outcome Measures.

Hazard ratios for cardiovascular events at one year (defined as hospital admissions with

  • acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and
  • admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina).

Secondary outcomes were all cause and cardiovascular mortality at one year.

Results.

  •  268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and
  • 171 in the community acquired pneumonia cohort over one year.

After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease

  • was associated with an increased risk of cardiovascular events and acute coronary syndrome—
  • hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68).
After multivariable adjustment, clarithromycin use in community acquired pneumonia
  •  was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38)
  • but not acute coronary syndrome (1.65, 0.97 to 2.80).
This association was found between clarithromycin use in acute exacerbations of COPD and
  • cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26)
  • but not all cause mortality (1.16, 0.90 to 1.51) .

No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality.
Use of β lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with

  • acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin.

 Timing of Cardiovascular Events

The study found no significantly increased risk of cardiovascular events while patients were taking clarithromycin in the COPD cohort
(hazard ratio 1.73, 0.71 to 4.25), but
  • an increased risk was present after the clarithromycin course ended (1.41, 1.05 to 1.89).
In the community acquired pneumonia cohort, the hazard ratio for association between clarithromycin use and cardiovascular events
was 1.84 (0.75 to 4.51) during clarithromycin use and 1.66 (1.14 to 2.43) after the antibiotic was stopped.

Association With Duration of Antibiotic Use

Longer courses of clarithromycin were associated with more cardiovascular events. The median duration of treatment was seven days in both cohorts.
Less than three days of clarithromycin treatment was not associated with cardiovascular events in the chronic obstructive pulmonary disease cohort
(hazard ratio 0.89, 0.50 to 1.57) or the community acquired pneumonia cohort (0.63, 0.15-2.65), compared with patients who did not receive clarithromycin.

Effect of Age and Cardiovascular Risk Status

The hazard ratios of the effect of clarithromycin on cardiovascular events in such patients were
  • 1.35 (0.94 to 1.95) in those with a high cardiovascular risk and 0.88 (0.20 to 3.96) in those with a low risk.

The lowest hazard ratios for cardiovascular events were in patients aged 60 or below (1.01, 0.36 to 2.91).
The hazard ratio was 1.47 (1.01 to 2.14) for patients aged 60-79, and a higher risk was associated with

  • clarithromycin use in patients aged over 80 (hazard ratio 1.68, 1.05 to 2.69).

Use of Other Antibiotics

Use of β lactam or doxycycline was not associated with increased cardiovascular events
  • (hazard ratios 1.06 (0.83 to 1.37) and 0.96 (0.61 to 1.51), respectively)
in the chronic obstructive pulmonary disease cohort compared with patients not receiving antibiotics.

Possible Explanations for Findings

There was a strong association between prolonged (more than seven days) courses of clarithromycin and
  • cardiovascular events,
    • which strengthens the case for a true biological cause.

The association between duration of antibiotic treatment and cardiovascular events

  • could also represent residual confounding by severity of illness.

How do the results point to the effect on outcome after cessation of the drug?  The authors support an ischaemic mechanism.
Clarithromycin may activate macrophages, leading to an inflammatory cascade resulting in more vulnerable plaques that

  • over time may lead to acute coronary syndromes or sudden cardiac death by plaque rupture.

 Conclusion

Prolonged courses of clarithromycin (more than seven days) may be associated with

  • increased risk of cardiovascular events,
  • especially in patients with a pre-existing history of coronary heart disease.

This may be of particular importance given recent data supporting long term macrolide use

  • to prevent exacerbations of chronic obstructive pulmonary disease.

Biomarkers Role in Drug Development

Biomarkers: An indispensible addition to the drug development toolkit

Biomarkers are becoming an essential part of clinical development. In this white paper, Thomson Reuters explores
the role of biomarkers as evaluative tools in improving clinical research and the challenges this presents.
The potential of biomarkers to

  • improve decision making,
  • accelerate drug development and
  • reduce development costs

is discussed with insights into a faster alternative to the conventional drug development approach and the promise of

  • safer drugs,
  • in greater numbers,
  • approved more quickly.
The attrition rate for drugs in clinical development is high: the percentage of tested products
  • entering phase I trials that eventually gain regulatory approval has been estimated at a paltry 8%.
Many of these failures happen late in clinical trials, with the consequence that expenditure in clinical drug development is increasing.
One study calculated that the cost of developing a drug increased by over 50% between 2002 and 2007. The related concern is that
very few drugs are making it out of the clinical research pipeline.
In 2007, the FDA approved just 17 new molecular entities and 2 biologic licenses, the lowest number since 1983.
The problem is mainly due to a gap in the industry’s ability to predict a drug candidate’s performance early, and with a large degree of certainty.
The convention in clinical research has been to measure the performance of novel therapies using clinical outcomes. This approach is
laborious, inexact and, as the US Food and Drug Administration (FDA ) puts it, decades old.

Why and what kinds of biomarkers do we determine are ESSENTIAL?

Biomarkers — a measure of
  • a normal biological process in the body,
  • a pathological process, or
  • the response of the body to a therapy —
may offer information about
  • the mechanism of action of the drug,
  • its efficacy, its safety and
  • its metabolic profile.
They feature heavily in the FDA ’s Critical Path Opportunities List for their potential
  • to speed the development and approval of medical products.
  • Moreover, they can predict drug efficacy more quickly than conventional clinical endpoints.
The first three examples are measures of drug efficacy and treatment response, but are not indicators of TOXICITY.

In 1960, researchers discovered that some patients with chronic myelogenous leukemia (CML), a form of adult leukemia

  • in which there is a proliferation of myeloid cells in the bone marrow,
  • have a specific genetic change associated with their cancer, a shortened version of chromosome.

The Philadelphia chromosome is caused by a translocation between chromosomes 9 and 22. The consequence of this genetic swap

  • is the creation of the BCR-ABL ‘oncogene’;
  • this cancer-causing gene produces a protein with elevated tyrosine kinase activity
  • that induces the onset of leukemia.

