Rôle de la pharmacogénétique et de la pharmacocinétique dans l efficacité analgésique et la toxicité des opioïdes

(1)

Rôle de la pharmacogénétique

et de la pharmacocinétique

dans l’efficacité analgésique et

la toxicité des opioïdes

Dr Caroline SAMER

Pharmacologie et Toxicologie Cliniques Centre multidisciplinaire de la douleur Hôpitaux Universitaires de Genève, Suisse Centre Suisse de Toxicologie Humaine Appliquée

(2)

Environnement

• Alimentation • Co-medications • Smoke • Pollution

Genetics

• Enzymes • Transporters • Receptors

Individual

• Age • Sex • Weight • Co-morbidities • Organ function

Interindividual variability

(3)

(4)

Drug metabolizing

enzymes

Drug transporters

Pharmacokinetics and

(5)

Phase I

Functionalisation

Phase II

Conjugation

Amidases Conjugation with amino acids

Cytochromes P450

Glutathion-S-transferases Deshydrogenases Methyl-transferases

Epoxyde-hydrolases N-acetyltransferases Esterases Sulfotransferases

Flavine monooxygenases

UDP-glucuronosyl-transferases

Monoamine oxidases Catechol-O-methyl-transferase

Reductases

(6)

Opioids Phase I Phase II

Codeine CYP2D6, CYP3A UGT2B7

Oxycodone CYP2D6, CYP3A UGT2B7

Hydrocodone CYP2D6, CYP3A UGT2B7, UGT 1A3

Tramadol CYP2D6, CYP3A

Fentanyl CYP3A

Morphine CYP3A UGT2B7, UGT1A

Methadone CYP3A, CYP2B6, CYP2D6, CYP2C9, CYP2C19

Buprenorphine CYP3A

Hydromorphone UGT2B7, UGT 1A3

Oxymorphone CYP2D6, CYP3A UGT2B7

(7)

CYP450 quantitative repartition

and contribution to drug metabolism

10 % 5 % 20 % 5 % 5 % 10 % 40 % 5 % CYP3A CYP2E1 CYP1A2 CYP2D6 CYP2C9 CYP2C19 CYP2B6 autres

10%

55%

30%

(8)

Modulation of CYP3A activity

CYP3A inducers

CYP3A inhibitors

CYP3A polymorphisms?

Increase

activity

Decrease

activity

(9)

CYP3A inhibitors

(10)

CYP3A inducers

(11)

Modulation of CYP2D6 activity

CYP2D6 ultrarapid metabolizers

CYP2D6 intermediate metabolizers

CYP2D6 poor metabolizers

CYP2D6 inhibitors

Increase

activity

Decrease

activity

(12)

CYP2D6 drug inhibitors



Antidepressants

:

bupropion, citalopram,

clomipramine, duloxetine, escitalopram, fluoxetine,

fluvoxamine, moclobemide, nefazodone, paroxetine,

reboxetine, sertraline, venlafaxine



Antipsychotics

:

chlorpromazine, haloperidol,

levomepromazine, promethazine, quetiapine,

risperidone, thioridazine



HIV protease inhibitors

:

ritonavir, indinavir



TKIs

:

gefitinib, imatinib, nilotinib, sorafenib



Others

:

cimetidine, methadone, metoclopramide,

quinidine, terbinafine

(13)

CYP2D6 genetic polymorphism

UM EM IM PM

(14)

Substance

Active metabolite

Reference

codeine

morphine

Dayer et al, Biochem

Biophys Res Comm 1988

tramadol

M1

Paar et al, Clin Invest 1992

hydrocodone

hydromorphone

Otton et al , Clin

Pharmacol Ther 1993

oxycodone

oxymorphone

Cleary et al, J Pharmacol

Exp Ther 1993

dihydrocodeine dihydromorphine

Fromm et al, J Pharmacol

Exp Ther 1995

ethylmorphine

morphine

Xu et al, Biochem

Pharmacol 1995

Bio-activation of pro-drug opioids

dependant on CYP2D6

(15)

UM

Codeine metabolic pathways

Gasche Y. et al NEJM 2004, 351: 2827-31.

PM

Desmeules et al Eur J Clin Pharmacol 1991, 4:1 79-86

(16)

Opioid intoxication with codeine

Gasche Y et al. NEJM 2004



62 yr male with CLL and pneumonia treated with clarithromycine, voriconazole

and codeine for cough (25 mg 3x/day)

Gasche Y. et al NEJM 2004, 351: 2827-31



Resolution after

naloxone



CYP2D6

genotype and phenotype:

UM

CYP3A

phenotype:

PM

(CYP3A inhibition by clarithromycine and voriconazole)



Coma and respiratory failure on day 4 requiring ventilation and ICU transfer



Morphine values in blood

20-80-fold

higher than expected

(17)

