Sample Assay Results Phenotype Clinical Consequences M · 2013-10-22 · Aripiprazole (Abilify)...

Personalized Genetic Test for Pain and Psychotropic MedicationsPatient: DOB:

Collection Date:Gender:

John Doe

2/6/2013

07/11/1969MaleAccession #: AB006

Ordered By: Report Generated: 9/6/2013Received Date: 2/6/2013

None SpecifiedIndications for Testing:

Test ResultsAssay Results Phenotype Clinical Consequences

CYP2C19 *1/*17 Rapid Metabolizer Consistent with a significant increase in CYP2C19 activity. Potential risk for side effects or loss of efficacy with drug substrates.

CYP2C9 *2/*3 Poor Metabolizer Consistent with a significant deficiency in CYP2C9 activity. Increased risk for side effects or loss of efficacy with drug substrates.

CYP2D6 *2/*41 Normal Metabolizer Consistent with a typical CYP2D6 activity. This test did not identify risks for side effects or loss of efficacy with drug substrates.

CYP3A4 *1/*1B Normal Metabolizer Consistent with a typical CYP3A4 activity. Caution is advised when prescribing narrow therapeutic index drugs. Alternative drugs or dose adjustment may be required if CYP3A inhibitors or inducers are co-prescribed.

CYP3A5 *1/*3 Intermediate Metabolizer Consistent with an intermediate CYP3A5 activity. Caution is advised when prescribing narrow therapeutic index drugs. Alternative drugs or dose adjustment may be required if CYP3A inhibitors or inducers are co-prescribed.

Phone: 360-693-8850CLIA# 50D20503972700 NE Andreson Rd.Vancouver, WA

Molecular Testing Labs

Laboratory Director: Dr. Safedin Beqaj

of 14Genetic Test Results For John Doe

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Pain MedicationsStandard Precautions Use With Caution Consider Alternatives

Codeine (Codeine)Hydrocodone (Vicodin)Oxycodone (Percocet)

Tramadol (Ultram)

Carisoprodol (Soma)Celecoxib (Celebrex)Flurbiprofen (Ansaid)Piroxicam (Feldene)

Psychotropic MedicationsStandard Precautions Use With Caution Consider Alternatives

Aripiprazole (Abilify)Atomoxetine (Strattera)

Clobazam (Onfi)Clozapine (Clozaril)

Desipramine (Norpramin)Desvenlafaxine (Pristiq)Duloxetine (Cymbalta)Haloperidol (Haldol)Iloperidone (Fanapt)

Mirtazapine (Remeron)Nortriptyline (Pamelor)Olanzapine (Zyprexa)Paliperidone (Invega)

Paroxetine (Paxil)Perphenazine (Trilafon)

Pimozide (Orap)Risperidone (Risperdal)

Sertraline (Zoloft)Venlafaxine (Effexor)

Diazepam (Valium)Phenytoin (Dilantin)

Tetrabenazine (Xenazine)

Amitriptyline (Elavil)Citalopram (Celexa)

Clomipramine (Anafranil)Doxepin (Silenor)

Escitalopram (Lexapro)Imipramine (Tofranil)

Trimipramine (Surmontil)

Amitriptyline (Elavil)Increased Sensitivity to Amitriptyline (CYP2C19 *1/*17 Rapid Metabolizer)Consider an alternative drug or consider prescribing amitriptyline at standard dose and monitor the plasmaconcentrations of amitriptyline and nortriptyline to guide dose adjustments.

Aripiprazole (Abilify)Normal Sensitivity to AripiprazoleAripiprazole can be prescribed at standard label recommended-dosage and administration. Careful titration isrecommended until a favorable response is achieved. The maximum recommended dose is 30 mg/day.

Atomoxetine (Strattera)Normal Sensitivity to AtomoxetineAtomoxetine can be prescribed at standard label recommended-dosage and administration. Careful titration isrecommended until a favorable response is achieved. The maximum recommended daily dose is 1.4 mg/kg forpatients with a body weight up to 70 kg and 100 mg for patients with a body weight above 70 kg.

Carisoprodol (Soma)Altered Sensitivity to Carisoprodol (CYP2C19 *1/*17 Rapid Metabolizer)There is insufficient data to allow calculation of dose adjustment and if carisodoprol is prescribed, it is recommendedto use a lower dose and to carefully monitor the patient for side effects.

Drug/therapy guidancePatient Medications Affected by Patient Genetic Results:Patient Medications for which there is no Pharmacogenetic Guidance:





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Celecoxib (Celebrex)High Sensitivity to Celecoxib (CYP2C9 *2/*3 Poor Metabolizer)Consider starting at half the lowest recommended dose and evaluate response the first week. Be alert togastrointestinal adverse events. Consider alternative medication for the management of Juvenile RheumatoidArthritis.

Citalopram (Celexa)Insufficient Response to Citalopram (CYP2C19 *1/*17 Rapid Metabolizer)The patient may not respond to usual doses. Monitor plasma concentration and increase dose to a maximum of 150%in response to efficacy and adverse events or select alternative drug.

Clobazam (Onfi)Normal Sensitivity to ClobazamThere is insufficient data to allow calculation of dose adjustment when clobazam is prescribed. Therefore, the dosingrecommendation for normal metabolizers is proposed. Clobazam can be prescribed at standard label-recommendeddosage and administration. Individualize dosing within each body weight group, based on clinical efficacy andtolerability. Do not proceed with dose escalation more rapidly than weekly, because serum concentrations of clobazamand its active metabolite require 5 and 9 days, respectively, to reach steady-state. Recommended daily dosing: ≤30kg body weight: starting dose 5 mg; day 7: 10 mg and day 14: 20 mg; >30 kg body weight: starting dose 10 mg, day 7:20 mg and day 14: 40 mg.

Clomipramine (Anafranil)Increased Sensitivity to Clomipramine (CYP2C19 *1/*17 Rapid Metabolizer)Consider an alternative drug or consider prescribing clomipramine at standard dose and monitor the plasmaconcentrations of clomipramine and desmethyl-clomipramine to guide dose adjustments.

Clozapine (Clozaril)Normal Sensitivity to ClozapineClozapine can be prescribed at standard label recommended-dosage and administration. Careful titration isrecommended with monitoring until a favorable response is achieved.

Codeine (Codeine)Normal Response to CodeineCodeine can be prescribed at standard label recommended-dosage and administration.

Desipramine (Norpramin)Normal Sensitivity to DesipramineDesipramine can be prescribed at standard label recommended-dosage and administration.

Desvenlafaxine (Pristiq)Normal Sensitivity to DesvenlafaxineDesvenlafaxine can be prescribed at standard label recommended-dosage and administration.

Diazepam (Valium)Altered Sensitivity to Diazepam (CYP2C19 *1/*17 Rapid Metabolizer)There is insufficient data to allow calculation of dose adjustment when diazepam is prescribed. Monitor the responseand adjust the dose accordingly or select an alternative drug.

Doxepin (Silenor)Increased Sensitivity to Doxepin (CYP2C19 *1/*17 Rapid Metabolizer)Consider an alternative drug or consider prescribing doxepin at standard dose and monitor the plasma concentrationsof doxepin and desmethyl-doxepin to guide dose adjustments.





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Duloxetine (Cymbalta)Normal Sensitivity to DuloxetineDuloxetine can be prescribed at standard label recommended-dosage and administration.

Escitalopram (Lexapro)Insufficient Reponse to Escitalopram (CYP2C19 *1/*17 Rapid Metabolizer)Monitor plasma concentration and titrate dose to a maximum of 150% in response to efficacy and adverse events orselect alternative drug.

Flurbiprofen (Ansaid)High Sensitivity to Flurbiprofen (CYP2C9 *2/*3 Poor Metabolizer)At standard dosge, plasma concentrations of flurbiprofen are expected to be high resulting in an increased risk oftoxicity. Administer flurbiprofen with caution and reduce dose if necessary.

Haloperidol (Haldol)Normal Sensitivity to HaloperidolHaloperidol can be prescribed at standard label recommended-dosage and administration. Careful titration isrecommended until a favorable response is achieved.

Hydrocodone (Vicodin)Normal Response to HydrocodoneHydrocodone can be prescribed at standard label recommended-dosage and administration.

