1. Pharmacogenomics and Therapy Dosing
Tracy Chen
Doctor of Pharmacy Candidate 2007 University of Washington
September 1, 2006
Pharmacogenetics=the study of variability in drug responses due to heredity (1).
Pharmacogenomics=a broader term excompassing all genes in the genome that may determine drug responses.
These two terms are now used interchangeably.

2. 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)

3. 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)

4. POLYMORPHIC ENZYMES Cytochrome P450 Enzymes: CYP 2D6 CYP 2C19 CYP 2C9
UDP-Glucuronosyl Transferase:
UGT 1A1
TPMT = Thiopurine S-Methyltransferase

5. CYP2D6 AND CYP2C19 CYP 2D6 in Caucasians: CYP 2C19 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):

6. 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):

7. TCA dose adjustments are recommended for 2D6 PM and UM.
CYP2D6 AND TCAs
2D6 PM: 50% OF THE STANDARD DOSES
TCA dose adjustments are recommended for 2D6 PM and UM.
Kirchheiner J, Nickchen K, Bauer M, et el. Mol Psychiatry 2004 May; 9 (5):

8. CYP2D6 AND OTHER ANTIDEPRESSANTS
PAROXETINE IS THE ONLY SSRI THAT NEEDS DOSE ADJUSTMENT ACCORDING TO 2D6 GENOTYPES! Though SSRIs like paroxetine, fluoxetine, and fluvoxamine are strong 2D6 inhibitors. Need to watch out for DDIs.
Kirchheiner J, Nickchen K, Bauer M, et el. Mol Psychiatry 2004 May; 9 (5):

9. Antipsychotic dose adjustments are recommended for 2D6 PM and UM.
2D6 AND ANTIPSYCHOTICS
RISPERIDONE: NO SIG DOSING DIFF FOR MULTIPLE DOSE DUE TO AN ACTIVE METABOLITE;
FLUPENTIXOL, ZUCLOPENTHIXOL, AND PERAZINE ARE NOT FDA APPROVED FOR ANTIPSYCHOTIC USAGE.
Antipsychotic dose adjustments are recommended for 2D6 PM and UM.
Kirchheiner J, Nickchen K, Bauer M, et el. Mol Psychiatry 2004 May; 9 (5):

10. 2C19 EM: 110% of standard doses
2C19 AND ANTIDEPRESSANTS
NO SIGNIFICANT EFFECTS ON ANTIPSYCHOTICS.
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):

11. CYP2C9 20% of hepatic CYP enzymes CYP2C9 *2 allelic frequencies: 10%
Anderson T, Flockhart DA, Goldstein DB, et el. Clin Pharmcol Thera Dec; 78(6):

12. 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 ( for prosthetic heart valves)
INR <2: risk of thromboembolic event
INR >3: risk of bleeding complications
Prophylaxis and treatment of venous and arterial thromboembolic disorders
Mushiroda T, Ohnishi Y, Saito S, et el. J Hum Genet. 2006;51(3):

13. The more potent S-warfarin is metabolized almost exclusively by CPY2C9 in the liver. Polymorphism of CYP2C9 in Caucasians accounts for some of the interpatient variability of warfarin daily dose. Blood clotting factors II, VII, IX, X, and endogenous anticoagulant proteins C, S, and Z are activated by gamma-glutamyl carboxylase with required cofactor, reduced fom of vitamin K, which is recycled by vitamin K 1,2 epoxide reductase complex (VKORC). Warfarin binds to the protein vitamin K reductase complex subunit 1 (VKORC1) encoded by gene VKORC1.
Gage B. Nov FDA Clin Pharm Advisor Committe

14. 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.

15. VKORC1 POLYMORPHISM
At least 10 different single-nucleotide-polymorphisms (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 2005;352:
Schalekamp T, Brasse BP, Roijers JF, et el. Clin Pharmacol Ther Jul; 80(1):7-12.
Herman D, Peternel p, Stegnar M, et el. Thromb Haemost 2006; 95:782-7.
Sconce EA, Khan TI, Wynne HA, et el. Blood Oct 2005;106(7):
Gage BF, MD, MSc.

