1. Laboratory Reports and Services
Kristen K. Reynolds, PhD
VP Laboratory Operations
Copyright 2010 PGXL Laboratories, Louisville KY
All materials herein are the exclusive property of PGXL Laboratories

2. Overview Test menu and clinical applications Report formats
Consultation and support services

3. Current Test Menu PHARMACOGENETICS MOLECULAR ONCOLOGY
- CYP2D6
- CYP2C19
- CYP2C9/VKORC1
- CYP2C9
- CYP1A2
- CYP3A4
- CYP3A5
- NAT2
- HLA-B*5701 Abacavir FUTURE
SLC6A4 Serotonin Transporter OPRM1 (opioid sensitivity/resistance)
SLCO1B1 Statins
SULT4A1 Olanzapine
- MTHFR
- Factor II (Prothrombin G>A)
Factor V Leiden
Hepatitis-B Virus DNA Quantitative
- CYP2D6 tamoxifen
KRAS
- BRAF
BCR/ABL (quantitative)
MOLECULAR ONCOLOGY
PHARMACOGENETICS 3

4. PGXL Core Panel
Metabolism of >85% of medications CYP2D6 CYP2C9 CYP2C19 CYP3A4 CYP3A5 CYP1A2

5. Panels* Panel 1: CYP2D6 CYP2C9 CYP2C19 CYP3A4 CYP3A5 CYP1A2
Panel 2: Panel 1 + thrombophilia (FVL, FII, MTHFR)
Panel Add-Ons (build specialty-specific):
VKORC1 (warfarin)
SLC6A4 (SSRIs)
SLCO1B1 (statins)
OPRM1 (opioids)
*All genes always orderable a la carte

6. Genotype Frequency % Gene EM IM PM UM 2D6 53 35 10 2 2C19 36 32 4 2857 40 3 NA
3A4 87 12 1
3A5 18 81

7. Genotype Interpretations
Regulations require
Summary of variants and methods
Clinical interpretation
Including limitations, clinical implications
Implications can be based on the patient-specific scenario
Clinical implications of geno-pheno correlation, not just po or neg without ramifications
CLIA; Mol 36000, 36125; MOLPATH Checklist, CAP 2010; NACB PGx LMPG 2010

8. Should the result be linked to a specific drug usage?
Associating genotype to clinical metabolizer status
Genotype AND substrate dependent
Prodrug versus active drug
Providing patient-specific drug-gene interaction information
Inducers, inhibitors
NACB PGx LMPG 2010

9. Application of PGx to Cardiology

10. Cardiology Med List
**indicates prodrug

11. Warfarin Genotyping CYP2C9 sets the rate, affects time to SS
(accumulation and elimination)
Avoid misinterpretation of INR and premature dose changes
6.7 ± 3.3 mg
VKORC1 sets the target concentration
(predicts warfarin sensitivity)
4.2 ± 2.2 mg
2.7 ± 1.2 mg

12. Warfarin Genotyping Guides dose selection
Estimates Maintenance Dose Requirement
Guides optimal INR interpretation
Estimates Time to Reach Steady-State
Avoid misinterpretation of INR and premature dose changes

13. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
CYP2C9 Poor Metabolizer (PM): This patient’s genotype is consistent with significantly reduced CYP2C9 enzymatic activity. Reduced CYP2C9 activity leads to lower dose requirement (e.g., warfarin) due to decreased clearance, increased elimination half-life, and increased time to reach steady-state blood concentrations.
VKORC1 Intermediate Warfarin Sensitivity: ‡The warfarin maintenance dose estimate was derived using a published formula that accounts for age, gender, weight, and CYP2C9 and VKORC1 genotypes. This estimate should be viewed as an example of how this information can be taken into consideration by the physician as part of the overall patient management strategy.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

14. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
CYP2C9
Celecoxib
Celebrex
Ibuprofen
Advil, Motrin
Naproxen
Aleve
Glyburide
Diabeta
Glipizide
Glucotrol
Tolbutamide
Orinase
Glimepiride
Amaryl
Phenytoin
Dilantin
Fluvastatin
Lescol
Rosuvastatin
Crestor
Losartan
Cozaar
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

15. Anti-platelet therapy

16. CYP2C19 - Plavix Clopidogrel (Plavix) is a PRODRUG
Active metabolite elicits the desired antiplatelet response
~ 30% of patients have deficiency in CYP2C19
Decreased amount of active metabolite
High on-treatment platelet reactivity

17. Influence of CYP2C19 on Clopidogrel Response

18. Gene-Dose dependency of therapeutic platelet inhibition
Mega et al. JAMA 2011;23/30; 306(20)

19. Cost-effectiveness
Cost model based on event occurrence in TRITON-TIMI 38
Treatment
CV Events
Bleed Events
ICER
Genotype guided
813
340
Clopidogrel
1210
380
$ 6,790
Prasugrel
990
500
$ 11,710
$2.9M
$3.9M
Genotype-guided therapy selection may be more cost effective and lead to fewer adverse outcomes
Reese, E.S. et. al., Pharmacotherapy 2012;32(4):323–332

20. 2C19 CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
**Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance.
CYP2C19 Poor Metabolizer (PM): This patient’s genotype is consistent with significantly reduced CYP2C19 enzymatic activity. PMs are at increased risk of drug-induced side effects due to diminished drug elimination of active drugs. Patients with no CYP2C19 function (PMs) taking clopidogrel lack adequate antiplatelet response and remain at risk for cardiovascular events, including thrombosis, myocardial infarction, stroke, and death.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

21. 2C19 all
RESULTS
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Gene
Phenotype
Avoid
Alternative Consideration
Adjust Dosage
Adjustment

22. CYP2C19 Clopidogrel Plavix Citalopram Celexa Escitalopram
Lexapro, various
Imipramine
Tofranil
Sertraline
Zoloft
Diazepam
Valium
Omeprazole
Prilosec
Esomeprazole
Nexium
Pantoprazole
Protonix
Rabeprazole
Aciphex
Lansoprazole
Prevacid
Nelfinavir
Viracept
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

23. Statin Therapy

24. Statin therapy reduces risk of CV events
Statin therapy can lead to muscle weakness
Myalgia
Myopathy
Rhabdomyolysis
Genotyping can guide statin choice and dose

25. CYP3A4 and 3A5 Together metabolize 50% of all medications
80% redundancy of function
Genetic variants in each
decrease enzyme function (clearance)
Increased risk of dose-dependent adverse events

26. CYP3A4/5 master drug list

27. CYP3A4/5 significant variants
Decreased dose requirements for tacrolimus, cyclosporin, simvastatin, atorvastatin, lovastatin, midazolam
4-8% frequency
CYP3A5*3
Decreased dose requirements vincristine, tacrolimus, cyclosporin
90% freq Cauc, 50% AA, 60% Asians

28. 3A4 Interpretation CYP3A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Extensive Metabolizer
Normal metabolic clearance expected. Common CYP3A4 medications below.
CYP3A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Partially Decreased Metabolizer
Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below.
CYP3A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased Metabolizer
Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below.
CYP3A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
*22 Decreased Metabolizer
Decreased metabolic clearance expected with increased risk of dose-dependent side effects.
Adjust Dosage
Adjustment
Simvastatin
max mg, or consider alternative statin if also SLCO1B1 *5/*5 genotype
Atorvastatin
max mg
Lovastatin
Tacrolimus
decrease by up to 40%

29. 3A5 Interpretation CYP3A5 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Extensive Metabolizer
Genotype consistent with the highest baseline enzymatic activity for CYP3A5. Patients with this genotype represent only 1% of the population. Maintenance dosages for most CYP3A5 drugs may be at the higher end of the typical dose range. Common CYP3A5 medications below.
CYP3A5 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Partially Decreased Metabolizer
Genotype consistent with intermediate CYP3A5 enzymatic activity and represents approximately 20% of the population. For PDMs, maintenance dosages for most CYP3A5 drugs are lower than extensive metabolizers and are higher than decreased metabolizers.
CYP3A5 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased Metabolizer
Genotype consistent with reduced CYP3A5 enzymatic activity and represents the majority (60-80%) of the population. For DMs, maintenance dosages for most CYP3A drugs are lower than extensive metabolizers. Common CYP3A5 medications below.

30. N Engl J Med 2008;359:

31. SLC01B OATP1B1
~35% of population are carriers of the SLC01B1*5 allele
Myalgia/muscle cramps
CK> 3x ULN
Myopathy:
SLCO1B1 *1/*5; OR = 4.5 (95% CI, 2.6 to 7.7)
SLCO1B1 *5/*5; OR 16.9 (95% CI, 4.7 to 61.1)
Most frequently associated with simvastatin > atorvastatin > pravastatin

32. Vanderbilt Algorithm
Wilke et al. Clin Pharmaco Ther 2012;92(1).

33. Statin Combo Interpretation
CYP3A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
*22 Decreased Metabolizer
Decreased metabolic clearance expected with increased risk of dose-dependent side effects.
Adjust Dosage
Adjustment
Simvastatin
max mg, or consider alternative statin if also SLCO1B1 *5/*5 genotype
Atorvastatin
max mg
Lovastatin
Tacrolimus
decrease by up to 40%
SLCO1B1 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
>5 Fold Increased Myopathy Risk
Avoid
Alternative Consideration
Adjust Dosage
Adjustment
Simvastatin
pravastatin, lovastatin, fluvastatin, rosuvastatin, mevastatin
Atorvastatin
max mg

34. Anti-arrhythmics and Anti-hypertensives

35. 3A4: Ca++ Channel Blockers
CYP3A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Extensive Metabolizer
Normal metabolic clearance expected. Common CYP3A4 medications below.
CYP3A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Partially Decreased Metabolizer
Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below.
CYP3A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased Metabolizer
Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below.

36. CYP2D6 CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
**Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

37. Application of PGx to Pain Management

38. Pain Meds Generic Brand Metabolic Route Alfentanil Alfenta
CYP3A4/CYP3A5
Carisoprodol**
Soma
CYP1A2
Celecoxib
Celebrex
CYP2C9
Codeine**
Various brands
CYP2D6
Cyclobenzaprine
Flexaril
CYP1A2, CYP3A4/CYP3A5
Fentanyl
Actiq, Duragesic
Hydrocodone**
Ibuprofen
Advil, Motrin
Lidocaine
Methadone
CYP2C19
Naproxen
Aleve
Oxycodone**
Oxycontin, various
Ropivicaine
Tizanidine
Zanaflex
Tramadol**
Ultram, various
Zolmipitran
Zomig
**Indicates prodrug

39. CYP2D6 - Opioids Hydrocodone Oxycodone Codeine
Propoxyphene Tramadol Others…

40. CODEINE Active opioid effects Morphine CYP3A4 CYP2D6
CYP2D6 PM: inadequate morphine
CYP2D6 UM: morphine toxicity
CYP3A4
CYP2D6
Active opioid effects
Morphine
Norcodeine
Morphine-6-glucuronide Morphine-3-glucuronide
Renal Excretion
Reynolds KR et al. Clin Lab Med 2008;28:581–598.

41. Effects of CYP2D6 Decreased drug metabolism = lack of efficacy
Poor pain control
Mis-interpretation of drug seeking behavior
Ultra-rapid drug metabolism = possible side effects
Over-production of active compound
Mis-interpretation of over-compliance
Possible lower doses required

42. CYP2D6 Variants Extensive Metabolizers (EM) 55 – 60 % of population
Intermediate Metabolizers (IM) 25 – 30% of population
Poor Metabolizers (PM) 7 – 10 % of population
Ultra-rapid Metabolizers (UM) 1 – 3 % of population

43. Morphine Overdose Case Report #1: Nursing neonate overdose
Healthy male infant difficulty breastfeeding and lethargy starting on day 7, found deceased day 13
Toxicology:
Blood morphine = 70 ng/mL (normal 0-2.2)
Day 10 breast milk morphine = 87 ng/mL (normal 2-20 ng/mL after repeated 60mg every 6hr )
Mother Rx 2 wks codeine 30mg+APA 500 mg (Tylenol #3)
4 tabs first day, only 2 tabs daily thereafter because of maternal somnolence and constipation
Koren et al. Lancet 2006;368:704.

44. Maternal CYP2D6 Genotype Results
CYP2D6 *1/*2xN = Ultra-rapid Metabolizer
(gene duplication) (UM)
Leads to increased formation of morphine from codeine
Infant was an EM
Koren et al. Lancet 2006;368:704.

45. Clinical Case Conclusions
CNS depressant effects of codeine due to morphine by CYP2D6
Inherited differences in CYP2D6 can be life-threatening for some breastfed babies
“Codeine cannot be considered as a safe drug for all infants during breastfeeding”
FDA issued Public Health Advisory August 17, 2007
“Anyone can be an Ultra-rapid Metabolizer without knowing it. The only way to find out is with a genetic test…
Among pain relievers, ultra-rapid metabolism has only been reported as a problem with codeine, although it has the potential to affect other narcotics”
Koren et al. Lancet 2006;368:704.

46. 8-15-12 FDA Drug Safety Case Report #2: Post-tonsillectomy overdose
Codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare, but life-threatening adverse events or death
3 deaths and 1 case of severe respiratory depression were reported in children (2-5yo) who received codeine after undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea
3 deaths in children who were CYP2D6 UMs; 1 life-threatening case in an EM
All children received typical codeine doses
Morphine toxicity signs developed within 1-2 days after starting codeine
Supratherpeutic post-mortem morphine concentrations in the 3 death cases

47. FDA recommendations for Physicians:
Use the lowest effective codeine dose for the shortest period of time on an as-needed basis (i.e., not scheduled around the clock)
Counsel parents:
how to recognize the signs of morphine toxicity
Advise them to stop giving the child codeine
Seek medical attention immediately if child exhibits these signs
FDA-cleared tests are available for determining a patient’s CYP2D6 genotype
Consider prescribing alternative analgesics for children

48. Application of PGx to behavioral health

49. Psychiatry Medications – Metabolic Routes
Antidepressants
Antipsychotics, Mood Stabilizers
Generic
Brand
Metabolic Route
Amitriptyline
Various brands
CYP2D6
Alprazolam
Xanax
CYP3A4/CYP3A5
Bupropion
Wellbutrin
CYP1A2, (CYP2B6)
Amphetamine
Adderall
Citalopram
Celexa
CYP2C19
Aripiprazole
Abilify
Clomipramine
Ananfranil
CYP2D6, CYP1A2
Asenapine
Saphris
CYP1A2
Atomoxetine
Strattera
Desipramine
Norpramin
Buspirone
Buspar
Desvenlafaxine
Pristiq
Carbamazepine
Doxepin
Sinequan
Chlorpromazine
Thorazine
Duloxetine
Cymbalta
Clozapine
Clozaril
Escitalopram
Lexapro, various
Diazepam
Valium
Fluoxetine
Prozac
Haloperidol
Haldol
Fluvoxamine
Luvox
Iloperidine
Fanapt
Imipramine
Tofranil
CYP2D6, CYP2C19, CYP1A2
Lurasidone
Latuda
Maprotiline
Ludiomil
Midazolam
Versed
Mianserin
Olanzapine
Zyprexa
Mirtazapine
Remeron
Perphenazine
Trilafon
Nefazadone
Serzone
Promazine
Sparine
Nortriptyline
Pamelor, Aventyl
CYP2D6, CYP3A4/CYP3A5
Quetiapine
Seroquel
Paroxetine
Paxil
Risperidone
Risperidol
Reboxetine
Edronax
Thioridazine
Mellaril
Sertraline
Zoloft
Triazolam
Halcion
Trazadone
Desyrel
Ziprasidone
Geodon
Trimipramine
Surmontil
Zuclopenthixol
Venlafaxine
Effexor
Vilazodone
Viibryd

50. CASE: Depression/ADHD
51 y/o male
Problematic Polypharmacy (Atomoxetine, Topiramate, Oxcarbazapine, Aripaprazole,Valproic acid)
Genotyping results

51. Relevance to case (drugs affected)
Medication
PGx Gene
PM Effect
atomoxetine
CYP2D6
Reduced clearance
Half life ~ 5x longer
aripiprazole
80% increase in exposure
half-life 2x longer

52. 2D6 Atomoxetine PMs 4x longer to SS 4x higher drug levels
20 mg q12h
PMs
4x longer to SS
4x higher drug levels
4x longer to wash-out
More likely to have AE

53. Strattera and Abilify Monographs
Higher blood levels in PMs may lead to higher rate of ADRs
PM blood levels ≈ blood levels in EMs taking strong 2D6 inhibitors
Dosage adjustment for Strattera or Abilify with CYP2D6 inhibitors:
Initiate at 50% of the usual target dose

