pharmacogenomics and therapy dosing

Pharmacogenomics and Pharmacogenomics and Therapy DosingTherapy Dosing

Tracy ChenTracy ChenDoctor of Pharmacy Candidate 2007 Doctor of Pharmacy Candidate 2007

University of WashingtonUniversity of WashingtonSeptember 1, 2006September 1, 2006

SOME FACTS AND STATISTICSSOME FACTS AND STATISTICS

Factors to drug responsesFactors to drug responses:: Intrinsic factors: age, gender, race/ethnicity, disease states, Intrinsic factors: age, gender, race/ethnicity, disease states,

organ dysfunctions, and organ dysfunctions, and geneticsgenetics Physiological changes: pregnancy, lactationPhysiological changes: pregnancy, lactation Extrinsic factors: smoking, diet, concomitant medicationsExtrinsic factors: smoking, diet, concomitant medications

Adverse drug reactions (ADRs):Adverse drug reactions (ADRs): Caused 5% of hospitalizationCaused 5% of hospitalization Experienced by 10% of the hospitalized patientsExperienced by 10% of the hospitalized patients 700,000 injuries/deaths per year700,000 injuries/deaths per year estimated to be the 4estimated to be the 4thth or 6 or 6thth leading cause of death in the US leading cause of death in the US

for the hospitalized patients back at 1998for the hospitalized patients back at 1998

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

SOME FACTS AND STATISTICSSOME FACTS AND STATISTICS

59% of drugs causing ADRs are metabolized by 59% of drugs causing ADRs are metabolized by polymorphic enzymespolymorphic enzymes

7-22% of other randomly selected drugs are substrates 7-22% of other randomly selected drugs are substrates for polymorphic enzymesfor polymorphic enzymes

Polymorphisms occur in transporters, receptors, and Polymorphisms occur in transporters, receptors, and other therapeutic targets are also associated with other therapeutic targets are also associated with interindividual variability in drug response. interindividual variability in drug response.

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

POLYMORPHIC ENZYMESPOLYMORPHIC ENZYMES

Cytochrome P450 EnzymesCytochrome P450 Enzymes:: CYP 2D6CYP 2D6 CYP 2C19CYP 2C19 CYP 2C9CYP 2C9

UDP-Glucuronosyl TransferaseUDP-Glucuronosyl Transferase:: UGT 1A1UGT 1A1

TPMT = Thiopurine TPMT = Thiopurine SS-Methyltransferase-Methyltransferase

CYP2D6 AND CYP2C19CYP2D6 AND CYP2C19CYP 2D6 in Caucasians:CYP 2D6 in Caucasians:

PM: 7% PM: 7% IM: 40%IM: 40% EM: 50% (normal metabolizers)EM: 50% (normal metabolizers) UM: 3%UM: 3%

CYP 2C19 in Caucasians:CYP 2C19 in Caucasians: PM: 3%PM: 3% IM: 27% IM: 27% EM: 70% (normal metabolizers)EM: 70% (normal metabolizers)

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

ANTIPSYCHOTICS AND ANTIPSYCHOTICS AND ANTIDEPRESSANTSANTIDEPRESSANTS

Psychological disorders are among the most Psychological disorders are among the most important causes of death and disability important causes of death and disability worldwideworldwide

Great impact on public healthGreat impact on public health Only 35-45% of the patients respond to the Only 35-45% of the patients respond to the

treatments and return to functional leveltreatments and return to functional level 30-50% of the patients will not respond 30-50% of the patients will not respond

sufficientlysufficiently


CYP2D6 AND TCAsCYP2D6 AND TCAs

130155167172 183

142171

111 121125 127 131119 131

9287 83 82 79 96 9173

6042

3628

53 510

50

100

150

200

Pe

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of

sta

nd

ard

do

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CYP 2D6 Genotypes and dosage recommended

