Pharmacogenomics and Therapy Dosing

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Pharmacogenomics and Therapy Dosing

• Tracy Chen
• Doctor of Pharmacy Candidate 2007 University of
  Washington
• September 1, 2006

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SOME FACTS AND STATISTICS

• Factors to drug responses
• Intrinsic factors age, gender, race/ethnicity,
  disease states, organ dysfunctions, and genetics
• Physiological changes pregnancy, lactation
• Extrinsic factors smoking, diet, concomitant
  medications
• Adverse drug reactions (ADRs)
• Caused 5 of hospitalization
• Experienced by 10 of the hospitalized patients
• 700,000 injuries/deaths per year
• estimated to be the 4th or 6th leading cause of
  death in the US for the hospitalized patients
  back at 1998

Huang SM, Goodsaid F, Rahman A, et el. Toxicology
Mechanisms and Methods. 2006(16) 89-99.
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SOME FACTS AND STATISTICS

• 59 of drugs causing ADRs are metabolized by
  polymorphic enzymes
• 7-22 of other randomly selected drugs are
  substrates for polymorphic enzymes
• Polymorphisms occur in transporters, receptors,
  and other therapeutic targets are also associated
  with interindividual variability in drug
  response.

Huang SM, Goodsaid F, Rahman A, et el. Toxicology
Mechanisms and Methods. 2006(16) 89-99.
4
POLYMORPHIC ENZYMES

• Cytochrome P450 Enzymes
• CYP 2D6
• CYP 2C19
• CYP 2C9
• UDP-Glucuronosyl Transferase
• UGT 1A1
• TPMT Thiopurine S-Methyltransferase

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CYP2D6 AND CYP2C19

• CYP 2D6 in Caucasians
• PM 7
• IM 40
• EM 50 (normal metabolizers)
• UM 3
• CYP 2C19 in Caucasians
• PM 3
• IM 27
• EM 70 (normal metabolizers)

Kirchheiner J, Nickchen K, Bauer M, et el. Mol
Psychiatry 2004 May 9 (5)442-73.
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ANTIPSYCHOTICS AND ANTIDEPRESSANTS

• Psychological disorders are among the most
  important causes of death and disability
  worldwide
• Great impact on public health
• Only 35-45 of the patients respond to the
  treatments and return to functional level
• 30-50 of the patients will not respond
  sufficiently

Kirchheiner J, Nickchen K, Bauer M, et el. Mol
Psychiatry 2004 May 9 (5)442-73.
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CYP2D6 AND TCAs
TCA dose adjustments are recommended for 2D6 PM
and UM.
Kirchheiner J, Nickchen K, Bauer M, et el. Mol
Psychiatry 2004 May 9 (5)442-73.
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CYP2D6 AND OTHER ANTIDEPRESSANTS
Kirchheiner J, Nickchen K, Bauer M, et el. Mol
Psychiatry 2004 May 9 (5)442-73.
9
2D6 AND ANTIPSYCHOTICS

• Antipsychotic dose adjustments are recommended
  for 2D6 PM and UM.

Kirchheiner J, Nickchen K, Bauer M, et el. Mol
Psychiatry 2004 May 9 (5)442-73.
10
2C19 AND ANTIDEPRESSANTS

• Recommendation 2C19 PM 60 of standard doses
• 2C19 EM 110 of standard doses

Kirchheiner J, Nickchen K, Bauer M, et el. Mol
Psychiatry 2004 May 9 (5)442-73.
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CYP2C9

• 20 of hepatic CYP enzymes
• CYP2C9 2 allelic frequencies 10
• CYP2C9 3 allelic frequencies 8

Anderson T, Flockhart DA, Goldstein DB, et el.
Clin Pharmcol Thera. 2005 Dec 78(6)559-81.
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CYP2C9 AND WARFARIN

• Warfarin is the most common oral anticoagulant in
  the world
• The only anticoagulant available in the united
  states
• Therapeutic range INR 2-3 (2.5-3.5 for
  prosthetic heart valves)
• INR lt2 risk of thromboembolic event
• INR gt3 risk of bleeding complications

Mushiroda T, Ohnishi Y, Saito S, et el. J Hum
Genet. 200651(3)249-53.
13
Gage B. Nov 14 2005 FDA Clin Pharm Advisor
Committe
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CYP2C9 POLYMORPHISM

• Clearance of S-warfarin and time to achieve
  steady-state (5x T1/2)
• 1/1 3 days
• 1/2 6 days
• 1/3 12 days

