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TPMT

Predominantly genotyping or phenotyping for TPMT variant alleles is

• recommended before thiopurine therapy.

TPMT

‐ deficient metabolizers:

• dose of thiopurine and monitor CBC

give 6 ‐ 10% of the standard

• carefully.

TPMT

‐ intermediate metabolizers:

• usually start on full dose, but dose reduction is recommended to

• avoid toxicity.

Imuran (azathioprine) package insert: http://www.prometheuslabs.com/pi/Imuran.pdf

com/pi/Imuran.pdf

http://www.prometheuslabs.

Eichelbaum M, Ingelman‐

Sundberg M, Evans WE. Annu Rev Med. 2006.57:119‐

‐ 137

Ingelman 2006.57:119 Cattedra di Patologia Clinica

Università degli Studi di Foggia

Anticancer Drugs Approved by the Food and Drug Administration

(FDA) with Labeling Regarding Pharmacogenomic Biomarkers

Type of Biomarker and Associated Drug

Biomarker with pharmacokinetic effect

TPMT: Mercaptopurine, Thioguanine

UGT1A1: Irinotecan, Nilotinib

Biomarker with pharmacodynamic effect

EGFR: Cetuximab, Erlotinib, Gefitinib, Panitumumab

KRAS: Cetuximab, Panitumumab

ABL: Imatinib, Dasatinib, Nilotinib

C‐Kit (KIT): Imatinib

HER2/neu (ERBB2): Lapatinib, Trastuzumab

Estrogen receptor: Tamoxifen Cattedra di Patologia Clinica

Università degli Studi di Foggia

Cancer Pharmacogenomics and

Tumor and Germline Genomes

Both the tumor genome (e.g., in the case of

• gefitinib therapy) and the patient’s germline

genome (e.g., in the case of irinotecan

therapy) can contribute to pharmacogenomic

variation in response to antineoplastic drugs.

The tumor genome plays a critical role in the

• response to gefitinib (Panel A), since the

of non–small‐cell lung cancer to this

sensitivity

drug is enhanced by activating mutations in

the kinase domain of the gene encoding

epidermal growth factor receptor (EGFR).

Tumor EGFR encoding activating mutations

within the kinase domain results in enhanced

tumor sensitivity to gefitinib.

The rate of toxic effects associated with

• and myelosuppression) is

irinotecan (diarrhea

increased in patients with seven TA

dinucleotide repeats rather than the more

common six repeats in the promoter region of

UGT1A1 encoding a UDP‐

glucuronosyltransferase in germline DNA,

resulting in lower enzyme activity and a

decreased rate of drug metabolism (Panel B).

Cattedra di Patologia Clinica

Università degli Studi di Foggia

Examples of FDA

Approved Drugs and

FDA‐Approved

Companion Diagnostics in Clinical Practice

Today, about 10% of labels for FDA‐approved drugs contain

• pharmacogenomic information Cattedra di Patologia Clinica

Università degli Studi di Foggia

Hepatitis C

Infectious disease affecting primarily the liver, caused by the

• hepatitis C virus (HCV)

The infection is often asymptomatic, but chronic infection can lead to

• scarring of the liver and ultimately to cirrhosis, generally apparent

after many years. In some cases, those with cirrhosis will go on to

develop liver failure, liver cancer or life‐threatening esophageal and

gastric varices The existence of hepatitis C was postulated in the 1970s

• and proven in 1989

HCV is spread primarily by blood‐to‐blood contact (i.v. drug

• use, poorly sterilized medical equipment and transfusions)

Hepatitis C is the leading cause of liver transplantation

• though the virus usually recurs after transplantation

against hepatitis C is currently available

No vaccine

• Cattedra di Patologia Clinica

Università degli Studi di Foggia

HCV Infection

Nearly 200 million people worldwide

• are chronically infected with the

hepatitis C virus (HCV). In the

absence of therapy, a quarter of

these patients will go on to develop

cirrhosis

The aim of treatment against HCV is eradication of the virus. This goal is presumed

• to have been reached when viraemia is no longer recognized 6 months following

discontinuation of therapy.

Unfortunately, this sustained virological response (SVR) is achieved in fewer than

• (pegIFNα/RBV) and

half of patients treated with peginterferon‐α plus ribavirin

who have HCV genotype 1, which is the most prevalent worldwide. Treatment

outcomes are worse in HIV/HCV‐coinfected subjects, in whom interactions

between HCV medications and antiretroviral agents may contribute to impaired

virological responses. Given the wide variability in HCV treatment outcomes,

prediction of SVR may help to individualize therapy and make rational decisions on

the initiation of antiviral drugs Cattedra di Patologia Clinica

Università degli Studi di Foggia

Host and viral factors and SVR in HCV Infection

Viral predictors of SVR include:

Host predictors of SVR include: HCV genotype

Age •

• plasma HCV RNA level

Gender •

• early viral kinetics on therapy

liver fibrosis stage •

• metabolic abnormalities

• Race

• However, even after considering host and viral factors, there is still a large

amount of unexplained variability in treatment outcomes, suggesting that

the genetic background modulates the likelihood of viral eradication when

pegIFNα/RBV therapy is used. Cattedra di Patologia Clinica

Università degli Studi di Foggia

Recovery Persistence

Cattedra di Patologia Clinica

Università degli Studi di Foggia

Kinetics of HCV RNA decline differ early

in IL28b haplotypes

Genotype 1 Caucasian patients Cattedra di Patologia Clinica

Università degli Studi di Foggia

ITPA gene polymorphisms and

ribavirin

‐ induced haemolytic anaemia

ribavirin‐induced

Ribavirin‐induced haemolytic anaemia can complicate the management of

• patients treated for hepatitis C. Up to 15% of patients have to reduce ribavirin

dosing due to severe anaemia.