Iloperidone (Fanapt)Normal Sensitivity to IloperidoneIloperidone can be prescribed at standard label recommended-dosage and administration. Iloperidone must be titratedslowly from a low starting dose to avoid orthostatic hypotension. If patients taking iloperidone experience symptomsthat could indicate the occurrence of cardiac arrhythmias, e.g., dizziness, palpitations, or syncope, the prescribershould initiate further evaluation, including cardiac monitoring.

Imipramine (Tofranil)Increased Sensitivity to Imipramine (CYP2C19 *1/*17 Rapid Metabolizer)Consider an alternative drug or consider prescribing imipramine at standard dose and monitor the plasmaconcentrations of imipramine and desipramine to guide dose adjustments.

Mirtazapine (Remeron)Normal Sensitivity to MirtazapineMirtazapine can be prescribed at standard label recommended-dosage and administration. Careful titration isrecommended until a favorable response is achieved.

Nortriptyline (Pamelor)Normal Sensitivity to NortriptylineNortriptyline can be prescribed at standard label recommended-dosage and administration.

Olanzapine (Zyprexa)Normal Sensitivity to OlanzapineOlanzapine can be prescribed at standard label recommended-dosage and administration. Careful titration isrecommended until a favorable response is achieved.





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Oxycodone (Percocet)Normal Response to OxycodoneOxycodone can be prescribed at standard label recommended-dosage and administration.

Paliperidone (Invega)Normal Sensitivity to PaliperidonePaliperidone can be prescribed at standard label recommended-dosage and administration.

Paroxetine (Paxil)Normal Sensitivity to ParoxetineParoxetine can be prescribed at standard label recommended-dosage and administration. Careful titration isrecommended until a favorable response is achieved.

Perphenazine (Trilafon)Normal Sensitivity to PerphenazinePerphenazine can be prescribed at standard label recommended-dosage and administration.

Phenytoin (Dilantin)High Sensitivity to Phenytoin (CYP2C9 *2/*3 Poor Metabolizer)Consider a standard loading dose and reduce maintenance dose by 50%. Evaluate response and serumconcentrations after 7-10 days. Be alert to neurological concentration-related adverse events.

Pimozide (Orap)Normal Sensitivity to PimozidePimozide can be prescribed at standard label recommended-dosage and administration. Starting dose: 1 to 2 mg/day(adult) or 0.05 mg/kg/day (children) - Doses may be increased to a maximum of 10 mg/day or 0.2 mg/kg/day.

Piroxicam (Feldene)High Sensitivity to Piroxicam (CYP2C9 *2/*3 Poor Metabolizer)At standard dosge, plasma concentrations of piroxicam are expected to be high resulting in an increased risk oftoxicity. Administer piroxicam with caution and reduce dose if necessary.

Risperidone (Risperdal)Normal Sensitivity to RisperidoneRisperidone can be prescribed at standard label recommended-dosage and administration. Careful titration isrecommended until a favorable response is achieved.

Sertraline (Zoloft)Normal Sensitivity to SertralineSertraline can be prescribed at standard label-recommended dosage and administration.

Tetrabenazine (Xenazine)Normal Sensitivity to Tetrabenazine (CYP2D6 *2/*41 Normal Metabolizer)Individualization of dose with careful weekly titration is required. The first week’s starting dose is 12.5 mg daily; secondweek, 25 mg (12.5 mg twice daily); then slowly titrate at weekly intervals by 12.5 mg to a tolerated dose. The maximum daily dose in CYP2D6 normal metabolizers is 100 mg with a maximum single dose of 37.5 mg . Ifserious adverse events occur, titration should be stopped and the dose of tetrabenazine should be reduced. If theadverse event(s) do not resolve, consider withdrawal of tetrabenazine.





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Tramadol (Ultram)Normal Response to TramadolTramadol can be prescribed at standard label recommended-dosage and administration. Individualization of dose withcareful weekly titration is recommended.

Trimipramine (Surmontil)Increased Sensitivity to Trimipramine (CYP2C19 *1/*17 Rapid Metabolizer)Consider an alternative drug or consider prescribing trimipramine at standard dose and monitor the plasmaconcentrations of trimipramine and desmethy-ltrimipramine to guide dose adjustments.