PM

IM

EM

UM

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

CYP2D6 AND OTHER CYP2D6 AND OTHER ANTIDEPRESSANTSANTIDEPRESSANTS

paroxe

tine

mians

erin

venlafaxin

e PMIM

EMUM

138 138

186

114 114 10990 90

8666 74

68

0

50

100

150

200

Pe

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nta

ge

of

sta

nd

ard

do

se

Medications Genotypes

PM

IM

EM

UM


2D6 AND ANTIPSYCHOTICS2D6 AND ANTIPSYCHOTICS

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

134146

126 139117

178

116

169

142113116107122

110129106126 11692 86 97 105 91

80 96

83 9070 74 76

6186

31

87

40 63020406080

100120140160180

Per

cent

age

of s

tand

ard

dose

Medications

PM

IM

EM

UM


2C19 AND ANTIDEPRESSANTS2C19 AND ANTIDEPRESSANTS

Recommendation: 2C19 PM: 60% of standard dosesRecommendation: 2C19 PM: 60% of standard doses2C19 EM: 110% of standard doses2C19 EM: 110% of standard doses

109110105108107 108105 107

81 7991

8361

84 908653 62

48 5845 61

7565

0

20

40

60

80

100

120

Pe

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ard

do

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TCAs SSRIs

PM

IM

EM


CYP2C9CYP2C9

20% of hepatic CYP enzymes20% of hepatic CYP enzymes CYP2C9 *2 allelic frequencies: 10%CYP2C9 *2 allelic frequencies: 10% CYP2C9 *3 allelic frequencies: 8%CYP2C9 *3 allelic frequencies: 8%

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

CYP2C9 AND WARFARINCYP2C9 AND WARFARIN Warfarin is the most common oral Warfarin is the most common oral

anticoagulant in the worldanticoagulant in the world The only anticoagulant available in the united The only anticoagulant available in the united

statesstates Therapeutic range: INR 2-3 (2.5-3.5 for Therapeutic range: INR 2-3 (2.5-3.5 for

prosthetic heart valves)prosthetic heart valves) INR <2: risk of thromboembolic eventINR <2: risk of thromboembolic event INR >3: risk of bleeding complicationsINR >3: risk of bleeding complications

Mushiroda T, Ohnishi Y, Saito S, et el. J Hum Genet. 2006;51(3):249-53.Mushiroda T, Ohnishi Y, Saito S, et el. J Hum Genet. 2006;51(3):249-53.

CYP2C9CYP2C9

CYP1A1CYP1A1CYP1A2CYP1A2CYP3A4CYP3A4

Oxidized Vitamin KOxidized Vitamin K Reduced Vitamin KReduced Vitamin K

OO22

HypofunctionalHypofunctionalF. II, VII, IX, XF. II, VII, IX, X

Protein C, S, ZProtein C, S, Z

Functional Functional F. II, VII, IX, XF. II, VII, IX, X

Proteins C, S, ZProteins C, S, Z

γ--glutamyl glutamyl carboxylasecarboxylase

Vitamin K Vitamin K ReductaseReductase

COCO22

WarfarinWarfarin

Calumenin

Gage B. Nov 14 2005 FDA Clin Pharm Advisor Committe

CYP2C9 POLYMORPHISMCYP2C9 POLYMORPHISM

Clearance of S-warfarin and time to Clearance of S-warfarin and time to achieve steady-state (5x T1/2):achieve steady-state (5x T1/2):

*1/*1: ~ 3 days*1/*1: ~ 3 days

*1/*2: ~ 6 days*1/*2: ~ 6 days

*1/*3: ~ 12 days*1/*3: ~ 12 days

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

VKORC1 POLYMORPHISMVKORC1 POLYMORPHISM

At least 10 different single-nucleotide-polymorphisms At least 10 different single-nucleotide-polymorphisms (SNPs) were identified(SNPs) were identified

Haplotype A (-1639GA, 1173CT): lower maintenance dose Haplotype A (-1639GA, 1173CT): lower maintenance dose Haplotype B (9041GA): higher maintenance doseHaplotype B (9041GA): higher maintenance dose

VKORC1 A/A: 2.7 ± 0.2 mg/dVKORC1 A/A: 2.7 ± 0.2 mg/d VKORC1 A/B: 4.9 ± 0.2 mg/dVKORC1 A/B: 4.9 ± 0.2 mg/d VKORC1 B/B: 6.2 ± 0.3 mg/dVKORC1 B/B: 6.2 ± 0.3 mg/d Mean maintenance dose: 5.1 ± 0.2 mg/dMean maintenance dose: 5.1 ± 0.2 mg/d

Rieder MJ, Reiner AP, Gage BF, et el. N Eng J Med 2005;352:2285-93.Rieder MJ, Reiner AP, Gage BF, et el. N Eng J Med 2005;352:2285-93. Schalekamp T, Brasse BP, Roijers JF, et el. Clin Pharmacol Ther. 2006 Jul; 80(1):7-12.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; 95:782-7.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):2329-33 Sconce EA, Khan TI, Wynne HA, et el. Blood Oct 2005;106(7):2329-33 Gage BF, MD, MSc. http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4194S1_04_Gage.pptGage BF, MD, MSc. http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4194S1_04_Gage.ppt

DOSING ALGORITHM 2005DOSING ALGORITHM 2005PROPOSEDPROPOSED

Sconce EA, Khan TI, Wynne HA, et el. Blood Oct 2005;106(7):2329-33 Sconce EA, Khan TI, Wynne HA, et el. Blood Oct 2005;106(7):2329-33

DOSING ALGORITHM 2006 DOSING ALGORITHM 2006 PROPOSEDPROPOSED


THERAPY INITIAIONTHERAPY INITIAION

Start with standard induction protocol with 5 Start with standard induction protocol with 5 mg/d for 3 days mg/d for 3 days

Genotype recommended for both 2C9 and Genotype recommended for both 2C9 and VKORC1 for maintenance dose and clearance VKORC1 for maintenance dose and clearance (T1/2) estimate(T1/2) estimate

Start with target maintenance dose on day 4Start with target maintenance dose on day 4 Measure INR at appropriate time frame, day 3, Measure INR at appropriate time frame, day 3,

6, or 12 for monitoring6, or 12 for monitoring


UGT1A1UGT1A1 Homozygous UGT1A1*28 allele with reduced Homozygous UGT1A1*28 allele with reduced

enzyme activity in Caucasian: 10%.enzyme activity in Caucasian: 10%. Irinotecan Irinotecan carboxylesterase carboxylesterase SN-38SN-38 (active) (active) SN-38 SN-38 UDP-glucuronosyl transferase 1A1 UDP-glucuronosyl transferase 1A1

(UGT1A1)(UGT1A1) conjugated inactive metabolite. conjugated inactive metabolite. SN-38 can be metabolized by UGT1A6, 1A7, 1A9, and SN-38 can be metabolized by UGT1A6, 1A7, 1A9, and

1A10 as well.1A10 as well.

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

UGT1A1UGT1A1

SN-38 is associated with neutropenia and life-SN-38 is associated with neutropenia and life-threatening diarrhea.threatening diarrhea.

Patients with homozygous UGT1A1*28 allele are at Patients with homozygous UGT1A1*28 allele are at increased risk for ADRs following the initiation of increased risk for ADRs following the initiation of therapy due to increased level of SN-38. therapy due to increased level of SN-38.

Recommend decrease the starting dose of irinotecan Recommend decrease the starting dose of irinotecan by at least 1 dose level to avoid cytotoxicity for by at least 1 dose level to avoid cytotoxicity for homozygous UGT1A1*28 allele carriers.homozygous UGT1A1*28 allele carriers.

Camptosar (irinotecan) package insert: http://www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Camptosar_PI.pdfCamptosar (irinotecan) package insert: http://www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Camptosar_PI.pdf

TPMTTPMT TPMT- normal metabolizer (homozygous TPMT- normal metabolizer (homozygous

functional alleles): 90% functional alleles): 90% TPMT- intermediate metabolizer (heterozygous TPMT- intermediate metabolizer (heterozygous

with one nonfunctional allele): 10% with one nonfunctional allele): 10% TPMT- deficient metabolizer (homozygous TPMT- deficient metabolizer (homozygous

nonfunctional alleles): 0.3% nonfunctional alleles): 0.3%

Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137.Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137.

TPMTTPMT

Azathioprine and 6-mercaptopurine are immunosuppressive antimetabolites.

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

TPMTTPMT The active thiopurine metabolite, 6-TGN, can The active thiopurine metabolite, 6-TGN, can

eventually results in myelosuppresion, a dose eventually results in myelosuppresion, a dose limiting factor for therapy. limiting factor for therapy.

TPMT- deficient metabolizers can have TPMT- deficient metabolizers can have increased level of 6-TGN and are at higher increased level of 6-TGN and are at higher risk for severe, sometimes fatal, risk for severe, sometimes fatal, myelosuppresion.myelosuppresion.

Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137.Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137.

TPMTTPMT Predominantly genotyping or phenotyping for Predominantly genotyping or phenotyping for

TPMT variant alleles is recommended before TPMT variant alleles is recommended before thiopurine therapy.thiopurine therapy.

TPMT- deficient metabolizers: TPMT- deficient metabolizers: give give 6-10%6-10% of the standard dose of thiopurine and of the standard dose of thiopurine and

monitor CBC carefully. monitor CBC carefully.

TPMT- intermediate metabolizers:TPMT- intermediate metabolizers: usually start on full dose, but dose reduction is usually start on full dose, but dose reduction is

recommended to avoid toxicity.recommended to avoid toxicity.

Imuran (azathioprine) package insert: http://www.prometheuslabs.com/pi/Imuran.pdfImuran (azathioprine) package insert: http://www.prometheuslabs.com/pi/Imuran.pdfEichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137

DDIDDI

THIOPURINES VS ALLOPURINOLTHIOPURINES VS ALLOPURINOL Allopurinol is a xanthine oxidase inhibitor.Allopurinol is a xanthine oxidase inhibitor. Give 1/3 -1/4 of the usual dose of Give 1/3 -1/4 of the usual dose of

azathioprine if patients receive both azathioprine if patients receive both allopurinol and azathioprine concomitantly.allopurinol and azathioprine concomitantly.

Use further dose reduction or alternative Use further dose reduction or alternative therapies for TPMT- deficient metabolizers therapies for TPMT- deficient metabolizers receiving both azathioprine and allopurinol. receiving both azathioprine and allopurinol.

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

ATOMOXETINEATOMOXETINE VS 2D6 PM VS 2D6 PM

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

ATOMOXETINE VS 2D6 INHIBITORSATOMOXETINE VS 2D6 INHIBITORS

Atomoxetine concentration increases by 3-4 fold when Atomoxetine concentration increases by 3-4 fold when coadministered with paroxetine.coadministered with paroxetine.

Sauer JM, Ring BJ, Witcher JW. Clin Pharmacokinet. 2005; 44(6): 571-90Sauer JM, Ring BJ, Witcher JW. Clin Pharmacokinet. 2005; 44(6): 571-90Strattera (atomoxetine) package insert: http://pi.lilly.com/us/strattera-pi.pdfStrattera (atomoxetine) package insert: http://pi.lilly.com/us/strattera-pi.pdf

ATOMOXETINEATOMOXETINERecommend dosage adjustment in Recommend dosage adjustment in CYP2D6 PM and those taking CYP2D6 PM and those taking strong 2D6 inhibitorsstrong 2D6 inhibitors

Individual > 70 kg: start at 40 mg/dayIndividual > 70 kg: start at 40 mg/dayIndividual ≤ 70 kg: start at 0.5 mg/kg/day. Individual ≤ 70 kg: start at 0.5 mg/kg/day.

*Increase to the usual target dose of 80 mg/day and *Increase to the usual target dose of 80 mg/day and 1.2 mg/kg/day, respectively, only if treatment fails to 1.2 mg/kg/day, respectively, only if treatment fails to improve symptoms after 4 weeks and the initial improve symptoms after 4 weeks and the initial doses are well tolerated.doses are well tolerated.

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

CONCLUSIONCONCLUSION Genotyping recommended for different Genotyping recommended for different

polymorphic enzymes before initiation polymorphic enzymes before initiation of therapiesof therapies

Dose recommendationsDose recommendations Improve better therapeutic outcomes Improve better therapeutic outcomes Minimizing adverse drug reactions Minimizing adverse drug reactions Further studies on ethnicities, Further studies on ethnicities,

pharmacoeconomics, dosing algorithms pharmacoeconomics, dosing algorithms (prospective) required.(prospective) required.

QUESTIONSQUESTIONS

CYP 2D6?

CYP 2C19?

CYP 2C9?

UGT1A1?

TPMT?

RXs!!

REFERENCESREFERENCES

Anderson T, Flockhart DA, Goldstein DB, et el. Drug-metabolizing enzymes: Evidence for clinical utility of pharmacogenomic tests. Clin 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) Pharmcol Thera. 2005 Dec; 78(6):559-81. (16338273)

Camptosar (irinotecan) package insert: http://www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Camptosar_PI.pdfCamptosar (irinotecan) package insert: http://www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Camptosar_PI.pdfEichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmcogenomics and individualized drug therapy. Annu Rev Med. 2006.57:119-137. Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmcogenomics and individualized drug therapy. Annu Rev Med. 2006.57:119-137.

(16409140) (16409140) Gage BF, MD, MSc. New insights on warfarin: how CYP2C9 and VKORC1 information may improve benefit-risk ratio. Gage BF, MD, MSc. New insights on warfarin: how CYP2C9 and VKORC1 information may improve benefit-risk ratio.

http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4194S1_04_Gage.ppt http://www.fda.gov/ohrms/dockets/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 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.pdf Methods. 2006;(16) 89-99. http://www.fda.gov/cder/genomics/publications/2006_Huang_Cogenomicis_Clin_pharm.pdf Herman D, Peternel p, Stegnar M, et el. The influence of sequence variations in factor VII, gamm-glutamyl carboxylase and vitamin K 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; 95:782-7. (16676068)expoxide reductase complex genes on warfarin dose requirement. Thromb Haemost 2006; 95:782-7. (16676068)Imuran (azathioprine) package insert: http://www.prometheuslabs.com/pi/Imuran.pdf 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 Kirchheiner J, Fuhr U, Brockmoller J. Pharmacogenetics-based therapeutic recoomendations-ready for clinical practice? Nature Aug

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variations to the phenotype of drug response. Mol Psychiatry 2004 May; 9 (5):442-73. (15037866) variations to the phenotype of drug response. Mol Psychiatry 2004 May; 9 (5):442-73. (15037866) Leon, JD MD; Armstrong SC MD; Cozza KL MD. Clinical guidelines for psychiatrists for the use of pharmacogenetic testing for 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):75-85CYP450 2D6 and CYP450 2C19. Psychosomatics. Jan-Feb 2006; 47(1):75-85Mushiroda T, Ohnishi Y, Saito S, et el. Association of VKORC1 and CYP2C9 polymorphisms with warfarin dose requirements in 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):249-53. (16432637)Japanese patients. J Hum Genet. 2006;51(3):249-53. (16432637)Linder MW Ph.D. DABCC, Manage the “Over-steer” in warfarin dose titration. Presented 08/31/2006Linder 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 Rieder MJ, Reiner AP, Gage BF, et el. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Eng J Med

2005;352:2285-93. (15930419)2005;352:2285-93. (15930419)Sauer JM, Ring BJ, Witcher JW. Clinical pharmacokinetics of atomoxetine. Clin Pharmacokinet. 2005; 44(6): 571-90 (15910008)Sauer JM, Ring BJ, Witcher JW. Clinical pharmacokinetics of atomoxetine. Clin Pharmacokinet. 2005; 44(6): 571-90 (15910008)Schalekamp T, Brasse BP, Roijers JF, et el. VKORC1 and CYP2C9 genotypes and acenocoumarol anticoagulation status: interaction 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. 2006 Jul; 80(1):7-12. (16815313)between both genotypes affects overanticoagulation. Clin Pharmacol Ther. 2006 Jul; 80(1):7-12. (16815313)Sconce EA, Khan TI, Wynne HA, et el. The impact of Sconce EA, Khan TI, Wynne HA, et el. The impact of CYP2C9 CYP2C9 and and VKORC1 VKORC1 genetic polymorphism and patient characteristics upon genetic polymorphism and patient characteristics upon

warfarin dose requirements: proposal for a new dosing regimen. Blood Oct 2005;106(7):2329-33 (15947090)warfarin dose requirements: proposal for a new dosing regimen. Blood Oct 2005;106(7):2329-33 (15947090)Strattera (atomoxetine) package insert: http://pi.lilly.com/us/strattera-pi.pdfStrattera (atomoxetine) package insert: http://pi.lilly.com/us/strattera-pi.pdfWeinshilboum RM. Pharmacogenomics: catechol O-methyltransferase to thiopurine S-methyltransferase. Cell Mol Neurobiol 2006 Jun Weinshilboum RM. Pharmacogenomics: catechol O-methyltransferase to thiopurine S-methyltransferase. Cell Mol Neurobiol 2006 Jun

29. (16807786)29. (16807786)

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