Researchers were able to use the Philadelphia chromosome as a biomarker

  • to indicate which patients would benefit from drug candidates (tyrosine-kinase inhibitors)
    • specifically targeting the rogue protein.

The drug imatinib (Gleevec) is a Tyr kinase inhibitor and

  • decreases the proliferation of Philadelphia chromosome+ cells,
  • slowing the progression of the disease.

Specific mutations in the BCR–ABL gene were biomarkers that predicted resistance to imatinib,

  • leading to the development of newer tyrosine-kinase inhibitors dasatinib and nilotinib.

In the late 1980’s, scientists discovered that HIV viral load could be used as a marker of disease progression
Viral load was used to show that patients receiving combination therapy had

  • a higher reduction in viral load than those on monotherapy.

Eventually, the viral load biomarker was used in the development and assessment of Highly Active Antiretroviral Therapy (HAART)
treatment regimens taken by many people living with HIV today.

The HER-2 gene and receptor was also discovered in the mid 1980’s. Between 20–30% of breast cancer patients show an

  • over-expression of the HER-2 receptor on their cancer cells (usually postmenopausal).

This biomarker indicates a higher risk of adverse outcomes, but it gave clinicians a new target for novel therapies, and

  • the antibody trastuzumab (Herceptin) was developed
  • to target HER-2 receptors in these ‘overexpressing’ patients.

 Preventing Drug Development Disasters

The need for biomarkers to guide clinical research is perhaps best highlighted in the stories of recent drug development failures.
Between 1995 and 2005, at least 34 drugs were withdrawn from the market, mainly as a result of hepatotoxic or cardiotoxic effects.

Many of us are familiar with the withdrawal in 2004 of the anti-inflammatory drug rofecoxib (Vioxx) due to concerns about its

  • increased risk of heart attack and stroke, and more recently with
  • the extremely serious adverse effects in the phase I clinical trial and subsequent failure of the monoclonal antibody, TGN1412.

TG N1412, a ‘superagonist’, produced by the firm TeGenero, stimulates an immune response. While originally intended to treat B cell
chronic lymphocytic leukemia and rheumatoid arthritis, it had been tested pre-clinically with no toxic or pro-inflammatory effects.
In 2006, six healthy male volunteers took part in a phase I clinical trial to test the safety of the candidate. Within 90 minutes of receiving the drug,

  • all six men were experiencing the beginnings of a ‘cytokine storm’, a term that describes
  • a cascade of proinflammatory cytokine release
  • leading to organ failure due to hypotension.

Although all the men survived, they required weeks of hospitalization. The cost of a failure, such as TGN1412,

  • in terms of patient health and lost resources is huge.

The TGN1412 trial failure highlighted a need for improved preclinical safety testing. It has been suggested that had procedures using safety biomarkers to

  • guide dosing and predict the toxicity of this drug been used, the disaster may not have occurred.

Biomarkers today

Today you “would not even conceive” of developing a new drug without simultaneously looking for biomarkers for
  • efficacy,
  • safety, and
  • to measure the pharmacodynamics of the drug,
says Dr Jeffrey Ross, Head of Pathology at the Albany Medical Center in New York, involved in the original work on HER-2.
The field of oncology is leading the way in the use of biomarkers in drug development. “Clinical trials are designed upon biomarker assays,”
“abstracts of phase II and III cancer trials talk about what biomarkers were selected.
  • In vivo biomarkers,
  • imaging biomarkers,
  • blood and tissue based biomarkers,

One example of a biomarker in use in oncology is circulating tumor cells (CTCs), a biomarker present in the blood of cancer patients.
At the moment, CTCs are used in the development of anti-cancer drugs as

  • an objective and direct measurement of the response of the cancer to a novel agent.

The way that clinical trials had been done previously was to enroll all patients

  • with a given disease independent of gene or phenotypic makers.
  • By selecting a population with the particular gene which is predicted
  • to be important for response to a novel therapeutic, then
    • a smaller clinical trial should be sufficient to see whether it works or not.

The chemotherapy drug irinotecan (Camptosar) is an example of personalized medicine,

  • using a biomarker to guide both clinical practice and subsequent clinical trials.

Irinotecan is used to treat advanced colorectal cancer. Once administered, irinotecan is

  • activated to the metabolite SN-38, and then
  • eventually inactivated in the body by the UGT1A1 enzyme.

In 2005, the US Food and Drug Administration added a warning to the label of the drug, stating that patients

  • homozygous for a particular a version of the UGT1A1 gene — the UGT1A1*28 allele,
  • associated with decreased UGT1A1 enzyme activity —
    • should be given a reduced dose.
Because patients with this allele clear the drug less quickly from their body than the rest of the population,
  • they effectively receive a greater exposure to the drug from the same dose.
As a consequence, they are at higher risk of potentially life-threatening side effects such as neutropenia (a decrease in white blood cells) and diarrhea.
The toxicity of irinotecan has long been a concern, and this biomarker now allows clinicians to better identify those patients who are at high risk of
  • serious side-effects (about 10% of the population are homozygous for UGT1A1*28).
And while this pharmacogenomics information has helped improve the clinical use and efficacy of irinotecan, it has also fed back into
the development of other drugs; this new understanding prompted the use of the UGT1A1 biomarker to guide other studies,
including several new irinotecan and oxaliplatin-based chemotherapy regimens.

Using preclinical biomarkers as evidence of efficacy

  • biomarkers can accelerate research by substituting for clinical symptoms as a measure of efficacy.
  • biomarkers can also replace clinical symptoms when it comes to measuring drug safety
  • an efficacy biomarker plus a safety biomarker will define not just whether a drug will work, but also what kind of dose might be relevant in humans

 Improving efficacy in cardiology

Consider the role of inflammatory marker C-reactive-protein (CRP) in cardiovascular disease. CRP is released by inflamed atherosclerotic plaques in the arteries
of individuals with coronary heart disease, and increased levels of CRP are associated with a greater risk of plaque rupture, but also of a silent heart attack.
CRP is being used as a biomarker to measure drug efficacy, in particular whether rosuvastatin (Crestor)

  • reduces the risk of cardiovascular morbidity and mortality
  • in apparently healthy individuals with low LDL-cholesterol levels but elevated CRP.