Venlafaxine (Effexor)Normal Sensitivity to VenlafaxineVenlafaxine can be prescribed at standard label recommended-dosage and administration. Careful titration isrecommended until a favorable response is achieved.

Test DetailsGene Genotype Phenotype Alleles TestedCYP2C19 *1/*17 Rapid Metabolizer *2, *3, *4, *4B, *5, *6, *7, *8, *9, *10, *17CYP2C9 *2/*3 Poor Metabolizer *2, *3, *4, *5, *6, *11CYP2D6 *2/*41 Normal Metabolizer *2, *2A, *3, *4, *4K, *4M, *6, *7, *8, *9, *10, *12,

*14A, *17, *41, *5 (gene deletion), XN (gene duplication)

CYP3A4 *1/*1B Normal Metabolizer *1B, *2, *3, *12, *17CYP3A5 *1/*3 Intermediate Metabolizer *3C, *1D, *2, *3, *3B, *6, *7, *8, *9

Results reviewed by: Dr. Safedin Beqaj

[email protected] and coments regarding this test:

Methodology and Limitations: Testing for genetic variation/mutation on listed genes was performed using multiplex PCR and Allele Specific Primer Extension (ASPE)fallowed by hybridization microarray technology. These results do not rule out the possibility that this individual could be a carrier of othermutations/variations not detected by this gene mutation/variation panel. Rare mutations surrounding these alleles may also affect ourdetection of genetic variations. Other non-genetic and genetic factors that are not tested by this assay can affect the management andsensitivity of drugs. Thus, the interpretation is given as a probability. Therefore, this genetic information shall be interpreted in conjunctionwith other clinical findings and familial history for the administration of specific drug.

FDA Disclaimer: This test was developed and its performance characteristics determined by Molecular Testing Labs. It has not been approved by the USFederal and Drug Administration (FDA). The FDA has determined that such clearance or approval is not necessary. This test is used forclinical purposes. It should not be regarded as investigational or for research. The laboratory is regulated under the Clinical LaboratoryImprovement Act of 1988 as qualified to perform high complexity clinical testing.





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Appendix: Clinical Utility of Tested Enzymes/GenesCYP2C19

Clinical Utility: The Cytochrome P450 2C19 (CYP2C19) is involved in the metabolism of 10% of clinically importantmedications. This enzyme is highly polymorphic and more than 30 different variant alleles have been identified. The CYP2C19assay identifies some common variants that are associated variability in CY2C19 enzyme activity, which has importantpharmacological and toxicological implications for antidepressants and some benzodiazepines.

Assay Interpretation: CYP2C19 enzyme activity defines either a normal or an abnormal (intermediate, poor and rapid)metabolizer status for a given individual. Several variant alleles have been identified within the CYP2C19 gene and result intodifferent forms of the CYP2C19 enzyme that functionally are fully active, partially active, inactive or with increased activity. TheCYP2C19*1 allele is considered the wild type and encodes a functionally active enzyme (normal). The alleles *2, *3 *4, *5, *6and *8 encodes an inactive enzyme and are referred to as loss-of function alleles. Individuals with a *17 allele have an increasedCYP2C19 activity.

The genotype-phenotype relationship is established based on the alleles detected. Individuals 2 fully functional alleles areconsidered normal (extensive) metabolizers. Individuals with one or two loss-of-function allele are considered intermediate andpoor metabolizers, respectively. Individuals with one or two increased activity allele(s) are considered rapid (ultra-rapid)metabolizers. Because of limited evidence, an individual with one increased activity allele and one loss-of-function allele isprovisionally classified as intermediate metabolizer.

The reference range for CYP2C19 metabolic activity is CYP2C19 *1/ *1 which is consistent with a normal metabolizer.

