Farmacogenomica

CO2 2Calumeninγ-glutamyl FunctionalHypofunctional carboxylase F. II, VII, IX, XF. II, VII, IX, X Proteins C, S, ZProtein C, S, Z Cattedra di Patologia ClinicaUniversità degli Studi di FoggiaGage B. Nov 14 2005 FDA Clin Pharm Advisor CommitteCYP2C9 POLYMORPHISMClearance of S ‐warfarin and time to achieve steady ‐• state (5x T1/2):*1/*1: ~ 3 days*1/*2: ~ 6 days*1/*3: ~ 12 daysLinder MW Ph.D. DABCC, Manage the “ Over‐‐steer”” in warfarin dose titration.Over steer Cattedra di Patologia ClinicaUniversità degli Studi di FoggiaVKORC1 POLYMORPHISMAt least 10 different single ‐ nucleotide ‐ polymorphisms (SNPs) wereidentifiedHaplotype A ( ‐1639GA, 1173CT): lower maintenance dose• Haplotype B (9041GA): higher maintenance dose•VKORC1 A/A: 2.7 0.2 mg/d• ±VKORC1 A/B: 4.9 0.2 mg/d• ±VKORC1 B/B: 6.2 0.3 mg/d• ±Mean maintenance dose: 5.1 0.2 mg/d• ±Rieder MJ, Reiner AP, Gage BF, et el. N

38. Recommend decrease the starting dose of irinotecan by at least 1 dose

• avoid cytotoxicity for homozygous UGT1A1*28 allele carriers.

Level to Camptosar (irinotecan) package insert: http://www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Camptosar_PI.pdf

Thiopurine S‐Methyltransferase (TPMT)

S‐Methyltransferase

TPMT‐ normal metabolizer (homozygous functional alleles): 90%

• TPMT‐ intermediate metabolizer (heterozygous with one nonfunctional allele): 10%

TPMT‐ deficient metabolizer (homozygous nonfunctional alleles): 0.3%

Eichelbaum M, Ingelman‐Sundberg M, Evans WE. Annu Rev Med. 2006.57:119‐137.

Ingelman 2006.57:119

Azathioprine and 6‐mercaptopurine are immunosuppressive antimetabolites.

Cattedra di Patologia Clinica

Università degli Studi di Foggia

The active thiopurine metabolite, 6 ‐ TGN, can eventually results in myelosuppresion, a dose limiting factor for therapy.

level of 6 ‐ TGN andTPMT‐ deficient metabolizers can have increased are at higher risk for severe, sometimes fatal, myelosuppresion.

Eichelbaum M, Ingelman‐‐Sundberg M, Evans WE. Annu Rev Med. 2006.57:119‐‐ 137.

Ingelman 2006.57:119 Cattedra di Patologia ClinicaUniversità degli Studi di FoggiaTPMT

Predominantly genotyping or phenotyping for TPMT variant alleles is recommended before thiopurine therapy.

TPMT‐ deficient metabolizers: give 6 ‐ 10% of the standard dose of thiopurine and monitor CBC 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

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

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

No vaccine against hepatitis C is currently available

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 half of patients treated with peginterferon‐α plus ribavirin (pegIFNα/RBV) and 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 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.