The JUPITER study (Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin) was halted in March 2008

  • due to firm evidence that the drug is indeed more beneficial than placebo and
  • improves the prognosis of individuals with high CRP levels.
A related biomarker of cardiovascular risk called neopterin. Just as CRP is produced by inflamed atherosclerotic plaques at risk of rupture,
neopterin is produced by activated macrophages in this inflammatory process. Circulating neopterin levels are higher in patients with ACS and may be
a marker of coronary disease activity. In addition, “Neopterin could also potentially be a marker of drug efficacy because
if you reduce the number of active macrophages in the plaque or the circulation, the levels of neopterin also decrease,” says Dr Juan Carlos Kaski,
Professor of Cardiovascular Science and Director of the Cardiovascular Biology Research Centre at St George’s University of London.

Other uses of biomarkers

These types of biomarkers can be used to drive critical ‘go/no go’ decision in drug development
Mechanistic or ‘target’ biomarkers can be used in pre-clinical or phase I trials to measure the pharmacological effect of the drug, i.e.
  • whether the drug interacts with its receptor, enzyme, or protein target,
  • whether it is distributed to the site where it needs to act,whether there is some
    • form of downstream pharmacology, and
  • the dose ranges in which the drug is pharmacologically active.
Drugs such as 5-HT4 receptor agonists (e.g. cisapride, mosapride), used in gastro-esophageal reflux disease (GERD), stimulate
  • the secretion of aldosterone as a side-effect.
Although aldosterone is not linked to GERD (and can’t be used as a biomarker of the disease), the hormone can be used
  • as a mechanistic biomarker in drug development to assess whether
    • novel 5-HT4 agonists in development have a pharmacological effect.

Discovering new biomarkers

The fundamental issue we have to deal with, both with target selection and developing better biomarkers,
  • is a better understanding of pathophysiology.
The clinical need is huge, not least in diseases like chronic obstructive pulmonary disease (COPD), an illness about which we know very little.

“COPD has very few markers to indicate severity and disease progression,” says Dr Trevor Hansel, Medical Director of the National Heart &
Lung Institute Clinical Studies Unit in London. Many pharmaceutical companies have begun to invest in ‘omics’ —

  • genomics,
  • proteomics,
  • metabonomics —

to begin to sort through this mountain of molecules and characterize biomarkers based on a molecular understanding of disease.

The ‘omics’ approach enables
  • the detection of small changes in tissue composition through protein profiling technologies such as
  • mass spectrometry and gel electrophoresis.

Essentially, it is about capturing a molecular profile from a clinical sample and converting this into

  • information about a clinical condition — for example the stage of disease or
  • what players are involved in the disease pathways.
“We will be able to look at diseases and catagorize them based on
  • biochemical or physiological findings, rather than just on symptoms” …  David Roblin, Pfizer

Companion Diagnostics and the Drug–Diagnostic Codevelopment Model

 Jan Trøst Jørgensen   Drug Development Research Nov 2012; 73(7):390-397.   http://dx.doi.org/10.1002/ddr.21029

The concept of using a predictive or selective diagnostic assay in relation to drug development goes back to the 1970s when

  • the selective estrogen receptor modulator, tamoxifen (AstraZeneca) was developed for metastatic breast cancer.
Clinical data showed that the estrogen receptor status correlated well with the clinical outcome when the patients were treated with tamoxifen.
It is only within the last decade that this model has gained widespread acceptance. The drug and the diagnostic are interdependent, and
if the development project proves successful, the companion diagnostic assay (CoDx) will end up determining the conditions for the use of the drug.
This gatekeeper role obviously requires that the CoDx assays adhere to the same strict rules and regulations that are known from the development of drugs.
For any CoDx assay, it must be documented that it is robust and reliable and that it possesses clinical utility. The article focus on some of the most important
aspects of the CoDx development process with emphasis on the clinical validation and clinical utility but also other critical issues, such as,
  • the biomarker selection process,
  • determination of the cut-off value, and
  • the analytical validation.

 Detecting Potential Toxicity in Mitochondria

 Brad Larson, Principal Scientist; Peter Banks, Scientific Director; BioTek Instruments, Winooski, Vt.
Mitochondrial dysfunction may be
  • inherited,
  • arise spontaneously, or
  • develop as a result of drug toxicity.
Mitochondrial toxicity as a result of pharmaceutical use may damage key organs, such as the liver and heart. For example,
  • nefazodone—a depression treatment—was withdrawn from the U.S. market after it was shown to
significantly inhibit mitochondrial respiration in liver cells, leading to liver failure. Troglitazone, an anti-diabetic and anti-inflammatory,
was withdrawn from all markets after research concluded that it caused acute mitochondrial membrane depolarization, also leading to liver failure.
Drug recalls are costly to a manufacturer’s bottom line and reputation, and more importantly, can be harmful or even fatal to users. As drug
discovery continues to evolve, much lead compound research now includes careful review of its interaction and potential toxicity with mitochondria.
Cytotoxicity and ATP production are measured in cancerous and normal hepatocytes using a known inducer of cellular necrosis. (All figures: BioTek Instruments)
Cell-based mitochondrial assays in microplate format may include
  • mitochondrial membrane potential,
  • total energy metabolism,
  • oxygen consumption, and
  • metabolic activity;
and offer a truer environment for mitochondrial function in the presence of drug compounds compared to isolated mitochondria-based tests.
Combining more than one assay in a multiplex format increases the amount of data per well while decreasing data variability arising from running the assays separately.
The aggregated data also provides a more encompassing analysis of the drug’s effect on mitochondria than a single test.
Human cardiac muscle

Human cardiac muscle (Photo credit: Carolina Biological Supply Company)

English: Non-sustained run of ventricular tach...