Reported Frequencies of CYP2C19 Phenotypes

Reported Genotypes CYP2D6 Activity Predicted Phenotype Frequencies

Two Functional Alleles Normal Normal Metabolizer Caucasians: 42%African Americans: 39%Asians: 41%

One fully functional allele and one inactive alleleOne increased activity allele with an inactive allele

Abnormal: reduced Intermediate Metabolizer Caucasians: 19%African Americans: 15%Asians: 30-50%

Two copies of inactive alleles

Abnormal: absent Poor Metabolizer Caucasians: 3%African Americans: 7%Asians: 2-20%

One increased activity allele and one fully functional alleleTo increased activity alleles

Abnormal: increased Rapid Metabolizer Caucasians: 5-27%African Americans: 7%Asians: <1%





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CYP2C19 Inhibitors and Inducers

Strong Inhibitors Inducers

Fluvoxamine, fluoxetine, felbamate, ticlopidine, omeprazole, esomeprazole, voriconazole, modafinil, oxcarbazepine, cimetidine, etravirine, topiramate

Rifampin, carbamazepine, St John’s Wort, artemisinin

References: 1: Preskorn SH. Clinically important differences in the pharmacokinetics of the ten newer "atypical" antipsychotics: Part 2.Metabolism and elimination. J Psychiatr Pract. 2012 Sep;18(5):361-8. 2: Preskorn SH. Clinically important differences in the pharmacokineticsof the ten newer "atypical" antipsychotics: part 1. J Psychiatr Pract. 2012 May;18(3):199-204. 3: Hicks et al. Clinical PharmacogeneticsImplementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants. Clin Pharmacol Ther.2013 Jan 16 4: Swen et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther. 2011 May;89(5):662-73. 5:Wilffert et al. KNMP working group Pharmacogenetics. From evidence based medicine to mechanism based medicine. Reviewing the role ofpharmacogenetics. Int J Clin Pharm. 2011 Feb;33(1):3-9. 6-Psychiatric Pharmacogenomics. David A. Mrazek. Publisher: Oxford UniversityPress, USA; 1 edition (May 28, 2010)

Clinical Implications: There is substantial evidence linking the CYP2C19 polymorphisms to variability in the pharmacologicaland safety profiles of the following therapies used in psychiatric conditions: Amitriptyline (Elavil), Sertraline (Zoloft), Citalopram(Celexa), Escitalopram (Lexapro) and Diazepam (Valium) and Imipramine (Tofranil).

Inhibitors of CYP2C19 enzyme may modify its activity and change the patient’s metabolizer status. This can result in drug-druginteractions when a drug substrate is prescribed with the known CYP2C19 inhibitors or inducers.





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CYP2C9

Clinical Utility: The Cytochrome P450 2C9 (CYP2C9) is involved in the metabolism of 15% of clinically important medications.This enzyme is highly polymorphic and to date, 30 different variant alleles have been identified. The CYP2C9 assay identifiessome common variants that are associated variability in CY2C19 enzyme activity, which has important pharmacological andtoxicological implications for anticonvulsants and certain antidepressants.

Assay Interpretation: CYP2C9 enzyme activity defines either a normal or an abnormal (intermediate and poor) metabolizerstatus for a given individual. Several variant alleles have been identified within the gene and result into different forms of theCYP2C9 enzyme that functionally are either fully active, partially active, or inactive. The CYP2C9*1 allele is considered the wildtype and encodes a functionally active enzyme (normal). The alleles *2, *3, *4 and *4 encodes a partially active enzyme. Theallele *6 is a null allele corresponding to a whole gene deletion and therefore result in an enzyme with no activity at all.

The genotype-phenotype relationship is established based on the alleles detected. Individuals with two fully active alleles areconsidered normal (extensive) metabolizers. Individuals with one fully active allele with either a partially active or an inactiveallele are considered intermediate metabolizers. Individuals with two partially active alleles or with two inactive alleles areconsidered poor metabolizers.

The reference range for CYP2C9 metabolic activity is CYP2C9 *1/ *1 which is consistent with a normal metabolizer.

Reported Frequencies of CYP2C9 Phenotypes

Reported Genotypes CYP2D6 Activity Predicted Phenotype Frequencies

Two fully active alleles Normal Normal Metabolizer Caucasians: 62%African Americans: 75%Asians: 84%

One fully active with either a partially active or with an inactive allele

Abnormal: reduced Intermediate Metabolizer Caucasians: 9-24%African Americans: 3.5-5%

Two inactive alleles or two partially inactive alleles

Abnormal: poor Poor Metabolizer Caucasians: 0.3-2.3%African Americans: 0.1-2.3%Asians: 0.2%

Clinical Implications: CYP2C9 plays a role in the metabolism of the following drugs used to treat depression and epilepsy:fluoxetine (Zoloft), phenytoin (Dilantin), primidone (Mysoline) and amitriptyline (Elavil).

Inhibitors of CYP2C9 enzyme may modify its activity and change the patient’s metabolizer status. This can result in drug-druginteractions when a drug substrate is prescribed with the known CYP2C9 inhibitors or inducers.





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References: 1: Swen et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther. 2011 May;89(5):662-73. 2:Wilffert et al. KNMP working group Pharmacogenetics. From evidence based medicine to mechanism based medicine. Reviewing the role ofpharmacogenetics. Int J Clin Pharm. 2011 Feb;33(1):3-9. 3: Wang et al. Genetic polymorphism of the human cytochrome P450 2C9 gene andits clinical significance. Curr Drug Metab. 2009 Sep;10(7):781-834.

CYP2C9 Inhibitors and Inducers

Inhibitors Inducers

amiodarone,fluconazole,miconazole, oxandrolone, capecitabine, cotrimoxazole, etravirine, fluvastatin, metronidazole, miconazole, phenytoin, sulfinpyrazone, sulfamethoxazole, tigecycline, voriconazole, zafirlukast

carbamazepine, rifampin, St John’s Wort, aprepitant, bosentan, phenobarbital, primidone, phenytoin





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Clinical Implications: The high rate of therapeutic failure in psychiatric disorders may be in part attributed to adverse effects oraltered plasma concentrations of therapies used. There is substantial evidence linking the CYP2D6 polymorphisms to variabilityin the pharmacological and safety profiles of the following psychotropics: desipramine (Norpramin), imipramine (Tofranil),amitriptyline (Elavil), nortriptyline (Pamelor), haloperidol (Haldol), trimipramine (Surmontil), venlafaxine (Effexor), doxepin(Silenor), aripiprazole (Abilify), atomoxetine (Strattera), duloxetine (Cymbalta), risperidone (Risperdal), clomipramine (Anafranil),pimozide (Orap). Go to the suggested guide for management of psychotropic drugs (pages 2-3) for specific recommendations.

Inhibitors of CYP2D6 enzyme may modify its activity and change the patient’s metabolizer status. This can result in drug-druginteractions when a drug substrate is prescribed with the known CYP2D6 inhibitors. Although, there are no known clinicalinducers of CYP2D6, the pharmacokinetics of a drug substrate can be affected by inducers of other enzymes (like CYP3A) thatare involved in the metabolism of that drug.

Reported Frequencies of CYP2D6 Phenotypes Reported Genotypes CYP2D6 Activity Predicted Phenotype Frequencies

Activity Score: 1-2 Normal Normal Metabolizer Caucasians: 50-80%African Americans: 63%Asians: 50%

Activity Score: 0.5 Abnormal: reduced Intermediate Metabolizer Caucasians: 14-37%African Americans: 30%Asians: 49%

Activity Score: 0 Abnormal: absent Poor Metabolizer Caucasians: 3-8%African Americans: 2-7%Asians: 0-4.8%

Activity Score: >2 Abnormal: increased Rapid Metabolizer Caucasians: 1-10%African Americans: 3%Asians: 1%

CYP2D6

Clinical Utility: The Cytochrome P450 2D6 (CYP2D6) is involved in the metabolism of 25% of clinically important medications.This enzyme is highly polymorphic and more than 100 different variant alleles have been identified. The CYP2D6 assay identifiessome common variants that are associated variability in CYP2D6 enzyme activity, which has important pharmacological andtoxicological implications for antidepressants and antipsychotics.

Assay Interpretation: CYP2D6 enzyme activity defines either a normal or an abnormal (intermediate, poor and rapid)metabolizer status for a given individual. Commonly tested CYP2D6 variant alleles, are classified into functional groups: Fullfunction (e.g., CYP2D6 *1 and *2), Reduced function (e.g. CYP2D6*9, *10, *17, *29 and *41) and No function (e.g. CYP2D6 *3,*4, *5, *6, *7, *8, *12, *14). Increased CYP2D6 activity is found in individuals carrying multiple copies of functional alleles.CYP2D6 is subject to gene duplications and these are denoted “xN”, where xN represents the number of CYP2D6 gene copieswhen available.

The genotype -phenotype relationship is established using a scoring system that assigns an activity value to every CYP2D6allele in order to assign a predicted phenotype. For a given genotype, the activity values of the constituent alleles are addedtogether to calculate the CYP2D6 activity score. This activity score (AS) is then used to assign a predicted phenotype as follows:AS of 0 predicts a poor metabolizer, AS ranging between 1 and 2 predicts a normal (extensive) metabolizer, AS=0.5 predicts anintermediate metabolizer and AS greater than 2 predicts a rapid (ultra-rapid) metabolizer. Fully functional alleles are assigned anactivity value of 1, reduced function alleles have an activity value of 0.5 while non-functional alleles are assigned an activity valueof 0.





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References: 1- Swen et al. Pharmacogenetics: from bench to byte--an update of guidelines. Clin Pharmacol Ther. 2011 May;89(5):662-73. 2:Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet. 2009;48(12):761-804. 3:Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet. 2009;48(11):689-723. 4:Preskorn SH. Clinically important differences in the pharmacokinetics of the ten newer "atypical" antipsychotics: Part 2. Metabolism andelimination. J Psychiatr Pract. 2012 Sep;18(5):361-8. 5: Preskorn SH. Clinically important differences in the pharmacokinetics of the ten newer"atypical" antipsychotics: part 1. J Psychiatr Pract. 2012 May;18(3):199-204. 6: D'Empaire et al. Antidepressant treatment and altered CYP2D6activity: are pharmacokinetic variations clinically relevant? J Psychiatr Pract. 2011 Sep;17(5):330-9. 7: Hicks et al. Clinical PharmacogeneticsImplementation Consortium Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants. Clin Pharmacol Ther.2013 Jan 16. 8: Gaedigk et al. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. ClinPharmacol Ther. 2008 Feb;83(2):234-42.

CYP2D6 Inhibitors

Strong Inhibitors Moderate Inhibitors Weak Inhibitors

Bupropion, fluoxetine, quinidine, paroxetine

Cinacalcet, duloxetine, terbinafine

Amiodarone, celecoxib, clobazam, cimetidine, desvenlafaxine, diltiazem, diphenhydramine, echinacea, escitalopram, febuxostat, gefitinib, hydralazine, hydroxychloroquine, imatinib, methadone, oral contraceptives, pazopanib, perphenazine, propafenone, ranitidine, ritonavir, sertraline, telithromycin, verapamil, vemurafenib





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CYP3A4 and CYP3A5

Clinical Utility: The cytochrome P450 3A4 and 3A5 (CYP3A4 and CYP3A5) account for 40-80% of total CYP in human liver andintestine, respectively. Most importantly, CYP3A enzymes metabolize 50% of commonly used drugs. CYP3A4 and CYP3A5enzymes have overlapping substrate specificity and the contribution of CYP3A5 in the overall metabolism is smaller than the onefor CYP3A4. The overall CYP3A metabolism status is expected to affect drug that have a narrow therapeutic index.

Assay Interpretation: Amongst the many polymorphism variants identified within the CYP3A4 gene, very few have beenassociated with significant alterations in enzyme activity and subsequent, variability in therapeutic response. For CYP3A5,individuals with the less prevalent “normal metabolizer phenotype” may metabolize drugs faster than the more common “poormetabolizers” resulting in toxicity or loss of efficacy.

The CYP3A4*1B variant is the most studied and results in an enzyme with a moderately decreased activity. It occurs in 50% ofAfrican Americans, 3-5% of Caucasians and <1% of Asians. The CYP3A4*2, *3, *12 and *17 are also considered decreasedactivity alleles. The genotype-phenotype relationship for CYP3A4 is not well established and individuals are predicted to haveeither a CYP3A4 normal or intermediate metabolic capacity. No poor metabolizers have been reported to date.

The reference range for CYP3A4 metabolic activity is CYP3A4 *1/ *1 which is consistent with a normal metabolizer.