Linder MW Ph.D. DABCC, Manage the Over-steer in
warfarin dose titration.
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VKORC1 POLYMORPHISM

• At least 10 different single-nucleotide-polymorphi
  sms (SNPs) were identified
• Haplotype A (-1639GA, 1173CT) lower maintenance
  dose
• Haplotype B (9041GA) higher maintenance dose
• VKORC1 A/A 2.7 0.2 mg/d
• VKORC1 A/B 4.9 0.2 mg/d
• VKORC1 B/B 6.2 0.3 mg/d
• Mean maintenance dose 5.1 0.2 mg/d

Rieder MJ, Reiner AP, Gage BF, et el. N Eng J Med
20053522285-93. Schalekamp T, Brasse BP,
Roijers JF, et el. Clin Pharmacol Ther. 2006 Jul
80(1)7-12. Herman D, Peternel p, Stegnar M, et
el. Thromb Haemost 2006 95782-7. Sconce EA,
Khan TI, Wynne HA, et el. Blood Oct
2005106(7)2329-33 Gage BF, MD, MSc.
http//www.fda.gov/ohrms/dockets/ac/05/slides/2005
-4194S1_04_Gage.ppt
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DOSING ALGORITHM 2005PROPOSED

• Sconce EA, Khan TI, Wynne HA, et el. Blood Oct
  2005106(7)2329-33

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DOSING ALGORITHM 2006 PROPOSED

• Linder MW Ph.D. DABCC, Manage the Over-steer in
  warfarin dose titration.

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THERAPY INITIAION

• Start with standard induction protocol with 5
  mg/d for 3 days
• Genotype recommended for both 2C9 and VKORC1 for
  maintenance dose and clearance (T1/2) estimate
• Start with target maintenance dose on day 4
• Measure INR at appropriate time frame, day 3, 6,
  or 12 for monitoring

Linder MW Ph.D. DABCC, Manage the Over-steer in
warfarin dose titration.
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UGT1A1

• Homozygous UGT1A128 allele with reduced enzyme
  activity in Caucasian 10.
• Irinotecan ?carboxylesterase ?SN-38 (active)
• SN-38 ? UDP-glucuronosyl transferase 1A1
  (UGT1A1)? conjugated inactive metabolite.
• SN-38 can be metabolized by UGT1A6, 1A7, 1A9, and
  1A10 as well.

Anderson T, Flockhart DA, Goldstein DB, et el.
Clin Pharmcol Thera. 2005 Dec 78(6)559-81.
Camptosar (irinotecan) package insert
http//www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Cam
ptosar_PI.pdf
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UGT1A1

• SN-38 is associated with neutropenia and
  life-threatening diarrhea.
• Patients with homozygous UGT1A128 allele are at
  increased risk for ADRs following the initiation
  of therapy due to increased level of SN-38.
• Recommend decrease the starting dose of
  irinotecan by at least 1 dose level to avoid
  cytotoxicity for homozygous UGT1A128 allele
  carriers.

Camptosar (irinotecan) package insert
http//www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Cam
ptosar_PI.pdf
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TPMT

• TPMT- normal metabolizer (homozygous functional
  alleles) 90
• TPMT- intermediate metabolizer (heterozygous with
  one nonfunctional allele) 10
• TPMT- deficient metabolizer (homozygous
  nonfunctional alleles) 0.3

Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu
Rev Med. 2006.57119-137.
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TPMT

• Azathioprine and 6-mercaptopurine are
  immunosuppressive antimetabolites.

Imuran (azathioprine) package insert
http//www.prometheuslabs.com/pi/Imuran.pdf
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TPMT

• The active thiopurine metabolite, 6-TGN, can
  eventually results in myelosuppresion, a dose
  limiting factor for therapy.
• TPMT- deficient metabolizers can have increased
  level of 6-TGN and are at higher risk for severe,
  sometimes fatal, myelosuppresion.

Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu
Rev Med. 2006.57119-137.
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TPMT

• Predominantly genotyping or phenotyping for TPMT
  variant alleles is recommended before thiopurine
  therapy.
• TPMT- deficient metabolizers
• give 6-10 of the standard dose of thiopurine and
  monitor CBC carefully.
• TPMT- intermediate metabolizers
• usually start on full dose, but dose reduction is
  recommended to avoid toxicity.

