Francesco Scaglione, MD, PhD Department of Oncology and Hemato-oncology

Postgradute School of clinical pharmacology

University of Milan

Head of Clinical Pharmacology Unit Niguarda - Hospital

Milan,Italy

Pattern genetici e Farmacoterapia

Differenteefficaciadeifarmaci

Stessa malattia, Stessi sintomi,

Stesso paziente? Different Effects

Stesso farmaco Stessa dose

Exogenous&Endogenousfactorscontributetovaria4onindrugresponse

•  Giorno1-bambinomaschiosanonatoatermine,madreassume30mgdicodeina/500mgdiparacetamoloperdolore

•  Giorno7-difficoltàl'allaEamentoalsenoeletargia•  Giorno11-bambino,stazionariopermaneletargia•  Giorno12-pellegrigiastra,allaEamentodifficoltoso•  Giorno13-neonatotrovatomorto•  concentrazioneema4cadimorfinapostmortem=70ng/mL

(normaleinneona4allaEa4alsenodamadricheassumonocodeina0-2-2ng/mL)

•  analisigeno4poCYP2D6–madreconduplicazionegenicaCYP2D6*2x2-metabolizzatoreultra-rapido

•  ineona4generalmentehannoridoEacapacitàdimetabolizzareedeliminarelamorfina

Lancet368:704,2006

CASOCLINICO

CODEINA

CYP3A4 CYP2D6

Norcodeina

Mor0ina

Mor2ina-6-glucuronide

Mor2ina-3-glucuronide

effetti

oppioidi

EscrezioneRenale

DuplicazioneCYP2D6nellamadreAltaconcentrazionedimor2ina

Glicurono-coniugazione molto bassa nel neonato

•  Pharmacogene+ccontribu+ontopharmacokine+c

parameters.t1/2ofan3pyrineismoreconcordantiniden3calincomparisontofraternaltwinpairs.Barsshowthet1/2ofan3pyrineiniden3cal(monozygo3c)andfraternal(dizygo3c)twinpairs.(RedrawnfromdatainVesellandPage,1968.)

Drugtherapy

DRUGMETABOLIZINGENZYMES

PhaseI:biotransforma4onreac4ons:oxida4on,hydroxyla4on,reduc4on,hydrolysisPhaseII:conjuga4onreac4ons—toincreasetheirwatersolubilityandelimina4onfromthebody.Thereac4onsareglucuronida4on,sula4on,acetyla4on,glutathioneconjuga4on

TypesofPolymorphisms

• SingleNucleo4dePolymorphism(SNP): GAATTTAAG GAATTCAAG

• Inser4on/Dele4on: GAAATTCCAAG GAAA[]CCAAG

GENETICVARIATION

Pa4entpopula4onwithsamediseasephenotype Pa4entswithnormalresponse

todrugtherapy

Pa4entswithnon-responsetodrugtherapy

Pa4entswithdrugtoxicity

Genotyping

Toxicresponders

Non-responders

Responders

Ipazien3rispondonoinmododifferenteaifarmaci

“One size does not fit all …”

Drug Metabolic Route Alfentanil CYP3A4/CYP3A5 Carisoprodol** CYP2C19 Celecoxib CYP2C9 Codeine** CYP2D6 Cyclobenzaprine CYP1A2, CYP3A4/CYP3A5 Fentanyl CYP3A4/CYP3A5 Hydrocodone** CYP2D6 Hydromorphone UGT2B7

Ibuprofen CYP2C9

**prodrug;

Commonpainmedica4ons Pain Management

Drug Metabolic Route Lidocaine CYP1A2 Methadone CYP2C19, CYP2B6+

Morphine UGT2B7+ (OPRM1)

Naproxen CYP2C9 Oxycodone** CYP2D6, CYP3A4/5 Oxymorphone UGT2B7+ (OPRM1)

Ropivicaine CYP1A2 Tizanidine CYP1A2 Tramadol** CYP2D6 Zolmipitran CYP1A2

LIMITIdellafarmacogene4ca

•  Targe4ngcomplessosecoinvolgimentodipiùgeni

•  Difficileerichiedetempoperiden4ficarevariazionidigenipocono4

•  Interazioneconaltrifarmacieambientedadeterminare

Barrieredellafarmacogene4ca

•  Scarsitàdilaboratoridifarmacogene4ca•  Scarsaesperienzaneiclinici•  Pochifarmacologicliniciconesperienzanell’adaEamentodelladose

“Oh! She is a poor metabolizer”

Personalizedmedicine

“Here is my sequence”

• Grazie

Pharmacologic effect

Clinical response

Toxicity Efficacy

DISTRIBUTION

ABSORPTION

ELIMINATION

Pharmacokinetics

Pharmacodynamics

dose administered

drug in tissuesof distribution

concentration insystemic circulation

concentration atsite of action

metabolism and/or excretion

Ø Pharmacokinetic factors

- Absorption - Distribution - Metabolism -  Elimination

Ø Pharmacodynamic factors - Target proteins - Downstream messengers

Determinants of Drug Efficacy and Toxicity Apa4ent’sresponsetoadrugmaydependonfactorsthatcanvaryaccordingtotheallelesthatanindividualcarries,including: