Transcript Genetic polymorphism and drug interactions: their

Genetic polymorphism & drug
interactions in pain management
Prof Ian Whyte, FRACP, FRCPE
Calvary Mater Newcastle
University of Newcastle
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Napoleon Bonaparte
(1769 – 1821)

“Medicine is a collection of uncertain
prescriptions, the results of which,
taken collectively, are more fatal than
useful to mankind”
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Variability in drug response
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Common and multifactorial
– environment, genes, disease, other drugs
– absorption, distribution, metabolism,
excretion
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Optimise dosage regimen for each
individual patient
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Drug metabolism
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Analgesics
– need to get into the brain to work
– hydrophobic (fat soluble)
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Elimination
– hydrophilic (water soluble)
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Enzymatic conversion
– liver
– intestinal wall
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Drug metabolising enzymes
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Phase I (oxidating enzymes)
– reductases, oxidases, hydrolases
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Phase II (conjugating enzymes)
– transferases
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glucuronidase, sulphatase, acetylases,
methylases
Transmembrane transporters
– P-glycoprotein (P-gp)
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Cytochrome P-450 enzymes
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Superfamily of microsomal drugmetabolising enzymes (Phase I)
Biosynthesis and degradation
– steroids, lipids, vitamins
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Metabolism of chemicals in our diet
and the environment
– medications
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYPs
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Classified by amino acid similarities
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–
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family number
subfamily letter
number for each gene within the subfamily
asterisk followed by a number (and letter) for
each genetic (allelic) variant
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allele *1 is the normal function gene (wild allele)
CYP2D6*1a gene encodes wild-type protein CYP2D6.1
 http://www.imm.ki.se/CYPalleles/
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Genetic polymorphism
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Greek
– poly: different and morph: form
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Differences in gene expression
– frequency > 1% of the population
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Many enzymes
– drug metabolism
– drug transporters
– drug targets
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Significance
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Drug
– eliminated > 50% by a polymorphic enzyme
– narrow therapeutic window
– activity depends on metabolite (pro-drug)
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Drug interactions
– interacting drug is inhibitor or inducer
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mimic genetic variability
Phenotype
– different profile of enzyme activity
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Analgesic metabolism
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Main enzymes involved are
– CYP2C9, CYP2D6, CYP3A4
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can be inhibited and / or induced
Amount of enzyme related to
– mix of non-functional, decreased
function or fully functional alleles
– co-administration of inducers or
inhibitors
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
mefenamic acid
alfentanil
amitriptyline
buprenorphine
celecoxib
citalopram
clomipramine
codeine
dextromethorphan
diclofenac
dihydrocodeine
escitalopram
fentanyl
fluoxetine
flurbiprofen
fluvoxamine
hydrocodone
ibuprofen
imipramine
indomethacin
maprotiline
meloxicam
methadone
mianserin
naproxen
nortriptyline
oxycodone
paracetamol
paroxetine
piroxicam
sertraline
tenoxicam
tramadol
trimipramine
valdecoxib
major metabolic pathway
minor metabolic pathway
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
3A4
2E1
2D6
2C19
2C9
2B6
1A2
aceclofenac
CYP2C9 genotypes
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6 known allelic variants
In Caucasians
– CYP2C9*1, *2 and *3
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CYP2C9*1 (80 – 82%) encodes normal (wild type) activity
CYP2C9*2 (11%) slightly reduced enzymatic activity
CYP2C9*3 (7 to 9%) 5 – 10-fold decreased enzyme activity
Ethnic variability
– Ethiopia
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CYP2C9*2 is 4%
CYP2C9*3 is 2%
– Far East
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CYP2C9*2 is 0%
CYP2C9*3 is 2%
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2C9 function
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Most substrates are weak acids
– NSAIDs
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ibuprofen, indomethacin, flurbiprofen,
naproxen, diclofenac, piroxicam, lornoxicam,
mefenamic acid, meloxicam, celecoxib
Ibuprofen and celecoxib
– homozygous carriers of CYP2C9*3
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clearance is halved and half-life doubled
