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Dra. Diadelis Remirez. (National Centre of Quality Control of Drugs).
E-mail: [email protected]
Pharmacogenetics studies: Results and
Regulatory perspectives in Cuba.
1st Latin American Pharmacogenomics Congress.
Outline
A brief about Cuba and the most important scientific
results.
Assesment of glycoprotein P and 3 CYP isoenzymes
in a cuban population.
Regulatory perspective in Cuba.
Considerations about personalized medicine.
Health Cuban System.
SURFACE: 110 922 km2
INHABITANTS: 11 254 227
Cuba: Some Current Data
Literacy almost 100%
Primary education (up to 12 years old) almost 100%
Secondary education (up to 15 years old) 99.7%
Students (all systems) 2.8 millions
Rate birth 2009 5,3*1000 live birth.
Doctors per inhabitant 1:179
University centres 69
Scientists >12,000 (15% PhD)
Research institutions 210 (> 30,000 workers)
Cuba and Pharmacogenetic.
Manufacturer of:
Prophylactic and therapeutic vaccines.
Monoclonal antibodies.
Others biological products (blood derivatives,
interferon)
More than 70 % of generic drug.
8053 notifications of adverse reactions in 2009.
Commercial Products of the
Scientific Pole
1981 – 19901 Anti-meningococcus
bc vaccine
2 Heberon alfa rec.
3 Diagnostics
1991 – 20001.Meningitis vaccine2.Hepatitis B vaccine3.Heberkinasa4.Heberon alfa r5.Hebermin6.Gavac7.SUMA System8.DIRAMIC9.Hebertrans10.Culture media11.Policosanol12.Trofin13.Natural products14.Neurodiagnostic systems15.Anti-CD3 monoclonal
antibody16.Surfacen17.Generics18.Placenta derivatives19.Neurological restoration
services
2001 – 20091. Haemophylus B vaccine 2. Combined vaccines (HB-Hib,DPT-Hib, DPT-HBb-Hib,). 3. Vaccines and MAbs for cancer therapy 4. Meningitis vaccine5. Hepatitis B vaccine6. Meningococcus ACYW135 vaccine7. HB Uniject vaccine8. EPO (CIM, CIGB) 9. Products and equipment for Neurophysioloy and
Neuroinformatics10. New diagnostic systems 11. Streptokinase (w/o HSA)12. Neurological restoration services13. Leptospirae vaccine14. MEN B vaccine15. Salmonella vaccine16. Tethanus Toxoid17. GCSF18. Allergens19. Trofin20. Interferon (liquid, w/o HSA)21. Interferon (liofylized, w/o HSA)22. Interferon + ribavirine23. Gamma Interferon24. Interleukin-225. PPG-plus26. Humanized anti EGF-receptor antibody27. SUMA system28. Agriculture products (GAVAC, Bionematicide)29. EGF (parenteral)30. Hebertrans31. Culture media32. New advanced generics33. Cytostatics34. Technology transfers35. Placenta derivatives36. EPO plus37. Surfacen38. EGF viscous solution
Quimi – Hib®Advantages:
Product obtained by
chemical synthesis
Only in class
worldwide
Support by a
Canadian and Cuban
patent
ONN S
OANTIGEN TT
n
O
H
HH
H
O
OH
O
CH2OH
P
O
O
O
O
OH
OH
OH
Na
O
H
HH
H
O
OH
O
CH2OH
P
OOOH
OH
OH
OH
Na
O
NH
N
O
OO
CARBOHIDRATE----PROTEIN
PIPELINE OF CANCER PRODUCTS IN CUBAN BIOTECHNOLOGY
ProductMolecule
Characterization
Pre-clinica
Evaluation
Clinical Trial
(I)
Clinical Trial
(II)
Clinical Trial
(III)Registered
1. Human rec-Interferon α
2. Human rec Erithropoietin (EPO)
3. Colony Stimulating Factor (G-CSF)
4. Anti EGFR Humanized MoAb (hR3)
5. EGF Vaccine
6. PSA Immunoassay Kit
7. NGM3 Vaccine
8. Idiotype Vaccine (1E10)
9. Radioactive Antibody (hR3-Re188)
10. Antitumor Peptide (CIGB-300)
11. GnRH Vaccine
12. HPV Therapeutic Vaccine
13. Radioactive Antibody (C5-Re188)
14. Radioactive Antibody (anti-CEA-I131)
15. Her1 Vaccine
16. VEGF Vaccine
17. Anti-NGM3 (14F7) humanized MoAb
18. Anti-VEGF recombinant antibody
19. Antitumor peptide (CIGB-370)
20. Antitumor peptide (CIGB-552)
21. Biosimilar Monoclonal Antibodies
22. Anti- IL2 Monoclonal Antibody
Date Objetive Results
2000
NRA assessment within the
Prequalification process of
Cuban Hepatitis B
recombinant vaccine
Satisfactory performance
of CECMED. All regulatory
functions were implemen-
ted & WHO recognized
capacity for regulation of
vaccines.
