Transcript Pharmacogenomics and Therapy dosing

Pharmacogenomics and
Therapy Dosing
Tracy Chen
Doctor of Pharmacy Candidate 2007
University of Washington
September 1, 2006
SOME FACTS AND STATISTICS
Factors to drug responses:
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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):
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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.
SOME FACTS AND STATISTICS
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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.
POLYMORPHIC ENZYMES
Cytochrome P450 Enzymes:
 CYP 2D6
 CYP 2C19
 CYP 2C9
UDP-Glucuronosyl Transferase:
 UGT 1A1
TPMT = Thiopurine S-Methyltransferase
CYP2D6 AND CYP2C19
CYP 2D6 in Caucasians:
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PM: 7%
IM: 40%
EM: 50% (normal metabolizers)
UM: 3%
CYP 2C19 in Caucasians:
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PM: 3%
IM: 27%
EM: 70% (normal metabolizers)
Kirchheiner J, Nickchen K, Bauer M, et el. Mol Psychiatry 2004 May; 9 (5):442-73.
ANTIPSYCHOTICS AND
ANTIDEPRESSANTS
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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.
CYP2D6 AND TCAs
CYP 2D6 Genotypes and dosage recommended
200
130
0
87 83
82
171
119 131
79 96
91
60
42
36
28
53
am
cl itrip
om t
ip ylin
de ram e
si
pr ine
am
do in
xe e
im
pi
ip
n
ra e
no
m
rtr ine
ip
tri
ty
m
lin
ip
e
ra
m
in
e
Percentage of
standard dose
92
73
50
142
111 121125 127 131
150
100
155 167 172 183
51
UM
E
IM M
PM
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.
CYP2D6 AND OTHER
ANTIDEPRESSANTS
186
200
Percentage of
standard dose
138
138
150
114
100
90
50
114
90
PM
IM
86
74
66
109
EM
68
0
Medications
p
ox
r
a
in
et
e
m
se
n
ia
IM
rin
ve
a
af
l
n
e
xin
PM
UM
UM
EM
Genotypes
Kirchheiner J, Nickchen K, Bauer M, et el. Mol Psychiatry 2004 May; 9 (5):442-73.
2D6 AND ANTIPSYCHOTICS
Percentage of standard
dose
178
180
134146
169
160
139
126
140
117
142
113116
122
116
107
120
129
110
100
126
92 86 97 105 91
106
116
80
80 96
60 70 74
76
86
40
87 83 90
61
20
0
40 63
31
UM
ole tixol l
z
E
a
o
M
ipr pen erid pine ne
I
M
p
i
ar flu alop nza razi zine e
PM
h ola pe ena don ine ol
h peri daz thix
p
r
pe ris hiori pen
Medications
t
clo
zu
PM
IM
EM
UM
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.
2C19 AND ANTIDEPRESSANTS
Percentage of
standard dose
120
100
80
109110
105108107
81
79
108105
91
84 90
83
61
60 53 62
40
48 58
45
20
0
107
61
86
75
65
ne ine in e
i
l
ty am xep in ine
p
i
am line
tr ipr do r am am
i
r
r
p
a
p ip
ide
i
r
o
am lom
l
t
r
a
im r im
em
c
b
cit se
t
o
cl
o
TCAs
SSRIs
m
PM
IM
EM
PM
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.
EM
CYP2C9
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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.
CYP2C9 AND WARFARIN
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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 <2: risk of thromboembolic event
INR >3: risk of bleeding complications
Mushiroda T, Ohnishi Y, Saito S, et el. J Hum Genet. 2006;51(3):249-53.
in
r
a
rf
a
w
R-
Swa
r fa
rin
rin
fa
ar
w
S-
CYP1A1
CYP1A2
CYP3A4
R
-w
ar
fa
rin
Warfarin
Vitamin K
Reductase
Oxidized Vitamin K
CYP2C9
Reduced Vitamin K
CO2
O2
Calumenin
Hypofunctional
F. II, VII, IX, X
Protein C, S, Z
γ-glutamyl
carboxylase
Functional
F. II, VII, IX, X
Proteins C, S, Z
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.
VKORC1 POLYMORPHISM
At least 10 different single-nucleotide-polymorphisms
(SNPs) were identified
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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
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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.
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
Gage BF, MD, MSc. http://www.fda.gov/ohrms/dockets/ac/05/slides/2005-4194S1_04_Gage.ppt
DOSING ALGORITHM 2005
PROPOSED
Sconce EA, Khan TI, Wynne HA, et el. