TherapeuticDrug Management
Mike HallworthACB Training CourseCoventry, 17 June 2013
Pharmacokinetics
Processes involved in drug handling
Dose Prescribed
Dose taken
Drug in blood
Activesite EFFECT
Other tissues
Excreted/inactivated drug
concordance
absorption
Metabolism/elimination
distribution
pharmacokinetics pharmacodynamics
Concordance (compliance)Often poor. Improved by simplifying regimesAssessment:
Was Rx dispensed?Tablet countsDirect observation/ interviewMarkersDrug/metabolite levelsEffect
Bioavailability
Bioavailability, F = Dose absorbedDose administered
(IV dosing, bioavailability = 1)
First-pass metabolismMetabolism en route from gut to systemic circulation –in the LIVER
Drugs with extensive first-pass metabolism:Analgesics (aspirin, morphine, paracetamol, pethidine)
CNS-active drugs (chlormethiazole, chlorpromazine, imipramine. L-dopa, nortriptyline)
Cardiovascular (glyceryl trinitrate, isosorbide dinitrate, lignocaine, nifedipine, propanolol,
verapamil)
Respiratory (salbutamol, terbutaline)
Oral contraceptives
First-pass metabolism
One reason for apparent variations in drug “absorption” between individuals
Reduced in severe liver disease Greatly increased delivery of drug to active site
Salt-conversion factor (S)
Factor relating to the actual concentration of active drug in the preparation being used
e.g. 108 mg phenytoin sodium = 100 mg phenytoine.g. 200 mg aminophylline = 160 mg theophylline(aminophylline is the EDTA salt of theophylline, S = 0.8)
So, DRUG ABSORBED = S x F x DOSE ADMINISTERED
Distribution
We define:
Volume of Distribution, Vd = Amount of drug in body
Plasma concentration
Volume of distribution is the THEORETICAL VOLUME that would contain all the drug in the body if it were present everywhere at the same concentration that is found in plasma
Volume of distributionFor example:
Vd (L/kg)Amiodarone 1.3Digoxin 7.3Phenytoin 0.65Aspirin 0.14
Vd is LOW if – low lipid solubility- high plasma protein binding- low tissue binding
(and vice versa)
Calculation of size of loading dose
DOSE = Vd x desired concentration
E.g. I want to give a 70 kg man a loading dose of digoxin to produce a plasma concentration of 1.5 µg/L. The bioavailability of digoxin is 0.62
DOSE x 0.62 = 7.3 x 70 x 1.5= 1236 µg
(The usual approach would be to give this in divided doses)
Metabolism and Excretion
Metabolism – usually hepatic
Excretion - via kidneys into the urine- via liver into the bile
Both these processes are encompassed in the pharmacokinetic parameter CLEARANCE
Clearance
DefinitionThe theoretical volume of blood which can be completely cleared of drug in unit time(cf. creatinine clearance)
So,
RATE OF ELIMINATION = Clearance x Plasma conc.= Cl x C
At Steady StateRate of administration = Rate of elimination
(definition of steady state)
So,DOSE x S x F = Cl x C
Τwhere Τ is the dosage interval
Clearance = Dose x S x FΤ x C
Or,
Maintenance dose = Cl x C x ΤS x F
Clearance
If renal clearance of a drug is approximately 120 ml/min, this suggests that the drug is completely cleared by the kidneys and GFR is the only limiting factor to excretion.If hepatic clearance is of the order of 500 –1500 ml/min, this reflects hepatic blood flow and suggests that blood flow is the limiting factor on excretion (perfusion-limited clearance) e.g. lignocaine, morphine.
Clearance
Frequently expressed asVolume/unit time/kg body weight
A more accurate basis for comparison between patients is
Volume/unit time/unit body surface area
Surface area can be determined from standard nomograms
First-order kinetics
Rate of elimination ∝ C(assumes Cl is independent of conc)
Amount of drug in = A0e-kt
body at time t
where A0 is the amount at time 0 and k is the elimination rate constant - the percentage elimination per unit time
Elimination rate constant
k = Amount cleared in unit timeTotal amount in body
= Cl x CVd x C
= ClVd
Elimination rate constantOften expressed in terms of half-life, t½
Ao = Ao . e-kt½
2
ln (½) = - k.t½
t½ = 0.693k
Peak and trough concentrations
Conc
Time
Τ
Peak and trough concentrationsAt steady state:
Cssmax = S x F x Dose + Cssmaxe-kΤ
Vd
Cssmax ( 1 – e-kΤ ) = S x F x DoseVd
Cssmax = S x F x DoseVd ( 1 – e-kΤ )
Peak and trough concentrations
Cssmax = S x F x DoseVd ( 1 – e-kΤ )
Cssmin = S x F x Dose . e-kΤ
Vd ( 1 – e-kΤ )
Plasma protein binding
Primarily to ALBUMIN and α1 acid glycoprotein% plasma protein binding
Lithium 0%Gentamicin <10%Digoxin 20%Theophylline 60%Carbamazepine 70-80%Phenytoin 90-94%
Reduced plasma protein binding
Reduced protein binding (more free drug)
Low protein (liver disease, pregnancy, nephrotic syndrome)Displacement (renal failure, other drugs)Abnormal binding proteinsConcentration-dependent binding
0
50
100
150
0
Plasmaconc.
umol/L
100 200 300 400 500 600 700
GW
PHe
Dose mg/day
PHo
Non-linear (saturation) kinetics
Non-linear (saturation) kineticsMichaelis-Menten equation
Rate of elimination = Vmax x CKm + C
If C << Km Rate = Vmax x C FIRSTKm ORDER
If C>> Km Rate = Vmax x C = VmaxC
ZERO ORDER
Non-linear kinetics
Phenytoin:Km ranges from 0.5 to 15 mg/LVmax ranges from 3 to 12 mg/kg/day
Q1:
How much Chateau Plonque is required to put a 60 kg woman above the legal driving limit 1 hour after ingestion?
(assume:
Rapid ingestion and absorption
Elimination = 100 mg/kg/h
Total body water in women = 55% of total body weight
Chateau Plonque = 13% alcohol by volume
Density of ethanol = 0.8 g/mL
Atmospheric pressure at sea level = 101.325 kPa)
Therapeutic drug management
• Conventional TDM• Biomarkers of drug effect
• Pharmacodynamic monitoring
• Pharmacogenomics
Therapeutic Drug Monitoring
Definition:“Measuring drug or metabolite concentrations in
body fluids as an aid to optimising therapy”TIAFT definition (1997):“Measurement made in the laboratory of a
parameter that, with appropriate interpretation, will directly influence prescribing”
Patient
Drug
Initial dose
Revise dose
EffectPlasmaconcentration
Measure Measure
Interpret
Criteria for valid classical TDM• Drug has reversible action at receptor site• Dose has poor correlation with effect• Plasma concentration correlates well with
effect• Narrow therapeutic ratio• Well-established therapeutic range
Drugs for routine measurement
Established value• Aminoglycosides• Carbamazepine• Ciclosporin• Digoxin• Lithium• Methotrexate
• Phenytoin• Sirolimus• Tacrolimus• Theophylline• Vancomycin
Drugs for routine measurementLess well -established
• Amiodarone• Anti-retrovirals• Caffeine• Chloramphenicol• Clozapine• Disopyramide• Flecainide• Flucytosine• Haloperidol
• Lamotrigine• Mycophenolate• Olanzapine• Phenobarbital• Procainamide• Quinidine• Tricyclics• Valproate
Epilepsy
• Commonest neurological disorder• Highest therapeutic potential• 0.5-1% of population (0.75% UK)• 50 million worldwide• 5% will have fits at sometime during
life (excluding febrile convulsion)• 30-50% of patients still have fits
despite Rx
Antiepileptic drugs (UK)Bromide 1857Phenobarbitone 1912Phenytoin 1938Ethosuximide 1960Carbamazepine 1972Valproate 1972Clonazepam 1974Clobazam 1978Acetazolamide 1988Vigabatrin 1989
Lamotrigine 1991Gabapentin 1993Topiramate 1996Tiagabine 1998Oxcarbazepine 2000Levetiracetam 2000Pregabalin 2004Zonisamide 2005Rufinamide 2007Lacosamide 2008Eslicarbazine 2009Retigabine 2011
Epilepsy Rx (NICE, 2012)
ABSENCE GENERALISED FOCAL MYOCLONIC TONIC/TONIC-CLONIC (PARTIAL) ATONIC
Ethosuximide Valproate* CBZ Valproate* Valproate*Valproate* Lamotrigine Lamotrigine LevetiracetamLamotrigine Carbamazepine Levetiracetam Topiramate
Oxcarbazepine (cost)
OxcarbazepineValproate* _
Clobazam Clobazam Clobazam Clobazam LamotrigineClonazepam Levetiracetam Gabapentin Clonazepam RufinamideTopiramate Topiramate Topiramate Piracetam TopiramateZonisamide (Vigabatrin) ZonisamideLevetiracetam Retigabine
* NB teratogenicity
Epilepsy - Rx
Stabilize neuronal resting potential(mechanisms not well understood)
Inhibit excitation (Na/Ca channel blockers)(e.g. lamotrigine, phenytoin)
Enhance inhibition (GABA enhancers)(e.g. benzodiazepines, tiagabine, vigabatrin)
Modify cell excitability
Krebs
Glutamate Succinate
GABA GABA-TGAD
GABA(inhibitory)
presynapticneurone
Vigabatrin(inhibition)
Tiagabine(blocking)
BenzodiazepinesBarbiturates(potentiation)
postsynapticneurone
PhenytoinLong half-life (20 – 40 h, up to 100h at high concs)
timing unimportantSaturation kineticsMetabolism – hepatic oxidation
Faster in infants/children, slower in pretermInc by ethanol and carbamazepine, dec by enzyme inducers (e.g. cimetidine)
90-93% protein-boundSide effects – neurotoxicity (nausea, ataxia, drowsiness)Target range 10-20 mg/L (40-80 umol/L)
Only a guide – wide variationVery strong case for routine monitoring
0
50
100
150
0
Plasmaconc.
umol/L
100 200 300 400 500 600 700
GW
PHe
Dose mg/day
Phenytoin
PHo
(Richens and Dunlop. 1975)
CarbamazepineShort half-life (8-24h)
Trough samples preferableTarget range 4-10 mg/L (17-42 umol/L)Lower limit of range difficult to defineProtein binding 22-30%Side effects – rash (5%), haematological (rare), neurotoxicity (mild), ADH stimulation (hyponatraemia)Induces own metabolism (hepatic oxidation)Clearance inc by phenytoin/phenobarbitone, dec by enzyme inhibitorsMonitor if control difficultActive metabolite (CBZ 10,11 epoxide)
Metabolism of carbamazepine and oxcarbazepine
N
O
NH2O
N
NH2OOxcarbazepine Carbamazepine
ACTIVE
N
HO
NH2O
N
NH2O
O
10-hydroxy carbazepineACTIVE
Carbamazepine10,11 epoxideACTIVE
N
NH2O
HO OH
Carbamazepinetrans-diol
VigabatrinGamma-vinyl GABASuicide inhibitor of GABA transaminaseIrreversible - long pharmacodynamic half-lifeMonitoring not helpfulVisual field defects in 30%
GABA + α-ketoglutarate
Succinic semialdehyde + glutamate
VigabatrinRapidly absorbedElimination half-life 5-7 hoursBioavailability 80%Not protein-boundRenal eliminationChiral - only S-enantiomer activeVisual field defects limit use
HC
CH CH2
H2N
H2C C
OH
OCH2
LamotrigineRapidly absorbedBioavailability >95%Protein binding 55%Half life 24 - 35 h (varies on combination Rx)Hepatic metabolismTarget range
<15 mg/L ??
ClCl
N
NN
NH2H2N
TopiramateBioavailability 85%Protein binding 15%Half life 20 - 30 hTarget range ?? O
CH2OSO2NH2
OO CH3
CH3
O
OH3C
H3C
GabapentinBioavailability 60%Not protein boundRenal eliminationNo metabolitesHalf life 5 - 7hNo definite conc-effect relationship
NH2 COOH
ValproateHalf-life 8-15h Wide diurnal variation (rapid absorption and elimination)Hepatic metabolism (CBZ, phenytoin increase clearance)Very poor evidence for target range
Clinical effect may take weeks to developAntiepileptic effect persists after dose stoppedPoor correlation between conc and effect
Protein binding 90-95%Dose dependent (free fraction varies with concentration)Displaced from protein by fatty acids (meals), aspirin
Side effects: GI, drowsiness, tremor, hepatotoxicity (in young children), haematological. teratogenicMonitoring generally unnecessary
Valproate - psychiatric indications
Acute mania Acute depression ?Prophylaxis of bipolar and schizoaffective disorder
Valproate in mania(Bowden et al., 1996)
-120
-100
-80
-60
-40
-20
0
20
40
60
80
0 20 40 60 80 100 120 140 160 180
Valproate, mg/L
% change in mania
scale
AminoglycosidesPoor oral absorption – give parenterallyNo metabolism or protein binding – renal excretionHalf-life 2-4h (much longer in renal failure)Toxicity – nephrotoxicity and ototoxicityMonitoring essential for control/toxicityExtended dose interval
High peaks, low troughs7 mg/kg gentamicin
Use TDM to determine interval, not dose (e.g. Hartford nomogram)
Not applicable to children (?), pregnancy, ascites, endocarditis, CF, burns, neutropenia, CrCl < 20 mL/min
Extended interval aminoglycosides:dosing (Hartford nomogram)
0
5
10
15
20
25
30
35
6.00 14.00Time post dose (h)
Conc.(mg/L)
6 10 14
Every 48h
Every 36h
Every 24h
DigoxinSamples must be at least 6h post-doseOther factors (e.g. K+) influence response/toxicityMonitoring not indicated in most patientsMonitor if:
Response poor? Toxic? Stop drug
0
0.5
1
1.5
2
2.5
0
C/Css
5 10 15 20 25Hours post dose
Digoxin post-dose(Nicholson, 1980)
LithiumHalf-life 10-35 h (longer in elderly/poor renal function)Not protein boundExcreted in urine Side effects – thirst, polyuria, nephrogenic DI, hypothyroidism, renal impairment, comaMonitor at 12h post-doseTarget range @ 12h 0.4-0.8 mmol/L (up to 1.2 in acute Rx)Individualise frequency of monitoringInteractions – dec clearance: thiazides, NSAIDsMonitoring essential at start of Rx, advisable at intervals thereafter, especially if ill/pregnant or if other drugs changed(especially diuretics)
TheophyllineShort half-life (3-13h: 4h in smokers, 24-30 h in neonates) –trough measurementsHepatic metabolismProtein binding 50-65% (less in babies)Side effects: CNS, GI, cardiacTarget range 10-20 mg/L (55-110 umol/L) (lower in babies)
Interactions: erythromycin dec clearance, enzyme inducers (phenytoin, CBZ) inc clearance Monitoring useful to identify undertreated patients, adjust dosage and confirm toxicityCompliance often erratic
Anti-retroviral drugsDrug class Examples Action
Nucleoside/nucleotide reverse transcription inhibitors (NRTIs)
ZidovudineEmtricitabineTenofovir
Inhibit RT by mimicking bases and terminating chain
Non-nucleoside RT inhibitors (NNRTIs)
EfavirenzNevirapine
Inhibit RT by binding adjacent to active site
Protease inhibitors (PIs)
Ritonavir Bind to protease and block HIV core maturation
Entry and fusion inhibitors
MaravirocEnfuvirtide
Prevent HIV from entering cells
Integrase inhibitors Raltegravir Block insertion of human proviral DNA into host DNA
Anti-retroviral drugsDrug class Examples Action
Nucleoside/nucleotide reverse transcription inhibitors (NRTIs)
ZidovudineEmtricitabineTenofovir
Inhibit RT by mimicking bases and terminating chain
Non-nucleoside RT inhibitors (NNRTIs)
EfavirenzNevirapine
Inhibit RT by binding adjacent to active site
Protease inhibitors (PIs)
Ritonavir Bind to protease and block HIV core maturation
Entry and fusion inhibitors
MaravirocEnfuvirtide
Prevent HIV from entering cells
Integrase inhibitors Raltegravir Block insertion of human proviral DNA into host DNA
TDM used
Essentials for effective TDMRational indication for assayAppropriate sampleAccurate analysisCorrect interpretationNecessary action taken
TDM - questionsPatient not responding to therapy
Could this be due to inadequate plasma concentration?Why is plasma concentration inadequate?
Poor compliance?Inappropriate dosage?Rapid metabolism?Malabsorption?
Could patient’s symptoms be caused by drug toxicity?
SampleHas steady-state been reached?
(>4 to 5 half-lives after dose change)
? Appropriate timing after last dose
InterpretationConcept of the “Therapeutic Range”
a guide to aim at!
“Therapeutic decisions should never be based solely on the drug concentration in the serum”
(Koch-Weser, 1972)
Pharmacogenetics
Links differences in gene structure (polymorphisms) to drug metabolism and response
(Genotype) (Phenotype)
Genetic Drug metabolism
variation & response
“One of the most striking things about modern medicines is how often they fail to work”
Goldstein
NEJM 6.2.2003
Variation between individuals
Pharmacogenomics and pharmacogenetics
PharmacogeneticsRefers to the study of inherited differences in drug metabolism and responseSingle gene/phenotype
PharmacogenomicsRefers to the general study of genes determining drug behaviourMultiple genes/phenotypes
(In practice, the two terms are used interchangeably!)
Possible pharmacokinetic consequences of polymorphisms
• Decreased first-pass effect• greater bioavailability• higher peak Cp
• Reduced parent drug elimination• longer half-life• more/fewer active metabolites
• Altered concentration-effect relationship between poor and good metabolisers
Applications of pharmacogenomics
Drug developmentMore targeted, more powerful drugs
Individualization of therapyThe right drug and the right dose for every patient
Predicting ADRs (& reducing mortality)Defining susceptibilityIdentifying potential addictionReducing cost of health care
1Positive
Response, Works as intended
2No Response, Choose new
drug
Adverse drug reaction
3
(Michael Murphy, Gentris)
Use of PGx:
Use of PGx
• Don’t treat non-responders (stratification)
• Don’t treat those most susceptible to toxicity (stratification)
• Adjust dose to maximise efficacy while avoiding toxicity
Estimated cost of ADRs
US: $100 billion per year….(Ingelman-Sundberg, 2001)
NHS: £2 billion per year(Compass Thinktank, 2008)
Can PGx reduce ADRs?
Systematic review (Phillips KA et al, JAMA 2001; 286: 2270-9)
- Identified 27 drugs frequently cited in ADRs(among top 200 used in US);
- 59% of these metabolized by at least 1 enzyme with variant alleles known to cause poor metabolism
- Conversely, only 7 - 22% of randomly selected drugs are known to be metabolized by enzymes with genetic variability
Clinical applications of pharmacogeneticinformation
• Anti-coagulation• Warfarin
• Psychiatry• Tricyclic anti-
depressants• Atomoxetine
• Oncology• Thiopurines• 5-fluorouracil• Herceptin
(Her-2/neu)• Tamoxifen• KRAS
• Cardiovascular• Statins
• Pain control• Codeine, methadone
• Epilepsy• Phenytoin
• Risk analysis• ADR’s• Disease
• Etc..