54. How to apply PGx to atomoxetine therapy
Adjust dosage based on PK: decrease by 50%
Goal to normalize exposure and ADR risk
Adjust monitoring and wash-out expectations

55. CYP2D6 genotyping may be useful in predicting which patients are at increased risk of atomoxetine and aripiprazole–induced ADRs. Dosing guidelines for inhibitors may be considered for PM dose adjustments
Surja, Reynolds, Linder, El-Mallakh. Pers Med 2008;5(4):

56. 2D6 Paroxetine

57. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
**Lack of efficacy due to failure to produce active metabolite; †Increased risk of adverse events due to diminished drug clearance.
CYP2D6 Poor Metabolizer (PM): This patient’s genotype is consistent with a lack of CYP2D6 enzymatic activity. PMs are at increased risk of drug-induced side effects due to diminished drug elimination of active drugs or lack of therapeutic effect resulting from failure to generate the active form of the drug, as is the case with pro-drugs.
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

59. CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012
CYP2D6
Pain Management
Psychiatry
Codeine**
Various brands
Antidepressants
Antipsychotics
Oxycodone**
Oxycontin, various
Fluoxetine
Prozac
Haloperidol
Haldol
Hydrocodone**
Fluvoxamine
Luvox
Risperidone
Risperidol
Tramadol**
Ultram, various
Paroxetine
Paxil
Aripiprazole
Abilify
Venlafaxine
Effexor
Zuclopenthixol
Cardiology
Duloxetine
Cymbalta
Perphenazine
Trilafon
Carvedilol
Coreg
Maprotiline
Ludiomil
Thioridazine
Mellaril
Metoprolol
Toprol-XL
Mirtazapine
Remeron
Iloperidine
Fanapt
Propanolol
Inderal, various
Amitriptyline
Chlorpromazine
Thorazine
Timolol
Blocadren
Clomipramine
Ananfranil
Atomoxetine
Strattera
Propafenone
Rythmol
Desipramine
Norpramin
Amphetamine
Adderall
Flecainide
Tambocor
Doxepin
Sinequan
Imipramine
Tofranil
Other
Nortriptyline
Pamelor, Aventyl
Loratadine
Claritin
Trimipramine
Surmontil
Donepezil
Aricept
Dextromethorphan
Tamoxifen**
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

60. PGXL Psych Panels* PGXL Depression Panel STA2R Panel = Psychosis
Add on: SLC6A4
STA2R Panel = Psychosis
SULT4A1:olanzapine
2D6
2C19
2C9
1A2
3A4
3A5
SLC6A4
*updated as of

61. Serotonin Transporter (SLC6A4) add-on

62. SLC6A4
50-60% depressed patients have recurrence and % fail 1st line Rx (SSRIs)
TRD  increased # of Rx, hospitalization risk, costs (19x higher)
75% people carry S or LG
S/S, S/LG, or LG/LG should be considered for non-SSRI therapies

63. SLC6A4 interpretations SLC6A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Normal Responder
Normal serotonin transporter expression expected. Patients with the LA/LA genotype are more likely to respond within the first 4 weeks of therapy, achieve remission, and are less likely to have adverse effects when treated with SSRIs.
SLC6A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Intermediate Responder
Carriers of S or LG alleles may have decreased serotonin transporter expression compared to LA/LA subjects. Possible risk of decreased or slower response to SSRIs or increased risk of adverse events.
SLC6A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Poor Responder
Decreased serotonin transporter expression expected. Risk of decreased response to SSRI-based therapies and increased risk of adverse events. Consider non-SSRI antidepressant therapies, such as SNRIs or tricyclic antidepressants alternatives.

64. Antidepressants SSRIs SNRIs 2C19 citalopram Celexa 2D6,1A2 duloxetine
Cymbalta
escitalopram
Lexapro
2D6
venlafaxine
Effexor
fluoxetine
Prozac
3A4/5
desvenlafaxine
Pristiq
fluvoxamine
Luvox
renal
milnacipran
Savella
paroxetine
Paxil
2D6,1A2,3A4/5
mirtazapine
Remeron
sertraline
Zoloft
vilazodone
Viibryd
TCAs
amitriptyline
Elavil
Atypicals (NRIs, NDRIs)
clomipramine
Anafranil
2B6,1A2
bupropion
Wellbutrin
2D6,2C19
desipramine
Norpramin
trazadone
Desyrel
doxepin
Sinequan
nefazadone
Serzone
imipramine
Tofranil
maprotiline
Ludiomil
2D6,3A4/5
nortriptyline
Pamelor, Aventyl
mianserin
2D6,3A4/5,2C19
trimipramine
Surmontil
reboxetine
Edronax
MAOIs
phenelzine
Nardil
tranylcyromine
Parnate
isocarboxazid
Marplan
moclobemide
Black, major pathway; gray, minor pathway

65. PGXL Depression Panel (Panel + SLC6A4 add-on) DRAFT
CONFIDENTIAL COPYRIGHT PGXL LABORATORIES 2012

66. PGXL exclusive provider of SULT4A1 marker (schizophrenia, bipolar disorder)
Enhanced efficacy on olanzapine
Reduced risk of hospitalization
Reduced hospitalization costs

67. SULT4A1
Brain enzyme that interacts with neurochemicals Efficacy advantage with olanzapine
Hospitalization
Efficacy

68. SULT4A1 Interpretations
Gene
THERAPEUTIC IMPLICATIONS (adapted from published resources)
SULT4A1-1
POSITIVE
Consider olanzapine. SULT4A1-1 positive patients have been shown to demonstrate enhanced treatment efficacy and reduced hospitalization risk when treated with olanzapine compared to both SULT4A1-1 negative patients treated with olanzapine and SULT4A1-1 positive patients treated with risperidone.
NEGATIVE
SULT4A1-1 negative patients treated with olanzapine do not display the expected efficacy advantage compared to other atypical antipsychotics.

69. STA2R Panel Report

70. CYP3A4 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Partially Decreased Metabolizer
Decreased metabolic clearance expected with increased risk of dose-dependent side effects. Common CYP3A4 medications below.
CYP3A5 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Decreased Metabolizer
Genotype consistent with reduced CYP3A5 enzymatic activity and represents the majority (60-80%) of the population. For DMs, maintenance dosages for most CYP3A drugs are lower than extensive metabolizers. Common CYP3A5 medications below.
CYP1A2 Phenotype
THERAPEUTIC IMPLICATIONS (adapted from published resources)
Hyperinducer
Rapid metabolism expected, especially in smokers. Consider dose increases for medications inactivated by CYP1A2 particularly in smokers, or alternative medications not metabolized by CYP1A2. Common CYP1A2 medications below.

71. Thrombophilia panel

72. Thrombophilia Panel
Factor V Leiden
Factor II (prothrombin)
MTHFR

73. Factor V Leiden High Thrombosis Risk: This genotype result revealed that the patient is homozygous for (has two copies of) the Factor V Leiden (1691 G>A) variant, which has been associated with an increased risk of thromboembolic events.
This variant is found in approximately 4% of individuals in the U.S. Presence of the Factor V Leiden variant increases the risk of venous thromboembolism (VTE) by 3-8 fold in heterozygous carriers and >9 fold in homozygous carriers.
Factor II Moderate Thrombosis Risk: This genotype result revealed that the patient is heterozygous for (has one copy of) the Factor II (Prothrombin) G>A variant, which has been associated with an increased risk of thromboembolic events. This variant is found in approximately 2% of individuals in the U.S. Presence of the Factor II 20210G>A variant increases the risk of venous thromboembolism (VTE) by 2-3 fold in heterozygous carriers and >3 fold in homozygous carriers.
MTHFR Increased Risk: Presence of the 677 C>T polymorphism of MTHFR leads to decreased MTHFR enzymatic activity and elevated homocysteine. This patient’s genotype is consistent with an increased risk of hyperhomocysteinemia, atherosclerotic heart disease, myocardial infarction, cerebrovascular disease, and venous thrombosis. Additionally, associations between the 677 C>T polymorphism and increased risk for methotrexate toxicity, increased 5-fluorouracil chemosensitivity, and increased risk of fetal neural tube defects in pregnant women have also been reported in states of folate deficiency.

74. Consultation Services
PGXL provides state-of-the-art interpretive reports with actionable guidance PGXL medical directors are available for clinical consultation with ordering practitioners before and after testing Ongoing VIP review consultation after patients tested Educational lecture series and/or CME events as needed

75. Thank You! kreynolds@pgxlab.com