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Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects

Posted in Advanced Drug Manufacturing Technology, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Health Economics and Outcomes Research, tagged Adverse effect, Cardiomyopathy, Cardiovascular Disorders, Conditions and Diseases, Drug development, drug trial failuress, drug withdrawal costs, Ejection Fraction, health, Induced pluripotent stem cell on April 11, 2013| 5 Comments »

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

Cleveland Clinic

http://chemocare.com/chemotherapy/side-effects/cardiotoxicity-and-cardiomyopathy.aspx

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.

http://www.dddmag.com/articles/2012/08/detecting-potential-toxicity-mitochondria

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

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

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

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