Enzymes of drug metabolism
• Phase 1 (oxidative) - SERCYP 1A2 CYP2B CYP 2C9CYP 2C19 CYP 2D6 CYP 2E1CYP 3A4 NADPH-quinone oxidoreductase
• Phase 2 (conjugative) - cytosolGlutathione S-transferaseN-acetyltransferaseUDP-glucuronosyltransferaseSulphotransferases
Enzymes of drug metabolism(showing polymorphisms in humans)
• Phase 1 (oxidative) - SERCYP 1A2 CYP2B CYP 2C9CYP 2C19 CYP 2D6 CYP 2E1CYP 3A4 NADPH-quinone oxidoreductase
• Phase 2 (conjugative) - cytosolGlutathione S-transferaseN-acetyltransferaseUDP-glucuronosyltransferaseSulphotransferases
CYP enzymes have different, sometimes overlapping, substrate specificity
CYP2D6 debrisoquinetricyclicsantipsychoticsSSRI’santi-arrhythmicsanti-hypertensivesmorphine derivs
CYP2C19barbituratestricyclicssedatives
CYP3A4 tricyclicsantipsychoticsSSRI’sSedatives
CYP1A2 tricyclicsantipsychotics SSRI’sSedatives
CYP2C9anti-epilepticsanticoagulants
Nomenclature
Cytochrome P450 2 D 6 *4
Superfamily
Family
Subfamily
Isoenzyme
Allele variant
CYP 2C9 polymorphism
• 9 exons; 490 amino acids
144 359 360CYP2C9*1 Arg Ile AspCYP2C9*2 Cys Ile AspCYP2C9*3 Arg Leu AspCYP2C9*4 Arg Thr AspCYP2C9*5 Arg Ile Glu
CYP2C9 polymorphism
• CYP2C9*2 15% of Caucasians7% of Asians5-fold lower warfarinclearance
• CYP2C9*3 7% of Caucasians3% of Asians25-fold lower warfarinclearance
Warfarin
Narrow therapeutic indexMultiple clinically important drug interactionsErratic safety profile10-fold variability around dose, target INR and side-effectsPolymorphisms account for 30-50% of the variability in dosing
Warfarin PGx testing
• CYP2C9• Metabolism of S-warfarin• *2 and *3 deficiency alleles
• VKORC1 (vitamin K epoxide reductase complex subunit 1)
• Target of warfarin inhibition• Converts vit K epoxide to quinone (vit K
recycling)• Deficiency (1639 G>A) means less warfarin
target and smaller dose requirement
CYP2D6Most extensively characterised polymorphic
drug-metabolising enzyme
• more than 75 allelic variants described• more than 15 encode an inactive enzyme or
no enzyme at all • other alleles encode enzyme with reduced,
normal or increased enzyme activity
Phenotyping
• Phenotyping for the metabolism of psychoactive drugs results in 4 categories• Poor metabolizers (PM)• Intermediate metabolizers (IM)• Extensive metabolizers (EM)• Ultrarapid metabolizers (UM)
(up to 13 copies of gene)
Prevalence of CYP 2D6 phenotypes
W European ChinesePM 10% 1%IM 40%EM 49%UM 1%
0.1
1
Plasmaconc/dose(nmol/L/mg)
0 5 10 15 20 25 30 35Time (h)
Haloperidol by debrisoquine phenotype
EM
PM
(Bertilsson, 1992)
Cancer biomarkers for Rx (Milone, 2012)
Drug Disease Marker associations
Tamoxifen Breast ca CYP2D6
Irinotecan Colon ca UGTIA1*28
5-FU Colon ca DPDY, TYMS
EGFR-specific TKIs(erlotinib)
Non-small cell lung ca EGFR mutationsEGFR gene copy noKRAS mutations
EGFR-specific Ab(cetuximab)
Colon caNon-small cell lung ca
EGFR gene copy noKRAS mutations
Azathioprine, 6-MP ALL, IBD TPMT
Methotrexate Lymphoma Methotrexate conc
Busulfan Myeloablation for BMT Busulfan conc/AUC
Tamoxifen – survival by genotype
Kiyotani et al, J Clin Oncol 2010; 28: 1287-93
CYP2D6 ABCC2
Thiopurine drugs
AzathioprineProdrug for 6-mercaptopurine
Azathioprine 6-MP + imidazole
• Breakthrough in organ Tx• Extensive use as steroid-sparing agent
6-mercaptopurine
N
N
HS
NH
N
6-mercaptopurine
6-methyl-mercaptopurine
6-thiouric acid
Xanthineoxidase
TPMT
6-thioinosine 5’-monophosphate
TPMT
6-methyl thioinosine 5’-MP
6-thioxanthosine 5’-MP
6-thioguanine nucleotides
IMPdehydrogenase
GMPsynthetase
HGPRT
0
2
4
6
8
10