Imuran (azathioprine) package insert
http//www.prometheuslabs.com/pi/Imuran.pdf Eichel
baum M, Ingelman-Sundberg M, Evans WE. Annu Rev
Med. 2006.57119-137
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DDI

• THIOPURINES VS ALLOPURINOL
• Allopurinol is a xanthine oxidase inhibitor.
• Give 1/3 -1/4 of the usual dose of azathioprine
  if patients receive both allopurinol and
  azathioprine concomitantly.
• Use further dose reduction or alternative
  therapies for TPMT- deficient metabolizers
  receiving both azathioprine and allopurinol.

Imuran (azathioprine) package insert
http//www.prometheuslabs.com/pi/Imuran.pdf
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ATOMOXETINE VS 2D6 PM

• Cav,ss and AUC of atomoxetine are approximately
  10 fold higher in 2D6 PMs than in EMs. The mean
  T1/2 has increased from 5.2 hours to 21.6 hours.

ATOMOXETINE VS 2D6 INHIBITORS
Atomoxetine concentration increases by 3-4 fold
when coadministered with paroxetine.
Sauer JM, Ring BJ, Witcher JW. Clin
Pharmacokinet. 2005 44(6) 571-90 Strattera
(atomoxetine) package insert http//pi.lilly.com/
us/strattera-pi.pdf
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ATOMOXETINE

• Recommend dosage adjustment in CYP2D6 PM and
  those taking strong 2D6 inhibitors
• Individual gt 70 kg start at 40 mg/day
• Individual 70 kg start at 0.5 mg/kg/day.
• Increase to the usual target dose of 80 mg/day
  and 1.2 mg/kg/day, respectively, only if
  treatment fails to improve symptoms after 4 weeks
  and the initial doses are well tolerated.

Strattera (atomoxetine) package insert
http//pi.lilly.com/us/strattera-pi.pdf
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CONCLUSION

• Genotyping recommended for different polymorphic
  enzymes before initiation of therapies
• Dose recommendations
• Improve better therapeutic outcomes
• Minimizing adverse drug reactions
• Further studies on ethnicities,
  pharmacoeconomics, dosing algorithms
  (prospective) required.

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QUESTIONS
CYP 2D6?
UGT1A1?
CYP 2C19?
TPMT?
CYP 2C9?
RXs!!
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REFERENCES

• Anderson T, Flockhart DA, Goldstein DB, et el.
  Drug-metabolizing enzymes Evidence for clinical
  utility of pharmacogenomic tests. Clin Pharmcol
  Thera. 2005 Dec 78(6)559-81. (16338273)
• Camptosar (irinotecan) package insert
  http//www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Cam
  ptosar_PI.pdf
• Eichelbaum M, Ingelman-Sundberg M, Evans WE.
  Pharmcogenomics and individualized drug therapy.
  Annu Rev Med. 2006.57119-137. (16409140)
• Gage BF, MD, MSc. New insights on warfarin how
  CYP2C9 and VKORC1 information may improve
  benefit-risk ratio. http//www.fda.gov/ohrms/docke
  ts/ac/05/slides/2005-4194S1_04_Gage.ppt
• Huang SM, Goodsaid F, Rahman A, et el.
  Application of pharmacogenomics in clinical
  pharmacology. Toxicology Mechanisms and Methods.
  2006(16) 89-99. http//www.fda.gov/cder/genomics
  /publications/2006_Huang_Cogenomicis_Clin_pharm.pd
  f
• Herman D, Peternel p, Stegnar M, et el. The
  influence of sequence variations in factor VII,
  gamm-glutamyl carboxylase and vitamin K expoxide
  reductase complex genes on warfarin dose
  requirement. Thromb Haemost 2006 95782-7.
  (16676068)
• Imuran (azathioprine) package insert
  http//www.prometheuslabs.com/pi/Imuran.pdf
• Kirchheiner J, Fuhr U, Brockmoller J.
  Pharmacogenetics-based therapeutic
  recoomendations-ready for clinical practice?
  Nature Aug 2005 (4) 639-647
• Kirchheiner J, Nickchen K, Bauer M, et el.
  Pharmacogenetics of antidepressants and and
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• Leon, JD MD Armstrong SC MD Cozza KL MD.
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• Mushiroda T, Ohnishi Y, Saito S, et el.
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• Linder MW Ph.D. DABCC, Manage the Over-steer in
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• Sauer JM, Ring BJ, Witcher JW. Clinical
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  VKORC1 and CYP2C9 genotypes and acenocoumarol
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• Strattera (atomoxetine) package insert
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• Weinshilboum RM. Pharmacogenomics catechol
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Genelex!