No clinical correlates demonstrated
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 genotypes
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CYP2D6 polymorphism autosomal recessive
– almost 80 allelic variants
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Non-functional alleles
– CYP2D6*4
– CYP2D6*5
– CYP2D6*3
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Decreased function alleles
– CYP2D6*10
– CYP2D6*17
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Normal function (wild type) allele
– CYP2D6*1
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 phenotypes
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Poor metabolisers (PMs)
– homozygous for a non-functional allele
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CYP2D6*4 (20 – 25% Caucasians; 70 – 90% PMs)
CYP2D6*5 (5%)
CYP2D6*3 (2%)
– complete enzyme deficiency
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5 – 10% of Caucasians
Ethnic variability
– PMs rare outside Caucasians
– Asians and Africans < 2% non-functional alleles
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 phenotypes
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Intermediate metabolisers (IMs)
– homozygous for a decreased function allele
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CYP2D6*10
CYP2D6*17
– decreased enzyme activity
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10 – 15% of Caucasians
Ethnic variability
– 50% of Asians are carriers of CYP2D6*10
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Extensive metabolisers (EMs)
– homozygous for the normal function allele
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CYP2D6*1
60 – 70% of Caucasians
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 phenotypes
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Ultra-rapid metabolisers (UMs)
– multiple (2 – 13) copies of normal function alleles
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1 to 10% of Caucasians
Ethnic variability
– Middle East (20%)
– Ethiopia (up to 29%)
– Europe
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North / South gradient
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Sweden (1 – 2%)
Germany (3.6%)
Switzerland (3.9%)
Spain (7 – 10%)
Sicily (10%)
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 clinical implications
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Metabolism
– 25% of common drugs
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many opioids, most antidepressants
Effect varies
– activity of parent compound
– activity of any metabolite
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UMs have increased elimination
– antidepressants
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standard doses can result in ineffective treatment
PMs higher concentrations after standard doses
– increased efficacy but also toxicity
– dose adjustment is therefore essential
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and codeine
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Bioactivation by CYP2D6
– codeine, tramadol, hydrocodone, oxycodone
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affects efficacy and toxicity
Codeine is converted to morphine for analgesia
– EMs
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10% of codeine is converted to morphine
– PMs
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none (0%) is converted to morphine
– codeine is an ineffective analgesic
– UMs
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morphine production is increased
– severe intoxication with codeine at standard dosages
– death in a child
• UM mother breastfeeding while on codeine
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and tramadol
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CYP2D6 activity important for
– analgesic effect
– side effect profile
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Tramadol
– low affinity for μ-opioid receptor
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O-desmethyl-tramadol > 200-fold affinity
– inhibits reuptake of 5HT > NA
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PMs
– unlike codeine – tramadol retains activity
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opioid effect decreases but monoaminergic effect increases
non-responders twice as frequent (46.7%) as in EMs (21.6%)
increased risk of serotonin toxicity
UMs
– no issues reported
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and methadone
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Marked interindividual differences in
steady state blood concentrations
– higher in PMs on maintenance
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over 70% of PMs had effective treatment
28% of PMs required doses > 100 mg
– lower in UMs on maintenance
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40% of UMs had effective treatment
almost 50% of UMs required doses > 100 mg
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and opioid dependence
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PMs may be protected
– no PMs were found in those addicted to
codeine
– 4% in patients never substance addicted
– 6.5% in those with other dependencies
(alcohol, cocaine, amphetamines)
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Pharmacogenetic protection against
oral codeine dependence
– odds ratio > 7
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and antidepressants
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Antidepressants used as co-analgesics
– over 25% of patients do not respond
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Most metabolised by CYP2D6
– 30 to 40 fold variation in plasma levels
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UM phenotype
– risk factor for therapeutic ineffectiveness
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PMs
– toxic effects at recommended doses
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and antidepressants
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Clearance decreased in PMs
– amitriptyline, clomipramine, desipramine, imipramine,
nortriptyline, trimipramine, paroxetine, citalopram,
fluvoxamine, fluoxetine, venlafaxine
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Increased side effects in PMs
– desipramine
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only PMs had adverse reactions
– confusion, sedation, orthostatic hypotension
– venlafaxine
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cardiotoxicity
– palpitations, dyspnoea, arrhythmias
– twice as many PMs among patients reporting side effects
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and antidepressants
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Effective dosing in depression
– depends on PM or UM status
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nortriptyline 10 to 500 mg/day
amitriptyline 10 to 500 mg/day
clomipramine 25 to 300 mg/day
Chinese patients (majority IMs) need generally lower doses
Dose recommendations
– PMs
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50 to 80% dose reduction for tricyclic antidepressants
30% dose reduction for SSRIs
– UMs
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increase dose to 260% for desipramine
300% for mianserin
230% for nortriptyline
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP3A4
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CYP3A subfamily has a role in 45 to 60% of all drugs
– codeine, tramadol, buprenorphine, methadone, fentanyl,
dextromethorphan
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30-fold differences in expression of CYP3A exist in
certain populations
CYP3A subfamily consists of four enzymes
– CYP3A4, CYP3A5, CYP3A7, CYP3A43
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most important is CYP3A4
Allelic variants of CYP3A4 are described
– none results in a significant change of enzyme activity
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYPs and drug interactions
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Plasma levels of substrates may
increase with co-administration of
inhibitors
– potentially increased side effects
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Plasma levels of substrates may
decrease with co-administration of
inducers
– potentially less therapeutic effect
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2C9
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Inhibitors of CYP2C9
– amiodarone, fluvastatin, fluconazole,
phenylbutazone, sulphinpyrazone,
sulphonamides
– potentially increased NSAID side effects
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Inducers of CYP2C9
– carbamazepine, phenobarbitone,
ethanol
– potentially less NSAID therapeutic effect
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6
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Inhibitors of CYP2D6
– antiarrhythmics (quinidine), neuroleptics
(chlorpromazine, haloperidol,
thioridazine, levopromazine), many
antidepressants (paroxetine, fluoxetine)
– increase plasma concentrations
– inactivate pro-drugs (codeine)
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Inducers of CYP2D6
– None
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP3A4
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Inhibitors of CYP3A4
– grapefruit juice, macrolide antibiotics
(erythromycin), some antidepressants
(paroxetine), neuroleptics (olanzapine),
protease inhibitors (ritonavir, indinavir,
saquinavir), amiodarone
– increase methadone plasma levels
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toxicity (overdose)
– 4 – 5-fold reduction in metabolism
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fentanyl, alfentanil, sufentanil
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP3A4
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Inducers of CYP3A4
– rifampicin, carbamazepine, phenytoin
– decrease plasma levels of methadone
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symptoms of opioid withdrawal
– > 3-fold increase in clearance of
alfentanil
– unclear clinical significance
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
isoniazid
amiodarone
itraconazole
amprenavir
ketoconazole
bupropion
levomepromazine
celecoxib
losartan
St Mary’s thistle (silibinin)
methadone
chloroquine
metronidazole
chlorpromazine
miconazole
cimetidine
moclobemide
ciprofloxacin
nateglinide
citalopram
nefazodone
clarithromycin
nelfinavir
clomipramine
nifedipine
clopidogrel
nitrendipine
delavirdine
paroxetine
desogestrel
phenylbutazone
dihydralazine
phenytoin
diltiazem
promethazine
diphenhydramine
propafenone
efavirenz
quinidine
erythromycin
risperidone
ethinyloestradiol
ritonavir
flecainide
roxithromycin
fluconazole
saquinavir
fluoxetine
sertraline
fluvastatin
simvastatin
fluvoxamine
terbinafine
gemfibrozil
thioridazine
gestodene
tacrolimus
grapefruit
valdecoxib
halofantrine
venlafaxine
haloperidol
verapamil
imatinib
voriconazole
indinavir
zafirlukast
irbesartan
potent inhibitor
moderate inhibitor
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
3A4
2D6
2C9
3A4
2D6
2C9
valproic acid
amprenavir
carbamazepine
cyclophosphamide
dexamethasone
efavirenz
ethanol
felbamate
ifosfamide
meprobamate
St John’s wort
nevirapine
oxcarbazepine
phenobarbitone
phenylbutazone
phenytoin
primidone
rifabutin
rifampicin
ritonavir
topiramate
potent inducer
moderate inducer
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
3A4
2C9
aminoglutethimide
P-glycoprotein
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Transmembrane transport protein
– expels drugs out of cells
– decreases drug levels in the tissue
– ~ 30 mutations
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Substrates
– loperamide, morphine, methadone, meperidine,
hydromorphone, naloxone, naltrexone, pentazocine,
some endorphins and enkephalins
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Decreased intestinal P-gp function
– increased amount absorbed
– increased plasma concentration
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Minor influence on brain bioavailability of
morphine, methadone and fentanyl
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Phenotyping
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
Characterises enzyme activity in an
individual patient
Test substrate given
– parent drug, metabolite in blood / urine
– metabolic ratio
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amount of unchanged parent drug / amount
of metabolite
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Phenotyping
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Quick, simple, inexpensive and
reproducible
Must give a pharmacologically active
substance for a diagnostic purpose
– may raise ethical questions
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Information on the phenotyping of
specific groups is limited
– children, elderly, renal and liver disease
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Phenotyping availability
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CYP2C9
– 1 out of 507 (0.2%)
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Hospital / University facility
CYP2D6
– 6 out of 507 (1.2%)
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Hospital (2), Hospital / University (2), University (2)
CYP3A4
– None
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Genotyping (PCR)
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Advantages
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direct analysis of genetic mutations
does not require a substrate drug
not influenced by drugs or environmental factors
performed once in a lifetime
Disadvantages
– not commonly available
– cost and sensitivity varies with the CYP
– only detects currently described allelic variants
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not all mutations detected
– new allelic variants found on a regular basis
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may need to repeat the test
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Genotyping availability
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CYP2C9
– 5 out of 507 (1.0%)
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commercial pathology laboratory (1), state government
pathology service (1), university (2), university/hospital (1)
CYP2D6
– 4 out of 507 (0.6%)
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commercial pathology laboratory (1), state government
pathology service (1), hospital/university (1), university (1)
CYP3A4
– None
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
GenesFX Health Pty. Ltd
(http://www.genesfx.com)
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Individual gene tests
– CYP2C9 – $140
– CYP2D6 – $180
– CYP3A4/5 – Not available
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DNADose – $270
– CYP2D6, CYP2C9, CYP2C19, VKORC1
– "Personalised Drug-Specific report“
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Dosage guidance for all drugs that GenesFX is
informed about
Suggestions of alternative drugs when appropriate
Suggestions of drugs to avoid in the future
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Clinical utility
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May occasionally be justified retrospectively
– few cases of treatment failure or drug toxicity
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poor compliance vs fast metabolism
excessive intake vs poor metabolism
– suspected drug addiction vs metabolic defect
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high intake of codeine
Limited availability
Dose recommendations are preliminary
Efficacy and clinical utility remain to be validated
No economic analysis
– tests needed to prevent one case of toxicity vs cost
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Conclusions
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Analgesics
– importance of individualisation of drug prescription
– most are metabolised by CYPs subject to genetic polymorphism
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may help explain some of the ineffectiveness or toxicity
Detection of these polymorphisms could give us tools for
– optimising drug treatment
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anticipating therapeutic side effects and ineffective therapy
identifying the right drug and the right dose
predict the most effective and safest drug for each patient
– distinguish between rapid metabolism and drug abuse
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Cost / benefit analysis has not been done
We are not there yet but
– there is real potential
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle