clinical toxicology & pharmacology, calvary mater newcastle genetic polymorphism & drug...
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Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Genetic polymorphism & drug Genetic polymorphism & drug interactions in pain managementinteractions in pain management
Prof Ian Whyte, FRACP, FRCPECalvary Mater NewcastleUniversity of Newcastle
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Napoleon Bonaparte Napoleon Bonaparte (1769 – 1821)(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 responseVariability in drug response
Common and multifactorial– environment, genes, disease, other drugs– absorption, distribution, metabolism,
excretion Optimise dosage regimen for each
individual patient
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Drug metabolismDrug metabolism
Analgesics– need to get into the brain to work– hydrophobic (fat soluble)
Elimination– hydrophilic (water soluble)
Enzymatic conversion– liver– intestinal wall
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Drug metabolising enzymesDrug metabolising enzymes
Phase I (oxidating enzymes)– reductases, oxidases, hydrolases
Phase II (conjugating enzymes)– transferases
glucuronidase, sulphatase, acetylases, methylases
Transmembrane transporters– P-glycoprotein (P-gp)
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Cytochrome P-450 enzymesCytochrome P-450 enzymes
Superfamily of microsomal drug-metabolising enzymes (Phase I)
Biosynthesis and degradation– steroids, lipids, vitamins
Metabolism of chemicals in our diet and the environment– medications
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYPsCYPs
Classified by amino acid similarities – family number– subfamily letter – number for each gene within the subfamily– asterisk followed by a number (and letter) for
each genetic (allelic) variant 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 polymorphismGenetic polymorphism
Greek– poly: different and morph: form
Differences in gene expression– frequency > 1% of the population
Many enzymes– drug metabolism– drug transporters– drug targets
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
SignificanceSignificance
Drug– eliminated > 50% by a polymorphic enzyme– narrow therapeutic window– activity depends on metabolite (pro-drug)
Drug interactions– interacting drug is inhibitor or inducer
mimic genetic variability
Phenotype– different profile of enzyme activity
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Analgesic metabolismAnalgesic metabolism
Main enzymes involved are – CYP2C9, CYP2D6, CYP3A4
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
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2C9 genotypesCYP2C9 genotypes 6 known allelic variants In Caucasians
– CYP2C9*1, *2 and *3 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
CYP2C9*2 is 4% CYP2C9*3 is 2%
– Far East CYP2C9*2 is 0% CYP2C9*3 is 2%
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2C9 functionCYP2C9 function
Most substrates are weak acids– NSAIDs
ibuprofen, indomethacin, flurbiprofen, naproxen, diclofenac, piroxicam, lornoxicam, mefenamic acid, meloxicam, celecoxib
Ibuprofen and celecoxib– homozygous carriers of CYP2C9*3
clearance is halved and half-life doubled
No clinical correlates demonstrated
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 genotypesCYP2D6 genotypes CYP2D6 polymorphism autosomal recessive
– almost 80 allelic variants Non-functional alleles
– CYP2D6*4– CYP2D6*5– CYP2D6*3
Decreased function alleles– CYP2D6*10– CYP2D6*17
Normal function (wild type) allele– CYP2D6*1
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 phenotypesCYP2D6 phenotypes
Poor metabolisers (PMs)– homozygous for a non-functional allele
CYP2D6*4 (20 – 25% Caucasians; 70 – 90% PMs) CYP2D6*5 (5%) CYP2D6*3 (2%)
– complete enzyme deficiency 5 – 10% of Caucasians
Ethnic variability– PMs rare outside Caucasians– Asians and Africans < 2% non-functional alleles
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 phenotypesCYP2D6 phenotypes Intermediate metabolisers (IMs)
– homozygous for a decreased function allele CYP2D6*10 CYP2D6*17
– decreased enzyme activity 10 – 15% of Caucasians
Ethnic variability– 50% of Asians are carriers of CYP2D6*10
Extensive metabolisers (EMs)– homozygous for the normal function allele
CYP2D6*1 60 – 70% of Caucasians
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 phenotypesCYP2D6 phenotypes Ultra-rapid metabolisers (UMs)
– multiple (2 – 13) copies of normal function alleles 1 to 10% of Caucasians
Ethnic variability– Middle East (20%)– Ethiopia (up to 29%)– Europe
North / South gradient– Sweden (1 – 2%)– Germany (3.6%)– Switzerland (3.9%)– Spain (7 – 10%)– Sicily (10%)
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 clinical implicationsCYP2D6 clinical implications Metabolism
– 25% of common drugs many opioids, most antidepressants
Effect varies– activity of parent compound – activity of any metabolite
UMs have increased elimination– antidepressants
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 codeineCYP2D6 and codeine Bioactivation by CYP2D6
– codeine, tramadol, hydrocodone, oxycodone affects efficacy and toxicity
Codeine is converted to morphine for analgesia– EMs
10% of codeine is converted to morphine– PMs
none (0%) is converted to morphine– codeine is an ineffective analgesic
– UMs 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 tramadolCYP2D6 and tramadol CYP2D6 activity important for
– analgesic effect– side effect profile
Tramadol– low affinity for μ-opioid receptor
O-desmethyl-tramadol > 200-fold affinity– inhibits reuptake of 5HT > NA
PMs – unlike codeine – tramadol retains activity
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 methadoneCYP2D6 and methadone
Marked interindividual differences in steady state blood concentrations– higher in PMs on maintenance
over 70% of PMs had effective treatment 28% of PMs required doses > 100 mg
– lower in UMs on maintenance 40% of UMs had effective treatment almost 50% of UMs required doses > 100 mg
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and opioid dependenceCYP2D6 and opioid dependence
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) Pharmacogenetic protection against