2003 Follow up assessment for
vaccine regulation
Satisfactory performance
2004 Full assessment for drug
regulation
Satisfactory performance
2008 Full assessment for vaccine
regulation
Satisfactory performance
CIM
BioCen
CIGB
CIE
CENSA
I. FINLAY
LIORADNOVATEC
AICA
CIGBCENIC
Finlay
99.9% similarity
0.1% differences
3,000,000 diff.
Therapeutic Failure Adverse Effects Toxicity
Cuba
140 unrelated
Cubans subjects
Informed consent to participate in the study
Questionnaire • Ancestry
• Medical history
• Physical examination
Five milliliters venous blood (EDTA (0,5 M))
DNA isolation by QuiAmp DNA Mini Kit (QUIAGEN, Germany)
Polymerase Chain
Reaction-Restriction
METHODS
MDR1 C3435T
P-GLICOPROTEIN (Pgp)
Transporter proteins are important determinants in absorption tissue
targeting and elimination of drugs.
Genotype n
Observed
frequency (%)
MDR1
CC 65 46.4
CT 58 41.4
TT 17 12.1
AllelesObserved frequency (%)
MDR1White Black Intermediate
CC41.5 60 42.8
CT45.4 34.3 39.3
TT13.0 5.7 17.8
Demographic frequency of MDR1 in a Cuban population
Frequencies of MDR1 in a Cuban population
MDR1
C3435T variant
Group Observed frequency and 95% CI
CYP2D6 CYP2D6*1 CYP2D6*3 CYP2D6*10 CYP2D6*17
Study population
White 81.2 (74.9-87.3) 2.0 (0-4.1) 12.3 (7.1-17.5) 4.5 (1.2-7.8)
Black 71.4 (90.8-82.1)* - 12.9 (5.0-20.6)* 15.7 (7.1-24.2)*
Intermediate 68.5 (56.1-80.9)* - 18.5 (8.1-28.8) 13.0 (4.0-21.9)*
CYP2C9 CYP2C9*1 CYP2C9*2 CYP2C9*3
Study population
White 81.2 (74.9-87.3) 13.6 (8.2-19.0) 5.2 (1.6-8.6)
Black 88.6 (81.1-96.0)* 5.7 (0.2-11.1) 5.7 (0.2-11.1)
Intermediate 88.9 (80.5-97.2)* 7.4 (0.4-14.3) 3.7(0-8.7)
CYP2C19 CYP2C19*1 CYP2C19*2 CYP2C19*3
Study population -
White 86.0 (80.9-91.7) 14.0 (8.2-19.0) -
Black 84.0 (75.7-92.8)* 16.0 (7.1-24.2)* -
Intermediate 88.0 (80.5-97.2)* 12.0 (2.7-19.4)* -
ResultsDemographic frequency of CYP2C9, CYPC19 y CYP2D6 alleles in a Cuban
population of healthy volunteers.
(* P <0.05, Fisher exact test)
Population study No. of
subjects
Allelic frequencies (%) (95% CI)
CYP2C9 *1 *2 *3
Study population 140 84,3 10,7 5
White American 325 78.0* 15.0 7.0
Black American 100 94.6* 2.5 1.3*
Brazilian 331 84.9* 8.6 6.5
Spanish 157 69.4 14.3 16.2
German 367 81.5* 10.7 7.8
Chinese 102 95.0* 0.0 5.0
Ethiopia 150 93.3 4.3 2.3
CYP2C19 *1 *2 *3
Study population 140 86,4 13,6 -
White American 105 87.0 13.0 0.0
Black American 108 75.0 25.0* 0.0
Colombian 189 91.3 8.7 0
Portuguese 153 87.0 13.0 0.0
Germans 328 84.0* 15.9 0.2
Chinese 121 50.0* 45.5* 4.5*
Ethiopia 114 84.6 13.6 1.8
CYP2D6 *1 *3 *10 *17
Study population 140 45,8 0,6 8,4 5,6
White American 143 40.3* 1.4 8 0.3*
Black American 191 43.4* 12* 3.9* 20.9*
Mexican American 349 57.2* 0.3 7.4* NS
Spanish 217 35.3* 3.9 NS NS
British 195 35.6* 1 2* 0*
Tanzania 106 56.1 0.5 20.3* 20.3*
Frequencies of CYP2C9, CYPC19 y CYP2D6 genotypes
in Cuban and other ethnic populations
• Cuban healthy volunteers express in major percent a wild genotype for all
cytochromes in this study.
• The percent of poor metabolizers in Cuban population for the CYP2C9
and CYP2C19 is due to the allelic variant *2 in both cytochromes.
• The allelic variants of CYP2D6 *10 and *17 are expressed in 8,4 and 5,6
% respectively.
• Frequencies of the allelic variants of these CYPs in Cubans are similar to
Caucasian population from Spain and Latin American and some
populations from Africa.
Conclusions
Cuba
Study of debrisoquine hydroxylation polimorphism(CYP2D6) in the cuban population compared to Spaniards.
A project about the characterization of the main CYPisoenzymes in cuban population.
Characterization of the individual response to antiplateletetagents (Clopidrogel, Aspirin etc)
Pharmacogenomic Group for biological products:
– Kras as a marker for response to EGFR-targetedtherapy.
– Clinical trials (expression profiling as a marker ofpatiens response).
Curent status of pharmacogenetic
regulation.
1. Guidelines from WHO, EMEA, FDA, ICH.
WHO EMEA FDA ICH
Regulatory perspectives in Cuba.
Preclinical Studies Clinical studies.
Safety and efficacy for patients.
Metabolism and
Genetic pattern.Pharmacogenomics
(Isoenzyme involved
in the metabolism of drug)
Toxicogenomics
Points to consider.
Genomic data from animal studies are sufficient to be predictive of clinical (human) toxicity.
Technical validations of the assays (variability and reproducibility). Data analysis.
The use of Pharmacogenetics as inclusion/exclusion criteria.
How to use pharmacogenetic information in Phase I/II for optimizing phase II/III design.
What proportions of study populations with defined genetic variants would be required for analysis and interpretation.
How would the pharmacogenetic information affect the product label.?
Principles of Cuban’s policy.
Informed consent about the pharmacogenetic tests.
The patient need all necessary information to make the own
decision.
All anticipatable information of expected benefits or expected
harms.
Balancing risk-benefit.
Concern of individual participants regarding anonimity, privacy
and confidentiality should be respected and should be
addressed in a research agreement.
A researcher should support education and training.
Particular attention for Special populations, like children and
geriatrics patients.
Age range, race, sex.
Farmacogenetics
Drugs taylor- made
Doubts ¿ Would it be possible to do a genetic test in
order to know the diseases that you are goingto suffer in your life?
Other questions?
To replace defective genes for good ones
to introduce genes in healthy individuals
is not controversial; yet, is it ethical?
The same question applies to introducing
genes to individuals to make them more
intelligent or to turn them into athleets.
But how far should we go?
And then….
The understanding of the biological
terms is changing the planet and its
inhabitants.
Any Hopes of better world?
ETHICS
There are some applications that are
clearly unethical, i.e. biological weapons.
Many questions do not have a clear
answer.
Science fiction today will probably be the
real science in the near future.
Stephen Hawpking
Thank you
Pharmacology Havana 2010.
(13-16 december 2010) (www.pharmacologyhavana.com)
1st International Symposium on Pharmacogenetic and
Meeting of Iberoamerican Society of Pharmacogenetic.