English: Non-sustained run of ventricular tachycardia on telemonitoring from a patient with chemotherapy-induced cardiomyopathy. (Photo credit: Wikipedia)

English: Doxorubicin 3D model Русский: Трёхмер...

English: Doxorubicin 3D model Русский: Трёхмерная модель молекулы доксорубицина (Photo credit: Wikipedia)

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UPDATED: PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 9/1/2019

Extended DAPT with Brilinta: No Benefit for Stable CAD in T2D

Substudy in those with prior PCI might identify group where bleeding tradeoff is worthwhile

PARIS — Ticagrelor (Brilinta) as part of a dual antiplatelet therapy (DAPT) regimen didn’t improve net outcomes for stable coronary artery disease (CAD) among type 2 diabetes patients, except perhaps in the setting of percutaneous coronary intervention (PCI), the THEMIS trial showed.

Adding the potent antiplatelet agent to aspirin reduced cardiovascular (CV) death, myocardial infarction (MI), or stroke (7.7% vs 8.5%, HR 0.90, 95% CI 0.81-0.99), reported Deepak Bhatt, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, at the European Society of Cardiology (ESC) congress and online in the New England Journal of Medicine.

But it also increased

  • TIMI major bleeding (2.2% vs 1.0%, HR 2.32, 95% CI 1.82-2.94) and
  • intracranial hemorrhage (0.7% vs 0.5%, HR 1.71, 95% CI 1.18- 2.48) over aspirin alone, albeit
  • without more fatal bleeding (0.2% vs 0.1%, P=0.11).

The combined effect was neutral for the exploratory composite outcome of “irreversible harm” (death from any cause, MI, stroke, fatal bleeding, or intracranial hemorrhage 10.1% vs 10.8%, HR 0.93, 95% CI 0.86-1.02).

ESC session study discussant Colin Baigent, MD, of Oxford University in England, actually calculated 12 major bleeds for every eight events prevented.

“This is a consistent story: when we add an antiplatelet agent for risk reduction, we increase the risk of bleeding,” noted Richard Kovacs, MD, of Indiana University in Indianapolis and president of the American College of Cardiology.

THEMIS is the final part of a largely-disappointing PARTHENON development program for ticagrelor, he noted. “It hasn’t changed practice. …Will the main THEMIS trial change clinical practice? In my opinion, no.”

SOURCE

https://www.medpagetoday.com/meetingcoverage/esc/81925?xid=nl_mpt_ACC_Reporter_2019-09-01&eun=g5099207d2r

 

UPDATED on 10/4/2016

Soriot’s $3.5B Brilinta dream is dashed by yet another big trial flop for AstraZeneca

by john carroll
October 4, 2016 09:00 AM EDT
Updated: 09:33 AM

Brilinta, the drug failed to demonstrate a benefit over generic Plavix (clopidogrel) for peripheral artery disease. Back in March, the heart drug flopped in a large stroke study, unable to prove that it could beat aspirin. And Soriot can chalk up those expensive studies to proving Brilinta’s serious deficiencies.

“We don’t believe the goal of $3.5 billion is attainable. I think it would be unrealistic to believe that,” Ludovic Helfgott, head of AstraZeneca’s Brilinta business, told Reuters.

Brilinta brought in a total of $619 million last year after disappointing analysts repeatedly with lower-than-expected quarterly revenue.

Heart studies aren’t cheap. AstraZeneca recruited 13,500 patients for the EUCLID study, and it had enrolled close to that number for the earlier SOCRATES trial.

SOURCE

http://endpts.com/soriots-3-5b-brilinta-dream-is-dashed-by-yet-another-big-trial-flop-for-astrazeneca/?utm_medium=email&utm_campaign=75%20Dinner%20with%20Brent&utm_content=75%20Dinner%20with%20Brent+CID_8008d3b4f16d90576238cceef624d211&utm_source=ENDPOINTS%20emails&utm_term=Soriots%2035B%20Brilinta%20dream%20is%20dashed%20by%20yet%20another%20big%20trial%20flop%20for%20AstraZeneca

UPDATED on 9/4/2014

Prehospital Ticagrelor in ST-Segment Elevation Myocardial Infarction

Gilles Montalescot, M.D., Ph.D., Arnoud W. van ‘t Hof, M.D., Ph.D., Frédéric Lapostolle, M.D., Ph.D., Johanne Silvain, M.D., Ph.D., Jens Flensted Lassen, M.D., Ph.D., Leonardo Bolognese, M.D., Warren J. Cantor, M.D., Ángel Cequier, M.D., Ph.D., Mohamed Chettibi, M.D., Ph.D., Shaun G. Goodman, M.D., Christopher J. Hammett, M.B., Ch.B., M.D., Kurt Huber, M.D., Magnus Janzon, M.D., Ph.D., Béla Merkely, M.D., Ph.D., Robert F. Storey, M.D., D.M., Uwe Zeymer, M.D., Olivier Stibbe, M.D., Patrick Ecollan, M.D., Wim M.J.M. Heutz, M.D., Eva Swahn, M.D., Ph.D., Jean-Philippe Collet, M.D., Ph.D., Frank F. Willems, M.D., Ph.D., Caroline Baradat, M.Sc., Muriel Licour, M.Sc., Anne Tsatsaris, M.D., Eric Vicaut, M.D., Ph.D., and Christian W. Hamm, M.D., Ph.D. for the ATLANTIC Investigators

September 1, 2014DOI: 10.1056/NEJMoa1407024

BACKGROUND

The direct-acting platelet P2Y12 receptor antagonist ticagrelor can reduce the incidence of major adverse cardiovascular events when administered at hospital admission to patients with ST-segment elevation myocardial infarction (STEMI). Whether prehospital administration of ticagrelor can improve coronary reperfusion and the clinical outcome is unknown.

METHODS

We conducted an international, multicenter, randomized, double-blind study involving 1862 patients with ongoing STEMI of less than 6 hours’ duration, comparing prehospital (in the ambulance) versus in-hospital (in the catheterization laboratory) treatment with ticagrelor. The coprimary end points were the proportion of patients who did not have a 70% or greater resolution of ST-segment elevation before percutaneous coronary intervention (PCI) and the proportion of patients who did not have Thrombolysis in Myocardial Infarction flow grade 3 in the infarct-related artery at initial angiography. Secondary end points included the rates of major adverse cardiovascular events and definite stent thrombosis at 30 days.

RESULTS

The median time from randomization to angiography was 48 minutes, and the median time difference between the two treatment strategies was 31 minutes. The two coprimary end points did not differ significantly between the prehospital and in-hospital groups. The absence of ST-segment elevation resolution of 70% or greater after PCI (a secondary end point) was reported for 42.5% and 47.5% of the patients, respectively. The rates of major adverse cardiovascular events did not differ significantly between the two study groups. The rates of definite stent thrombosis were lower in the prehospital group than in the in-hospital group (0% vs. 0.8% in the first 24 hours; 0.2% vs. 1.2% at 30 days). Rates of major bleeding events were low and virtually identical in the two groups, regardless of the bleeding definition used.

CONCLUSIONS

Prehospital administration of ticagrelor in patients with acute STEMI appeared to be safe but did not improve pre-PCI coronary reperfusion. (Funded by AstraZeneca; ATLANTIC ClinicalTrials.gov number, NCT01347580.)

SOURCE

http://www.nejm.org/doi/full/10.1056/NEJMoa1407024?query=TOC

 

 

UPDATED on 2/7/2014

PLATO Controversy Hits the Wall Street Journal

February 05, 2014

NEW YORK, NY – The controversy surrounding the PLATOtrial of ticagrelor (Brilinta, AstraZeneca) continues unabated, according to a story published in the Wall Street Journal. Specifically, a sealed complaint filed in US district court in the District of Columbia by a researcher contends that the cardiovascular events in the study “may have been manipulated” [1].

Dr Victor Serebruany (HeartDrug Research Laboratories, Johns Hopkins University, Towson, MD), who has long been a thorn in the side of AstraZeneca and the PLATO investigators, filed the complaint under the False Claims Act, reports theWall Street Journal. The Journal notes that the US attorney’s office in Washington, DC, has contacted Serebruany and is currently investigating the clinical trial.As reported by heartwirein October 2013, the US Department of Justice issued a civil investigative demand from its civil division “seeking documents and information regarding PLATO.” AstraZeneca is complying with the request.

First reported by heart wirein 2009 , the PLATO trial was a positive study involving more 18 000 patients from 43 countries. PLATO investigators, led by Dr Lars Wallentin (Uppsala Clinical Research Center, Sweden), showed that treating acute coronary syndrome patients with ticagrelor significantly reduced the rate of MI, stroke, and cardiovascular death compared with patients taking clopidogrel. Results were presented at the European Society of Cardiology 2009 Congress and reported in the New England Journal of Medicine.

PLATO has been dogged by questions, including prior to approval. In the sealed complaint, Serebruany takes issue with a number of things, many of which have been reported previously. He alleges that the

  • number of clinical events among those taking clopidogrel was high compared with other studies, pointing out that the rate of all-cause death was 5.9% among clopidogrel-treated patients—nearly twice as high as earlier studies. In addition,
  • the sealed complaint documents the geographic discrepancies in the trial, noting there was a trend toward worse outcomes with ticagrelor at North American sites.The complaint also alleges that
  • an initial count of clinical events suggested the two drugs were equivalent, but adjudication by the Duke Clinical Research Institute attributed another 45 MIs to the clopidogrel group, which tipped the results in favor of ticagrelor. Other questions raised about the study include
  • site monitoring and timing of clinical events. Serebruany also alleges that
  • the trial may have unintentionally been unblinded because of the shape of clopidogrel’s “split capsules,” which would have enabled doctors and nurses to know which drug patients received.

AstraZeneca rebutted these issues, telling the Journal that it is cooperating with the government. It said it is confident in the integrity of the trial and noted the overall study showed the superiority of ticagrelor over clopidogrel. There is no evidence the trial was unblinded and researchers used the same standards when qualifying all clinical events, including MIs, they noted. In addition, the company said it is not possible to compare event rates with clopidogrel in PLATO with other studies because the patient populations differ.

The Journal reports that Serebruany became embroiled in the controversy when asked by the FDA‘s Dr Thomas Marciniak to advise the agency about the PLATO data in 2010. Marciniak, who led the FDA’s review of PLATO, called AstraZeneca’s submission on serious adverse events the “worst submission” he ever encountered. According to the submission, he noted, 12 patients reported their own deaths by telephone. Before approving ticagrelor, the FDA requested an additional analysis of PLATO, and it was eventually approved in the US in July 2011. Ticagrelor was approved in Europe in December 2010 and is authorized for use in more than 100 countries.

The Journal called Serebruany an expert in the antiplatelet field but said he is a “controversial figure,” partly because of his financial ties to industry and repeated criticisms of new drug approvals. Through HeartDrug Research, Serebruany has worked on prasugrel (Effient, Lily/Daiichi-Sankyo), a competing antiplatelet agent, but has also done work for AstraZeneca.

REFERENCE

Burton TM. Doctor challenges testing of AstraZeneca’s Brilinta. Wall Street Journal, February 2, 2014. Available here.

SOURCE

http://www.medscape.com/viewarticle/820236?nlid=47583_1984&src=wnl_edit_medn_card&uac=93761AJ&spon=2

UPDATED 3/28/2013

How AstraZeneca Will Use A Diagnostic To Market Its Blood Thinner

by Matthew Harper, Forbes Staff on 3/21/2013

Earlier today I wrote about how AstraZeneca is telling investors that its blood-thinner Brilinta, used to prevent second heart attacks, could be a multi-billion dollar drug, at least twice as big as Wall Street analysts expect. So far the drug has been a disappointment.

I wrote:

Another key data point Astra presented was that blood levels of troponin, a muscle protein released by the heart during a heart attack, predict which patients get the most benefit from Brilinta. This data is not in AstraZeneca’s label, but a spokeswoman said that she believed it would be something the company can market to doctors.

via Can Pascal Soriot Turn Around AstraZeneca? It May Come Down To One Drug – Forbes.