Opioid toxicity and CYP2D6 UM genotype

Case Indication Codeine dose Toxicity

Breastfead newborn (13days) Episiotomy pain (mother) 2x30mg then 2x15mg Death

Breastfed newborn Severe muscle pain 120 mg/day Mother: sedation, nausea dizziness; Child: drowsy, poor feeding

Child (2 years) Tonsillectomy 10-12.5mg q4-6h Death Child (29 mths)

Tonsillectomy 1.75mg/kg Apnea, unresponsiveness

Child (3 years) Tonsillectomy 15 mg q4 -6h Severe respiratory depression

Child (4 years) Adenotonsillectomy 8 mg q5h Death

Child (5 years) Adenotonsillectomy 12mg q4h Death

Male (33years) Dental pain 60mg Euphoria, dizziness, blurred vision, epigastric pain

(18)

(19)

Clinical Pharmacogenetics Implementation Consortium

guidelines for codeine therapy in the context of

CYP2D6 phenotype

Crews KR et al. Clin Pharmacol Ther. 2012;91:321-6.

(20)

Structural analogies tramadol and codeine

CYP 2D6

O-demethylation

(21)

Stamer U et al, Clin Pharmacol Ther 2007

CYP2D6 and tramadol post-operative analgesia

n= 187 major abdominal surgery patients (18 PM, 93 IM, 68 EM, 8 UM)

Cumulative analgesic consumption over the 48h

Therapeutic Resistance

x4

in

CYP2D6 PM

Non-responders to tramadol allocated to CYP2D6 genotypes

(22)

Tramadol «bimodal» mecanism of action

Cortex Thalamus Mesencephalus Brain stem Muscles Skin Dorsal root ggl Viscera Vessels Spinal cord Opioids Monoamines

↑

UM

CYP2D6

↑

PM

CYP2D6

tramadol M1

(23)

CYP 2D6

2D6

3A

N-demethylation CYP3A O-demethylation CYP2D6

Oxycodone

44x

1/3

x

mu opioid

receptor

affinity

Lalovic et al CPT 2006

Oxymorphone

Noroxycodone

Oxycodone and metabolites

(24)

CYP2D6 UM: ↑50% AUC

CYP2D6 PM: ↓75% AUC

PM

UM

EM

Samer at al., Br J Pharmacol 2010, 167: 907-18.

Oxymorphone plasma

concentrations according to

CYP2D6 genotype

(25)

0 1000 2000 3000 4000 5000 6000 A U EC 9 0 (Δ t0 ) s e c. m in

Cold pressor

PM EM UM ↑ 40% * *

Cold pressor test

-200 -150 -100 -50 0 A U E C 9 0 m m .m in ( Δ t0 )

Constriction pupille

PM EM UM x1.5 * *

Pupil size

0 500 1000 1500 2000 2500 3000 3500 4000 AU EC 90 ( Δt 0)

SPT après stimulation électrique

PM EM UM x6 * *

Electrical stimulation (SPT)

* p<0.05

Samer at al., Br J Pharmacol 2010, 167: 919-30.

Impact of

CYP2D6 genotype

on oxycodone

(26)

CYP2D6 inhibitor

CYP3A inhibitor

Oxy

CYP3A inhibition : ↑AUC 3.5X

CYP2D6 inhibition : ↓AUC 2x

Oxymorphone plasma concentrations

(27)

0 20 40 60 80 100 Keto + Oxy Oxy Quin + Oxy % volunteer Traitement %EM %PM %UM

Oxycodone toxicity

Toxicity in CYP2D6 UM

or

after CYP3A inhibition

(28)



CYP2D6 poor metabolizers/CYP2D6 inhibitors:

Reduced active metabolite formation

->

↓ analgesic efficacy

of codeine, tramadol and

oxycodone



CYP2D6 ultrarapid metabolizers/CYP3A inhibitors:

Active metabolite accumulation

->

↑ toxicity

of codeine, tramadol and oxycodone



Modification of the pharmacological properties

(tramadol, DEM)

(29)

Opioids Phase I Phase II

Codeine CYP2D6, CYP3A UGT2B7

Oxycodone CYP2D6, CYP3A UGT2B7

Hydrocodone CYP2D6, CYP3A UGT2B7, UGT 1A3

Tramadol CYP2D6, CYP3A

Fentanyl CYP3A

Morphine UGT2B7, UGT1A

Methadone CYP3A, CYP2B6, CYP2D6, CYP2C9, CYP2C19

Buprenorphine CYP3A

Hydromorphone UGT2B7, UGT 1A3

Oxymorphone CYP2D6, CYP3A UGT2B7

(30)

CYP3A activity and fentanyl PK-PD

Kharasch ED et al. Anesthesiology 2004, 101: 729-37. AUC x2

AUC /2

rifampin: CYP3A inducer

troleandomycin: CYP3A inhibitor n=12

AUC ↑30%

AUC ↓60%

(31)

Takane H, et al. Ann Pharmacother. 2005;39:2139-40.

Rifampin reduces the analgesic effect of fentanyl

61 year-old man

with recurrence of

parotid gland

adenocarcinoma

on a transdermal

fentanyl patch

(32)

CYP3A4*1G and IV fentanyl PCA consumption

<<<<<<<<<<

Zhang W et al. Eur J Clin Pharmacol 2010, 66: 61-66.

n= 143 Chinese patients (abdominal total hysterectomy or myomectomy)

Dong ZL et al. J Clin Pharm Ther. 2012 Apr;37(2):153-6.

CYP3A4*1G: 20230G>A -> reduced activity

Allele frequency in Japanese-Chinese = 0.25

(33)



CYP3A inhibitors

dramatically increase

the risk of opioid

toxicity

(black box

warning: oxycodone & fentanyl)



CYP3A inducers

may lead to therapeutic

failure



Impact of genetic polymorphisms

to be

confirmed

(34)

Adapted from Overholser BR et al, Am J Manag Care 2011 Codeine Tramadol Oxycodone Fentanyl Buprenorphine Methadone

(35)

Drug transporters:

P-glycoprotein (ABCB1)

Klein et al., Biochimica et Biophysica Acta 1999(1461):237



Efflux ATP dependant

transmembrane transporter



Expressed in the intestine, liver,

kidney, BBB



Protection and detoxification

(↓ drug levels at target site)



ABCB1 highly polymorphic

(3435C>T and 2677G>T)



ABCB1 inhibitors/inducers

(36)

Schaeffeler et al., Lancet 2001:383

C3435T ABCB1 polymorphism

(37)

ABCB1 and opioid efficacy

Campa D et al, CPT 2008, 83:559-66.

↓ opioid

consumption in

3435T carriers

↓ pain after a week

of morphine

in 3435T carriers

Lötsch J et al, Pharmacogenet Genom 2009, 19: 429-36. n= 145 cancer pain patients n= 149 chronic pain patients

(38)

ABCB1 haplotype and methadone

requirements

Coller JK et al, CPT 2006, 80: 682-90.

↓ methadone

mean dosage in

T allele carriers

Opioid-dependant subjects (n = 60)

(39)

ABCB1 diplotype and morphine toxicity

Coulbault L et al, Clin Pharmacol Ther 2006, 79: 316-24.

Colorectal surgery patients (n=74)

(40)

ABCB1 diplotype and fentanyl toxicity

Park HJ et al, CPT 2007, 81:539-46.

Carriers of ABCB1

diplotype

(2677TT, 3435TT)

had

increased

susceptibility to

early and intense

respiratory

depression

Korean subjects (n = 126) due to receive spinal anesthesia for surgery of lower extremities

(41)

CYP and P-gp phenotyping (cocktail)

Blood collection (1.5h)

Urine collection (8h)

CYP450 activity :

•

CYP3A (1-OH MDZ/MDZ)

•

CYP2D6 (DEM/DOR)

•

CYP2C9 (4-OH Flu/Flu)

•

CYP1A2 (Para/caf)

•

CYP2C19 (OPZ/5-OH OPZ)

•

CYP2B6 (Bup/OH-Bup)

P-gp activity

:

•

Fexofenadine AUC

_0-8h

Oral microdose cocktail :

•

Midazolam (75µg)

•

Dextromethorphan (2.5 mg)

•

Flurbiprofen (5 mg)

•

Caffeine (1 drink)

•

Omeprazole (2 mg)

•

Bupropion (5mg)

•

Fexofenadine (10mg)

1-OH MDZ: 1-hydroxymidazolam/ MDZ: midazolam/ 4-OH Flu: 4-hydroxyflurbiprofen/ Flu: flurbiprofen/ DEM:

dextromethorphan/ DOR: dextrorphan/ PARA: paraxanthine/ CAF: caffeine/ OPZ: omeprazole/ 5-OH OPZ:

5-hydroxyomeprazole / Bup: bupropion / OH-Bup : hydroxybupropion

(42)

(43)

Clinical use of pharmacogenetics and

pharmacokinetics in opioids therapy

To

offer retrospective insights

to explain

individual variability in response

(inefficacy/toxicity)

-> Measure of the phenotype

To pre-emptively

guide the choice of the opioid

:

-> pro-drugs and CYP2D6 activity

-> opioids and CYP3A interactions

-> support opioid rotation

(44)

Perspectives



Growing amount of pharmacogenetic data affecting the

PK of opioids available but some is scarce or ambiguous

(UGT, transporters)



Genome wide association studies (GWAS) to overcome

limitations of candidate gene association studies



Multigenic approaches to assess the interplay between

genes

(combined effects of SNPs of PK and PD targets)



Prospective highly powered studies in well-defined

phenotypic populations and adjustment for non genetic

confounders

(co-medications, environmental factors)



Cost-effectiveness studies

(45)