The CYP3A5*3 variant results in an enzyme with no activity and is the most common variant in the general population. TheCYP3A5*3B and *6 are also null alleles resulting in no enzyme activity. The CYP3A5 alleles *2, 8 and 9 result in an enzyme thatis partially active. The CYP3A5 *1 allele produces an active enzyme and is found in 5% of Caucasians, 20% of Asians and 15-50% of Africans. Individuals with two CYP3A5 inactive alleles are classified as poor metabolizers. Individuals carrying at leastone copy of a CYP3A active allele are either normal or intermediate metabolizers. CYP3A5 poor metabolizers represent 50% ofAsians and 90% of Caucasians.

The reference range for CYP3A5 is CYP3A5 *1/ *1 which is consistent with a normal metabolizer. This genotype is theleast prevalent in a given population.

Clinical Implications: CYP3A4 and CYP3A5 genotypes can help identify patients with high or low overall CYP3A activity.Although these two enzymes metabolize many drugs, the response of only a few (like narrow therapeutic index drugs) isexpected to change significantly by genetic polymorphisms. There is limited evidence on the impact of CYP3A polymorphism andtherapeutic outcome. The following drugs are metabolized extensively by CYP3A: Antiepileptics: carbamazepine (Tegretol);Antipsychotics: quetiapine (Seroquel); ziprasidone (Geodon). Benzodiazepines: alprazolam (Xanax), midazolam, triazolam(Halcion); Antidepressants: nefazodone (Serzone), trazodone (Oleptro), vilazodone (Vibryd). Other: zaleplon (Sonata), zolpidem(Ambien).

CYP3A metabolism is highly sensitive to inhibition and induction when multiple drugs are taken by a patient and the occurrenceof drug-drug interactions can have profound effects on the pharmacokinetics, the response and safety profiles of many CYP3Adrug substrates.





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CYP3A Inhibitors

Strong Inhibitors Moderate Inhibitors Weak Inhibitors

Ketoconazole, itraconazole,, posaconazole, voriconazole, clarithromycin, telithromycin, grapefruit juice (high dose) conivaptan, nefazodone, ritonavir, saquinavir, lopinavir, nelfinavir

Cinacalcet, duloxetine, terbinafine

Amiodarone, celecoxib, clobazam, cimetidine, desvenlafaxine, diltiazem, diphenhydramine, echinacea, escitalopram, febuxostat, gefitinib, hydralazine, hydroxychloroquine, imatinib, methadone, oral contraceptives, pazopanib, perphenazine, propafenone, ranitidine, ritonavir, sertraline, telithromycin, verapamil, vemurafenib

CYP3A Inducers

Strong Inducers Moderate Inducers Weak Inducers

Avasimibe, carbamazepine,, phenytoin, phenobarbital, rifampin, st John’s Wort

Bosentan, efavirenz, modafinil, nafcillin, rifabutin

Amprenavir, aprepitant, clobazam, echinacea,, pioglitazone, prednisolone

References: 1- Metabolic Drug Interac ons. RH Levy, KE Thummel, WF Trager. Publisher: Lippinco Williams & Wilkins (March 15, 2000). 2: Zhou et al.Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev. 2009;41(2):89-295 3- Isoherranen et al. The influence ofCYP3A5 expression on the extent of hepa c CYP3A inhibi on is substrate-dependent: an in vitro-in vivo evalua on. Drug Metab Dispos. 2008 Jan;36(1):146-54. 4- Williams et al. A significant drug-metabolizing role for CYP3A5? Drug Metab Dispos. 2003 Dec;31(12):1526-30. 5- Elens et al. A new func onalCYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokine cs in kidney transplant recipients. Clin Chem. 2011 Nov;57(11):1574-83. 6-Elens et al. Effect of a new func onal CYP3A4 polymorphism on calcineurin inhibitors' dose requirements and trough blood levels in stable renal transplantpa ents. Pharmacogenomics. 2011 Oct;12(10):1383-96. 7-Lamba et al. Gene c contribu on to variable human CYP3A-mediated metabolism. Adv DrugDeliv Rev. 2002 Nov 18;54(10):1271-94.





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