16. DOSING ALGORITHM 2005 PROPOSED
Sconce EA, Khan TI, Wynne HA, et el. Blood Oct 2005;106(7):

17. DOSING ALGORITHM 2006 PROPOSED
Linder MW Ph.D. DABCC, Manage the “Over-steer” in warfarin dose titration.

18. 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.

19. UGT1A1
Homozygous UGT1A1*28 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 Dec; 78(6):
Camptosar (irinotecan) package insert:

20. UGT1A1
SN-38 is associated with neutropenia and life-threatening diarrhea.
Patients with homozygous UGT1A1*28 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 UGT1A1*28 allele carriers.
Camptosar (irinotecan) package insert:

21. 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%
TPMT deficient metabolizer: no or low TPMT activity
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med :

22. TPMT
Azathioprine used in renal transplant and rheumatoid arthritis. 6-MP is used in chemotherapy.
Azathioprine is hydrolyzed to 6-MP, which is further metaboilized by TPMT and xanthine oxidase to inactive metabolites or by HGPRT pathway with other kinases to form 6-TGN, the active thiopurine metabolite.
Azathioprine and 6-mercaptopurine are immunosuppressive antimetabolites.
Imuran (azathioprine) package insert:

23. 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.
TPMT deficient metabolizer: no or low TPMT activity
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med :

24. 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.
TPMT deficient metabolizer: no or low TPMT activity
Imuran (azathioprine) package insert:
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med :

25. 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:

26. ATOMOXETINE VS 2D6 INHIBITORS
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):
Strattera (atomoxetine) package insert:

27. ATOMOXETINE
Recommend dosage adjustment in CYP2D6 PM and those taking strong 2D6 inhibitors
Individual > 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:

28. 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.

29. QUESTIONS
CYP 2D6?
UGT1A1?
CYP 2C19?
TPMT?
CYP 2C9?
RXs!!

30. REFERENCES
Anderson T, Flockhart DA, Goldstein DB, et el. Drug-metabolizing enzymes: Evidence for clinical utility of pharmacogenomic tests. Clin Pharmcol Thera Dec; 78(6): ( )
Camptosar (irinotecan) package insert:
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmcogenomics and individualized drug therapy. Annu Rev Med : ( )
Gage BF, MD, MSc. New insights on warfarin: how CYP2C9 and VKORC1 information may improve benefit-risk ratio.
Huang SM, Goodsaid F, Rahman A, et el. Application of pharmacogenomics in clinical pharmacology. Toxicology Mechanisms and Methods. 2006;(16)
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; 95: ( )
Imuran (azathioprine) package insert:
Kirchheiner J, Fuhr U, Brockmoller J. Pharmacogenetics-based therapeutic recoomendations-ready for clinical practice? Nature Aug 2005; (4)
Kirchheiner J, Nickchen K, Bauer M, et el. Pharmacogenetics of antidepressants and and antipsychotics: the contribution of allelic variations to the phenotype of drug response. Mol Psychiatry 2004 May; 9 (5): ( )
Leon, JD MD; Armstrong SC MD; Cozza KL MD. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for CYP450 2D6 and CYP450 2C19. Psychosomatics. Jan-Feb 2006; 47(1):75-85
Mushiroda T, Ohnishi Y, Saito S, et el. Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in Japanese patients. J Hum Genet. 2006;51(3): ( )
Linder MW Ph.D. DABCC, Manage the “Over-steer” in warfarin dose titration. Presented 08/31/2006
Rieder MJ, Reiner AP, Gage BF, et el. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Eng J Med 2005;352: ( )
Sauer JM, Ring BJ, Witcher JW. Clinical pharmacokinetics of atomoxetine. Clin Pharmacokinet. 2005; 44(6): ( )
Schalekamp T, Brasse BP, Roijers JF, et el. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction between both genotypes affects overanticoagulation. Clin Pharmacol Ther Jul; 80(1):7-12. ( )
Sconce EA, Khan TI, Wynne HA, et el. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood Oct 2005;106(7): ( )
Strattera (atomoxetine) package insert:
Weinshilboum RM. Pharmacogenomics: catechol O-methyltransferase to thiopurine S-methyltransferase. Cell Mol Neurobiol 2006 Jun 29. ( )

31. Genelex!