MARCO MARCHETTI FB HEALTH

USO ED ABUSO DEI FARMACI Venerdì 17 aprile 2015

Sala conferenze Digital for Business - Sesto San Giovanni (MI)

www.digitalforacademy.com

PHARMACOGENETICS IN NEUROLOGY & PSYCHIATRY

NEUROFARMAGEN®

PHARMACOGENETICS

“It is not the analysis of disease genetic risk factors that shows the most immediate promise for human health, but the application of genetic information to permit safer and more efficacious use of drugs”*

*) Caplan A. What Will Drive Genomics Over the Next 10 Years, Science 2011

Genome- Sequencing 10th Anniversary

PHARMACOGENETICS

“It is not the analysis of disease genetic risk factors that shows the most immediate promise for human health, but the application of genetic information to permit safer and more efficacious use of drugs”*

*) Caplan A. What Will Drive Genomics Over the Next 10 Years, Science 2011

Genome- Sequencing 10th Anniversary PHARMACOGENETICS

=

PHARMACOGENETICS

“It is not the analysis of disease genetic risk factors that shows the most immediate promise for human health, but the application of genetic information to permit safer and more efficacious use of drugs”*

*) Caplan A. What Will Drive Genomics Over the Next 10 Years, Science 2011

Genome- Sequencing 10th Anniversary

PERSONALIZED MEDICINE

PHARMACOGENETICS

Pharmacogenetics is not only about drug metabolism!

Genes can affect both pharmacokinetics and pharmacodynamics

Response profile to a given drug likely to depend on more than just one gene

Imagine checking only creatinine and glucose in a blood analysis

More specific guidelines than “use with caution” are desirable

Provide specific recommendations whenever possible

Adapt the wording to the available evidence

IMPLEMENT genotype-specific recommendations based on the available evidence

REVIEW of all genetic association studies in international scientific journals, FDA labels and CPIC and DPWG guidelines

Co

nti

nu

ou

s u

pd

ate

List of drugs used in psychiatry & neurology

NEUROFARMAGEN

CLOBAZAM DOSE AND CYTOCHROME CYP2C19

Plasma levels of Clobazam are significantly affected by genetic variations (polymorphisms) in CYP2C19

FDA has issued genotype-adjusted dosing guidelines:

EXAMPLES OF SCIENTIFIC BASIS

• CYP2D6 UMs: Avoid or increase dose (strong)

• CYP2D6 PMs: Avoid or consider 50% reduction of starting dose (strong)

• CYP2C19 UMs: Consider alternative drug (optional)

• CYP2C19 PMs: Consider 50% reduction of starting dose (moderate)

TRICYCLIC ANTIDEPRESSANTS AND CYTOCHROMES CYP2C19 & 2D6

Up to 30% of Caucasians carry genetic variants resulting in significantly altered CYP2C19 or 2D6 metabolism

CPIC has issued specific recommendations for TCAs affected by CYP2D6 only (Nortriptyline, Desipramine) or both CYPs (Amitriptyline, Clomipramine, Doxepin, Imipramine and Trimipramine)1

1) Hicks et al, Clin Pharmacol Therap 2013

EXAMPLES OF SCIENTIFIC BASIS

EFFICACY OF SSRIs AND BDNF

BDNF (Brain-Derived Neurotrophic Factor): Growth factor that stimulates neuronal survival and synapse formation.

A recent meta-analysis indicates that a BDNF polymorphism affects SSRIs efficacy: Val/Met heterozygotes more likely to respond1

1) Niitsu et al., Prog Neur-Psychopharmacol Biol Psychiatr 2013

EXAMPLES OF SCIENTIFIC BASIS

TOLERABILITY OF SSRIs AND 5-HTTLPr

5-HTTLPR is a degenerate repeat polymorphic region in the promoter of the 5HT transporter (SLC6A4 gene)

Meta-analyses have linked the short allele to lower risk of good response1 and to higher risk of adverse effects2 for Caucasian subjects

1) Porcelli et al., Eur Neuropsychopharmacol 2012; 2) Kato et al., Molecular Psychiatr 2010

EXAMPLES OF SCIENTIFIC BASIS

TEST IMPLEMENTATION

Saliva Sample

DNA Analysis & Interpretation Pharmacogenetic Report

TEST IMPLEMENTATION

Reports can be accessed online via username & password

Color coding indicates most relevant information for each drug:

1. Adverse effects

2. Metabolism

3. Good Response

4. Standard

- P

rio

rity

+

TEST IMPLEMENTATION

Double-click opens detailed information

• Detailed results for each relevant genetic variant

• Specific recommendations

USE OF PHARMACOGENETIC

INFORMATION AND PATIENT

STABILIZATION IN PSYCHIATRIC

PATIENTS

• Study conducted at 3 clinical settings in Madrid (Spain), coordinated by IRB from “Hospital Clínico San Carlos” (Madrid)

• Cross-sectional, naturalistic, retrospective, multi-centric study

• Entry criteria:

• ≥18 years old, with a psychiatric disorder

• CGI-S ≥ 3 at baseline (92% of subjects ≥4)

• Neurofarmagen CORE had been used

• Primary endpoint: rate of stabilization at 3 months, defined as CGI-S ≤ 3

STUDY DESIGN

PATIENT FLOWCHART

No significant differences between groups regarding demographic and clinical characteristics1

Significant difference at study endpoint (3 months) : number of non-stabilized patients reduced by 42% in group following NFG

RESULTS

1) years since diagnosis, psychiatric condition, baseline CGI-S , non psychiatric medication, smoking, substance abuse

Follows t0 Follows not t0 Follows t3 Follows not t3

CG

I-S

Baseline characteristics were included in a multiple regression model

Only baseline severity (CGI-S0) and Followed/Did not follow NFG had a statistically significant effect

Final model1: r=0.55, p=6x10-15

1) Homoscedasticity and normality of errors verified

RESULTS

WHAT NEXT?

Combine Pharmacogenetics,

Environment and Drug Interactions

REPORT UPGRADE

Checks interactions with:

Health condition

Environmental variables

Concomitant medication (psychiatric and non-psychiatric)

REPORT UPGRADE

Patient’s name and surname are optional

They are encrypted in the database, only the doctor can see them, not FB-Health or AB-Biotics

NEUROFARMAGEN REPORT

GENETICS ONLY GENETICS + PATIENT INFO.

Environmental interactions and drug interactions are added on top of the pharmacogenetic information

Designed to help physicians to better understand the drug response of

difficult-to-treat patients, and to achieve better therapeutic outcomes

Neurofarmagen is more than a cytochrome genotyping test:

Analyzes other genes related to drug metabolism (EPHX1, CES1) or transport (ABCB1)

Also many pharmacodynamic genes (5HT signaling, DRD2 cascade)

Provides genotype and drug-specific drug recommendations

Clinically tested, more trials ongoing

Environment and drug interactions implemented soon

… Thank You!!!

www.digitalforacademy.com | info@digitalforacademy.com