But will the Food and Drug Administration allow Astra to tell doctors that? Stratification using troponin is not in Brilinta’s FDA-approved label, and off-label promotion is illegal. But Ferguson says that communications about troponin will be allowed because all patients with high troponin are patients who would be included in the FDA-approved indication. He confirms that use of troponin testing will be part of the new marketing plan for Brilinta.

SOURCE:

http://www.forbes.com/sites/matthewherper/2013/03/21/how-astrazeneca-will-use-a-diagnostic-to-market-its-blood-thinner/

Can Pascal Soriot Turn Around AstraZeneca? It May Come Down To One Drug

by Matthew Herper, Forbes Staff on 3/21/2013

This morning in New York, new AstraZeneca chief executive Pascal Soriot is telling investors how he is going to turn around the company that has had the absolute worst track record in research and development among any big pharmaceutical firm. The plan is fairly wide-ranging and involves a lot of the steps one might expect:

  • new layoffs (2,300 jobs);
  • a re-focusing of research and development on three areas: heart disease and diabetes; oncology; and respiratory and inflammation;
  • new R&D initiatives involving Moderna, a biotech company, and the Karolinska Instutet;
  • moving the company’s headquarters to its R&D hub in Cambridge, U.K.;
  • re-focusing on emerging markets, where AZ already gets $6 billion in sales, especially China.

But the short-term key to delivering on his promises today seems to come down to a single drug: Brilinta, the Plavix competitor thatAstraZeneca introduced in 2011 which has so far disappointed, generating  just $324 $89 million in global sales last year. This is a medicine to prevent heart attacks and strokes in patients who suffer acute coronary syndrome, the condition that occurs after a heart attack or serious heart-related chest pain. It works by preventing the formation of blood clots.

Plavix was the second biggest drug in the world, with $6 billion in annual sales, but it is now generic. The conventional wisdom is that it will be difficult to compete with cheap generics. Brilinta is actually trailing Effient, a similar medicine from Eli Lilly, in usage. Wall Street consensus currently sees Brilinta growing to become a moderate-sized drug in 2018, with $1.3 billion in annual sales. But AstraZeneca is saying that it thinks Brilinta can be a multi-billion dollar product. Astra has confirmed that this means Brilinta will have to surpass Effient. The newer drugs also cause more bleeding than Plavix.

What is the company’s argument? In his presentation today, Paul Hudson, Astra’s Executive Vice President, North America, said that the key would be focusing on one key fact: Brilinta reduced cardiovascular deaths by 21% compared to Plavix in a big clinical trial. That would mean that if everyone eligible for Brilinta got it, 100,000 lives would be saved.

But the reality is that doctors have been skeptical of that data because in the part of that trial that was run in North America, the benefit was less clear. AstraZeneca says that this may have been due to an interaction of Brilinta and aspirin and that, according to current cardiovascular guidelines, doctors should be prescribing less aspirin anyway.

Another key data point Astra presented was that blood levels of troponin, a muscle protein released by the heart during a heart attack, predict which patients get the most benefit from Brilinta. This data is not in AstraZeneca’s label, but a spokeswoman said that she believed it would be something the company can market to doctors.

A lot of what Astra will do in the short term on Brilinta will be blocking and tackling. It needs to pay bigger rebates to insurers to make sure that patients can get cheap access to the drug. (This is how discounts happen in the American insurance system: the patient pays a co-payment and the insurer pays full price for the drug, but then the drug maker gives the insurer money back to make the end cost cheaper.) It will also be doing a lot of medical marketing, involving its internal experts or paid, external doctors, to get the word out about the benefits of Brilinta.

Brilinta has other advantages (it stops acting quickly) and disadvantages (it must be given twice a day). But the other big question for expanding results is whether large clinical trials that are now ongoing will show that it works in a broader array of heart patients. Astra is starting a big trial to show Brilinta prevents strokes. These trials are risky and expensive, but there will be a big payoff if they work.

Astra has some other commercial levers to point to. It’s diabetes pill Onglyza, which is sold with Bristol-Myers Squibb, will have results in a big study of its efficacy in preventing heart disease before a similar study of Merck’s top-selling Januvia, which started first. Soriot has smart ideas about which drugs to advance into later testing. But Brilinta is going to be the biggest single indicator of whether Soriot’s new strategies are paying off.

SOURCE:

http://www.forbes.com/sites/matthewherper/2013/03/21/can-pascal-soriot-turn-around-astrazeneca-it-may-come-down-to-one-drug/

BRILINTA is an antiplatelet medication

Taking BRILINTA is a first step in the treatment your physician has chosen for you. At BRILINTA.com, you will find helpful information and useful learning tools to help you complete your course of BRILINTA therapy. Make sure you and your loved ones read through all of the sections.

What is BRILINTA?

BRILINTA is a type of prescription antiplatelet medication for people who have had a recent heart attack or severe chest pain that happened because their heart wasn’t getting enough oxygen and who are being treated with medicines or procedures to open blocked arteries in the heart. BRILINTA is used with aspirin to stop platelets from sticking together and forming a blood clot that could block blood flow to the heart and cause another, possibly fatal, heart attack. Platelets are small cells in the blood that help with normal blood clotting.

Take BRILINTA and aspirin exactly as instructed by your doctor: BRILINTA twice a day, plus one 81-mg aspirin tablet once a day. You should not take a dose of aspirin higher than 100 mg each day because it can affect how well BRILINTA works. Tell your doctor about any medicines you are taking that contain aspirin. Do not take any new medicines that contain aspirin.

Why BRILINTA?

BRILINTA used with aspirin lowers your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clots in your stent if you received one. These can be fatal. In fact, in a large clinical study BRILINTA was even better than Plavix® (clopidogrel bisulfate) tablets at lowering your chances of having another heart attack.

BRILINTA is used to lower your chance of having another heart attack or dying from a heart attack, but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death.

Complete the
Course
 Program

IMPORTANT SAFETY INFORMATION ABOUT BRILINTA

BRILINTA is used to lower your chance of having another heart attack or dying from a heart attack or stroke, but BRILINTA (and similar drugs) can cause bleeding that can be serious and sometimes lead to death. Instances of serious bleeding, such as internal bleeding, may require blood transfusions or surgery. While you take BRILINTA, you may bruise and bleed more easily and be more likely to have nosebleeds. Bleeding will also take longer than usual to stop.

Call your doctor right away if you have any signs or symptoms of bleeding while taking BRILINTA, including: severe, uncontrollable bleeding; pink, red, or brown urine; vomit that is bloody or looks like coffee grounds; red or black stool; or if you cough up blood or blood clots.

Do not stop taking BRILINTA without talking to the doctor who prescribes it for you. People who are treated with a stent, and stop taking BRILINTA too soon, have a higher risk of getting a blood clot in the stent, having a heart attack, or dying. If you stop BRILINTA because of bleeding, or for other reasons, your risk of a heart attack or stroke may increase. Tell all your doctors and dentists that you are taking BRILINTA. To decrease your risk of bleeding, your doctor may instruct you to stop taking BRILINTA 5 days before you have elective surgery. Your doctor should tell you when to start taking BRILINTA again, as soon as possible after surgery.

Take BRILINTA and aspirin exactly as instructed by your doctor. You should not take a dose of aspirin higher than 100 mg daily because it can affect how well BRILINTA works. Tell your doctor if you take other medicines that contain aspirin. Do not take new medicines that contain aspirin.

Do not take BRILINTA if you are bleeding now, especially from your stomach or intestine (ulcer), have a history of bleeding in the brain, or have severe liver problems.

BRILINTA can cause serious side effects, including bleeding and shortness of breath. Call your doctor if you have new or unexpected shortness of breath or any side effect that bothers you or that does not go away. Your doctor can decide what treatment is needed.

Tell your doctor about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. BRILINTA may affect the way other medicines work, and other medicines may affect how BRILINTA works.

Approved uses
BRILINTA is a prescription medicine for people who have had a recent heart attack or severe chest pain that happened because their heart wasn’t getting enough oxygen and who are being treated with medicines or procedures to open blocked arteries in the heart.

BRILINTA is used with aspirin to lower your chance of having another serious problem with your heart or blood vessels such as heart attack, stroke, or blood clots in your stent if you received one. These can be fatal.

Please read Prescribing Information, including Boxed WARNINGS.

Please read Medication Guide.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

If you are without prescription coverage and cannot afford your medication, AstraZeneca may be able to help. For more information, please visit www.AstraZeneca.com.

This product information is intended for US consumers only.

BRILINTA is a trademark of the AstraZeneca group of companies.

Plavix® is a registered trademark of sanofi-aventis.

©2012 AstraZeneca.706809-1789005 8/12

SOURCE:

http://www.brilinta.com/antiplatelet-prescription-medication.aspx#au

http://www1.astrazeneca-us.com/pi/brilinta.pdf

BRILINTA (ticagrelor)

Ticagrelor (trade name Brilinta in the US, Brilique and Possia in the EU) is a platelet aggregation inhibitor produced by AstraZeneca. The drug was approved for use in the European Union by the European Commission on December 3, 2010.[1][2] The drug was approved by the US Food and Drug Administrationon July 20, 2011.[3]

Indications

Ticagrelor is indicated for the prevention of thrombotic events (for example stroke or heart attack) in patients with acute coronary syndrome or myocardial infarction with ST elevation. The drug is combined with acetylsalicylic acid unless the latter is contraindicated.[4] Treatment of acute coronary syndrome with ticagrelor as compared with clopidogrel significantly reduces the rate of death.[5]

Contraindications

Contraindications for ticagrelor are: active pathological bleeding and a history of intracranial bleeding, as well as reduced liver function and combination with drugs that strongly influence activity of the liver enzymeCYP3A4, because the drug is metabolized via CYP3A4 and excreted via the liver.[4]

Adverse effects

The most common side effects are shortness of breath (dyspnea, 14%)[6] and various types of bleeding, such as hematomanosebleedgastrointestinalsubcutaneous or dermal bleeding. Allergic skin reactions such as rash and itching have been observed in less than 1% of patients.[4]

Physical and chemical properties

Ticagrelor is a nucleoside analogue: the cyclopentane ring is similar to the sugar ribose, and the nitrogen rich aromatic ring system resembles the nucleobase purine, giving the molecule an overall similarity toadenosine. The substance has low solubility and low permeability under the Biopharmaceutics Classification System.[1]

Ticagrelor as a nucleoside analogue

The nucleoside adenosinefor comparison

Pharmacokinetics

Ticagrelor is absorbed quickly from the gut, the bioavailability being 36%, and reaches its peak concentration after about 1.5 hours. The main metabolite, AR-C124910XX, is formed quickly via CYP3A4 by de-hydroxyethylation at position 5 of the cyclopentane ring.[7] It peaks after about 2.5 hours. Both ticagrelor and AR-C124910XX are bound to plasma proteins (>99.7%), and both are pharmacologically active. Blood plasma concentrations are linearly dependent on the dose up to 1260 mg (the sevenfold daily dose). The metabolite reaches 30–40% of ticagrelor’s plasma concentrations. Drug and metabolite are mainly excreted via bile and feces.

Plasma concentrations of ticagrelor are slightly increased (12–23%) in elderly patients, women, patients of Asian ethnicity, and patients with mild hepatic impairment. They are decreased in patients that described themselves as ‘coloured’ and such with severe renal impairment. These differences are considered clinically irrelevant. In Japanese people, concentrations are 40% higher than in Caucasians, or 20% after body weight correction. The drug has not been tested in patients with severe hepatic impairment.[4]

Mechanism of action

Like the thienopyridines prasugrelclopidogrel and ticlopidine, ticagrelor blocks adenosine diphosphate (ADP) receptors of subtype P2Y12. In contrast to the other antiplatelet drugs, ticagrelor has a binding site different from ADP, making it an allosteric antagonist, and the blockage is reversible.[8] Moreover, the drug does not need hepatic activation, which might work better for patients with genetic variants regarding the enzyme CYP2C19 (although it is not certain whether clopidogrel is significantly influenced by such variants).[9][10][11]

Comparison with clopidogrel

The PLATO trial, funded by AstraZeneca, in mid-2009 found that ticagrelor had better mortality rates than clopidogrel (9.8% vs. 11.7%, p<0.001) in treating patients with acute coronary syndrome. Patients given ticagrelor were less likely to die from vascular causes, heart attack, or stroke but had greater chances of non-lethal bleeding (16.1% vs. 14.6%, p=0.0084), higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding. Rates of major bleeding were not different. Discontinuation of the study drug due to adverse events occurred more frequently with ticagrelor than with clopidogrel (in 7.4% of patients vs. 6.0%, P<0.001)[5] The PLATO trial showed a statistically insignificant trend toward worse outcomes with ticagrelor versus clopidogrel among US patients in the study – who comprised 1800 of the total 18,624 patients. The HR actually reversed for the composite end point cardiovascular (death, MI, or stroke): 12.6% for patients given ticagrelor and 10.1% for patients given clopidogrel (HR = 1.27). Some believe the results could be due to differences in aspirin maintenance doses, which are higher in the United States.[12] Others state that the central adjudicating committees found an extra 45 MIs in the clopidogrel (comparator) arm but none in the ticagrelor arm, which improved the MI outcomes with ticagrelor. Without this adjudication the trials’ primary efficacy outcomes should not be significant[13]

Consistently with its reversible mode of action, ticagrelor is known to act faster and shorter than clopidogrel.[14] This means it has to be taken twice instead of once a day which is a disadvantage in respect of compliance, but its effects are more quickly reversible which can be useful before surgery or if side effects occur.[4][15]

Interactions

Inhibitors of the liver enzyme CYP3A4, such as ketoconazole and possibly grapefruit juice, increase blood plasma levels and consequently can lead to bleeding and other adverse effects. Conversely, drugs that are metabolized by CYP3A4, for example simvastatin, show increased plasma levels and more side effects if combined with ticagrelor. CYP3A4 inductors, for example rifampicin and possibly St. John’s wort, can reduce the effectiveness of ticagrelor. There is no evidence for interactions via CYP2C9.

The drug also inhibits P-glycoprotein (P-gp), leading to increased plasma levels of digoxinciclosporin and other P-gp substrates. Ticagrelor and AR-C124910XX levels are not significantly influenced by P-gp inhibitors.[4]

In the US a boxed warning states that use of ticagrelor with aspirin doses exceeding 100 mg/day decreases the effectiveness of the medication.[16]

References

  1. a b “Assessment Report for Brilique”European Medicines Agency. January 2011.
  2. ^ European Public Assessment Report Possia
  3. ^ “FDA approves blood-thinning drug Brilinta to treat acute coronary syndromes”. FDA. 20 July 2011.
  4. a b c d e f Haberfeld, H, ed. (2010) (in German). Austria-Codex (2010/2011 ed.). Vienna: Österreichischer Apothekerverlag.
  5. a b Wallentin, Lars; Becker, RC; Budaj, A; Cannon, CP; Emanuelsson, H; Held, C; Horrow, J; Husted, S et al. (August 30, 2009). “Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes”NEJM 361 (11): 1045–57. doi:10.1056/NEJMoa0904327PMID 19717846.
  6. ^ Brilinta: Highlights of prescribing information
  7. ^ Teng, R; Oliver, S; Hayes, MA; Butler, K (2010). “Absorption, distribution, metabolism, and excretion of ticagrelor in healthy subjects”. Drug metabolism and disposition: the biological fate of chemicals 38 (9): 1514–21. doi:10.1124/dmd.110.032250PMID 20551239.
  8. ^ Birkeland, Kade; Parra, David; Rosenstein, Robert (2010). “Antiplatelet therapy in acute coronary syndromes: focus on ticagrelor”Journal of Blood Medicine 1: 197–219.
  9. ^ H. Spreitzer (February 4, 2008). “Neue Wirkstoffe – AZD6140” (in German). Österreichische Apothekerzeitung (3/2008): 135.
  10. ^ Owen, RT, Serradell, N, Bolos, J (2007). “AZD6140”. Drugs of the Future 32 (10): 845–853. doi:10.1358/dof.2007.032.10.1133832.
  11. ^ Tantry, Udaya S; Bliden, Kevin P (2010). “First Analysis of the Relation Between CYP2C19 Genotype and Pharmacodynamics in Patients Treated With Ticagrelor Versus Clopidogrel”. Circulation: Cardiovascular Genetics 3: 556–566. doi:10.1161/CIRCGENETICS.110.958561.
  12. ^ Bernardo Lombo, José G Díez. Ticagrelor: the evidence for its clinical potential as an oral antiplatelet treatment for the reduction of major adverse cardiac events in patients with acute coronary syndromes Core Evid. 2011; 6: 31–42. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065559/
  13. ^ Serebruany VL, Atar D. Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials—Common patterns in TRITON, RECORD, and PLATO? Thromb Haemost 2012; DOI: 10.1160/TH12-04-0251. http://www.theheart.org/article/1433145/print.do
  14. ^ Miller, R (24 February 2010). “Is there too much excitement for ticagrelor?”. TheHeart.org.
  15. ^ H. Spreitzer (17 January 2011). “Neue Wirkstoffe – Elinogrel” (in German). Österreichische Apothekerzeitung (2/2011): 10.
  16. ^ July 20, 2011 AstraZeneca: Ticagrelor (Brilinta) Gains FDA Approval Larry Husten cardiobrief.org/2011/07/20/astrazeneca-ticagrelor-brilinta-gains-fda-approval/

SOURCE:

 http://en.wikipedia.org/wiki/Ticagrelor

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