12
% ofsubjects
0 5 10 20RBC TPMT activity, U/mL
TPMT Genetic Polymorphism(Weinshilboum & Sladek, 1980)
15
10
100
1000
10 4
0 5 10 15 20TPMT activity, U/mL rbc
Adult dermatology patients on azathioprine(Lennard)
6 TGN (pmol/ 8 x 108 rbcs)
0
20
40
60
80
100
Relapse-freesurvival (%)
0 20 40 60 80 100
50Time (months)
Children with ALL on 6-MP
100
29 9
288
Rbc 6-TGNabove median
Rbc 6-TGNbelow median
(Lennard, 1989)
0
2
4
6
8
10
12
% of subjects
0 5 10 20RBC TPMT activity, U/mL
TPMT Genetic Polymorphism
15
Severe marrow suppression
Toxicity at full dose
Low risk
Risk of therapeutic failure
TPMT genetics
• TPMT coded by 27 kb gene• 10 exons, located on 6p22.3• Wild-type is TPMT*1• Very low activity associated with 8 variants,
most common = TPMT*3 (55-70%)• 2 point mutations
• G460-A (Ala 154 - Thr)• A719-G (Tyr 240 - Cys)
= *3B= *3C ) =*3A
TPMT – genotype and phenotype(Yates et al., Ann Intern Med 1997; 126: 608-14)
Phenotype GenotypeHigh activity (21) *1/*1 (21)
Intermediate activity (21) *1/*1 (1)*1/*2 (1)*1/*3A (18)*1/*3C (1)
Deficient (7) *2/*2 (2)*2/*3A (1)*3A/*3A (3)*3A/*3C (1)
TPMT - summary
• TPMT phenotype/genotype can prospectively identify• Deficient patients at risk of life-
threatening toxicity• Heterozygotes who will respond well to
low-dose aza therapy• Patients with high TPMT activity who will
need high doses from the start (phenotype only)
KRASGene present in colorectal cancer tumoursImportant role in cell growth and tumour developmentGene can be mutated or normal in colorectal ca. cellsIf KRAS is mutated, then anti-EGFR therapies such as cetuximab are not effective and should not be used KRAS gene mutations occur in about 40% of colorectal ca. patients Patients diagnosed with metastatic colon ca. should be tested for KRAS mutation status to determine eligibility for anti-EGFR Rx
KRAS in colorectal ca
NEJM 2004; 351:2827-31
• 62 y.o man with CLL• 3 day h/o fatigue, dyspnoea, fever,
cough• On valproate 1500 mg/day for
epilepsy• Bilateral lower lobe pneumonia• Rx antibiotics* + codeine 25mg tds
* ceftriaxone, clarithromycin, voriconazole
• Day 4: rapid deterioration of consciousness → unresponsive
• pO2 7.4 kPa; pC02 10.6 kPa. Ventilated• Transfer to ITU: GCS 6• Valproate 63 mg/L• Naloxone 0.4 mg iv x2 resulted in dramatic
improvement in conscious level.
Drug levels
• Plasma codeine 114 ug/L(expected level in pt with extensive CYP2D6 metabolism = 13-75)
• Plasma morphine 80 ug/L(expected level in pt with extensive CYP2D6 metabolism = 1-4)
CYP 2D6 genotyping
• 3 or more functional CYP2D6 alleles • Ultrarapid metabolism• Confirmed by phenotyping with
dextromethorphan
Codeine metabolism
Codeine Codeine-6-glucuronide
Norcodeine
CYP3A4
MorphineMorphine-6-glucuronide
Morphine-3-glucuronideCYP2D6
X
Strattera (atomoxetine HCl)
-prescribing information
Clopidogrel (Plavix®): FDA 2010
Effectiveness of Plavix is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 …Plavix at recommended doses forms less metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention given Plavixat recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function.Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategyConsider alternate treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers
Challenges for PGx
EthicsCostsUtilizationRegulatory
NACB consensus document, 2010
http://www.aacc.org/members/nacb/lmpg/pages/default.aspx
• “If it were not for the great variability among individuals, medicine might as well be a science and not an art”
Sir William Osler, 1892