Two SNPs at the ITPA gene, known to be functionally responsible for ITPA

• risk of ribavirin‐

deficiency, have been shown to be associated with the

induced anaemia.

ITP, inosine triphosphatase; RBV‐TP, ribavirin triphosphate. Cattedra di Patologia Clinica

Università degli Studi di Foggia

Main genetic determinants of hepatitis C

natural history and treatment response

IL28B

• ITPA

• LDL‐cholesterol receptor

• Others: IP‐10, HCV core mutations 70/91, etc.

• Cattedra di Patologia Clinica

Università degli Studi di Foggia

Quali ricadute degli studi di genetica e genomica

nella diagnosi e nella terapia?

…I Farmaci Biologici…

Cattedra di Patologia Clinica

Università degli Studi di Foggia

Diabete Mellito Cattedra di Patologia Clinica

Università degli Studi di Foggia

Insulina umana

Il primo prodotto “ricombinante” autorizzato per uso

• terapeutico Analoghi dell

’ Insulina

Prodotti la cui sequenza aminoacidica propria dell’insulina

• umana viene modificata ad arte con delle sostituzioni di uno

più aminoacidi Cattedra di Patologia Clinica

Università degli Studi di Foggia

Analoghi dell

’ Insulina (1)

dell’Insulina Cattedra di Patologia Clinica

Università degli Studi di Foggia

Analoghi dell

’ Insulina (2)

dell’Insulina Cattedra di Patologia Clinica

Università degli Studi di Foggia

Analoghi dell

’ Insulina (3)

dell’Insulina Cattedra di Patologia Clinica

Università degli Studi di Foggia

Ormoni Polipeptidici Cattedra di Patologia Clinica

Università degli Studi di Foggia

Proteine del Sangue Cattedra di Patologia Clinica

Università degli Studi di Foggia

Immunomodulatori ed Antitumorali

Cattedra di Patologia Clinica

Università degli Studi di Foggia

Immunomodulatori ed Antitumorali

Cattedra di Patologia Clinica

Università degli Studi di Foggia

Vaccini Ricombinanti

(anatossine) Cattedra di Patologia Clinica

Università degli Studi di Foggia

Infezione da HBV Cattedra di Patologia Clinica

Università degli Studi di Foggia

Infezione da HBV Cattedra di Patologia Clinica

Università degli Studi di Foggia

Vaccino anti

‐ Epatite B

anti‐Epatite Cattedra di Patologia Clinica

Università degli Studi di Foggia

Vaccino contro la Meningite Batterica

Cattedra di Patologia Clinica

Università degli Studi di Foggia

Protein(Tyrosin)

‐ kinases Inhibitors

Protein(Tyrosin)‐kinases Bcr‐Abl and Imatinib

Cattedra di Patologia Clinica

Università degli Studi di Foggia

What are some of the barriers to pharmacogenomics progress?

Pharmacogenomics is a developing research field that is still in its

infancy.

Several of the following barriers will have to be overcome before

many pharmacogenomics benefits can be realized.

1. Complexity of finding gene variations that affect drug response

2. Limited drug alternatives

3. Disincentives for drug companies to make multiple

pharmacogenomic products

4. Educating healthcare providers Cattedra di Patologia Clinica

Università degli Studi di Foggia

Is pharmacogenomics in use today?

To a limited degree. ..

The cytochrome P450 (CYP) family of liver enzymes is responsible for breaking down

• more than 30 different classes of drugs. DNA variations in genes that code for these

enzymes can influence their ability to metabolize certain drugs. Less active or inactive

eliminate drugs

forms of CYP enzymes that are unable to break down and efficiently

from the body can cause drug overdose in patients. Today, clinical trials researchers use

genetic tests for variations in cytochrome P450 genes to screen and monitor patients.

In addition, many pharmaceutical companies screen their chemical compounds to see

how well they are broken down by variant forms of CYP enzymes.

Another enzyme called TPMT (thiopurine methyltransferase) plays an important role in

• the chemotherapy treatment of a common childhood leukemia by breaking down a

class of therapeutic compounds called thiopurines. A small percentage of Caucasians

have genetic variants that prevent them from producing an active form of this protein.

thiopurines elevate to toxic levels in the patient because the inactive form

As a result,

of TMPT is unable to break down the drug. Today, doctors can use a genetic test to

screen patients for this deficiency, and the TMPT activity is monitored to determine

appropriate thiopurine dosage levels. Cattedra di Patologia Clinica

Università degli Studi di Foggia

Conclusions

Genotyping recommended for different

• polymorphic enzymes before initiation of

therapies

Dose recommendations

• Improve better therapeutic outcomes

• Minimizing adverse drug reactions

• Further studies on ethnicities,

• pharmacoeconomics, dosing algorithms

(prospective) required. Cattedra di Patologia Clinica

Università degli Studi di Foggia

“… Here ’ s my sequence …”

“…Here’s sequence…”

Cattedra di Patologia Clinica

Università degli Studi di Foggia


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DETTAGLI
Corso di laurea: Corso di laurea magistrale in medicina e chirurgia (a ciclo unico - 6 anni)
SSD:
Università: Foggia - Unifg
A.A.: 2012-2013

I contenuti di questa pagina costituiscono rielaborazioni personali del Publisher kalamaj di informazioni apprese con la frequenza delle lezioni di Medicina di Laboratorio - Patologia Clinica e studio autonomo di eventuali libri di riferimento in preparazione dell'esame finale o della tesi. Non devono intendersi come materiale ufficiale dell'università Foggia - Unifg o del prof Ranieri Elena.

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