oral codeine dependence– odds ratio > 7
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and antidepressantsCYP2D6 and antidepressants
Antidepressants used as co-analgesics– over 25% of patients do not respond
Most metabolised by CYP2D6– 30 to 40 fold variation in plasma levels
UM phenotype– risk factor for therapeutic ineffectiveness
PMs– toxic effects at recommended doses
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and antidepressantsCYP2D6 and antidepressants Clearance decreased in PMs
– amitriptyline, clomipramine, desipramine, imipramine, nortriptyline, trimipramine, paroxetine, citalopram, fluvoxamine, fluoxetine, venlafaxine
Increased side effects in PMs– desipramine
only PMs had adverse reactions – confusion, sedation, orthostatic hypotension
– venlafaxine cardiotoxicity
– palpitations, dyspnoea, arrhythmias
– twice as many PMs among patients reporting side effects
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6 and antidepressantsCYP2D6 and antidepressants Effective dosing in depression
– depends on PM or UM status 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
50 to 80% dose reduction for tricyclic antidepressants 30% dose reduction for SSRIs
– UMs increase dose to 260% for desipramine 300% for mianserin 230% for nortriptyline
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP3A4 CYP3A4 CYP3A subfamily has a role in 45 to 60% of all drugs
– codeine, tramadol, buprenorphine, methadone, fentanyl, dextromethorphan
30-fold differences in expression of CYP3A exist in certain populations
CYP3A subfamily consists of four enzymes– CYP3A4, CYP3A5, CYP3A7, CYP3A43
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 interactionsCYPs and drug interactions
Plasma levels of substrates may increase with co-administration of inhibitors– potentially increased side effects
Plasma levels of substrates may decrease with co-administration of inducers– potentially less therapeutic effect
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2C9CYP2C9
Inhibitors of CYP2C9– amiodarone, fluvastatin, fluconazole,
phenylbutazone, sulphinpyrazone, sulphonamides
– potentially increased NSAID side effects Inducers of CYP2C9
– carbamazepine, phenobarbitone, ethanol– potentially less NSAID therapeutic effect
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP2D6CYP2D6
Inhibitors of CYP2D6– antiarrhythmics (quinidine), neuroleptics
(chlorpromazine, haloperidol, thioridazine, levopromazine), many antidepressants (paroxetine, fluoxetine)
– increase plasma concentrations– inactivate pro-drugs (codeine)
Inducers of CYP2D6– None
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP3A4CYP3A4
Inhibitors of CYP3A4 – grapefruit juice, macrolide antibiotics
(erythromycin), some antidepressants (paroxetine), neuroleptics (olanzapine), protease inhibitors (ritonavir, indinavir, saquinavir), amiodarone
– increase methadone plasma levels toxicity (overdose)
– 4 – 5-fold reduction in metabolism fentanyl, alfentanil, sufentanil
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
CYP3A4CYP3A4
Inducers of CYP3A4– rifampicin, carbamazepine, phenytoin– decrease plasma levels of methadone
symptoms of opioid withdrawal– > 3-fold increase in clearance of
alfentanil– unclear clinical significance
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
P-glycoproteinP-glycoprotein Transmembrane transport protein
– expels drugs out of cells– decreases drug levels in the tissue– ~ 30 mutations
Substrates– loperamide, morphine, methadone, meperidine,
hydromorphone, naloxone, naltrexone, pentazocine, some endorphins and enkephalins
Decreased intestinal P-gp function– increased amount absorbed– increased plasma concentration
Minor influence on brain bioavailability of morphine, methadone and fentanyl
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
PhenotypingPhenotyping
Characterises enzyme activity in an individual patient
Test substrate given– parent drug, metabolite in blood / urine– metabolic ratio
amount of unchanged parent drug / amount of metabolite
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
PhenotypingPhenotyping
Quick, simple, inexpensive and reproducible
Must give a pharmacologically active substance for a diagnostic purpose– may raise ethical questions
Information on the phenotyping of specific groups is limited– children, elderly, renal and liver disease
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Phenotyping availabilityPhenotyping availability
CYP2C9– 1 out of 507 (0.2%)
Hospital / University facility
CYP2D6– 6 out of 507 (1.2%)
Hospital (2), Hospital / University (2), University (2)
CYP3A4– None
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Genotyping (PCR)Genotyping (PCR) Advantages
– 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
not all mutations detected– new allelic variants found on a regular basis
may need to repeat the test
Clinical Toxicology & Pharmacology, Calvary Mater Newcastle
Genotyping availabilityGenotyping availability CYP2C9
– 5 out of 507 (1.0%) commercial pathology laboratory (1), state government
pathology service (1), university (2), university/hospital (1)
CYP2D6– 4 out of 507 (0.6%)
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. LtdGenesFX Health Pty. Ltd(http://www.genesfx.com)(http://www.genesfx.com)
Individual gene tests– CYP2C9 – $140– CYP2D6 – $180– CYP3A4/5 – Not available
DNADose – $270– CYP2D6, CYP2C9, CYP2C19, VKORC1– "Personalised Drug-Specific report“
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 utilityClinical utility May occasionally be justified retrospectively
– few cases of treatment failure or drug toxicity poor compliance vs fast metabolism excessive intake vs poor metabolism
– suspected drug addiction vs metabolic defect 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
ConclusionsConclusions Analgesics
– importance of individualisation of drug prescription– most are metabolised by CYPs subject to genetic polymorphism
may help explain some of the ineffectiveness or toxicity Detection of these polymorphisms could give us tools for
– optimising drug treatment 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 Cost / benefit analysis has not been done We are not there yet but
– there is real potential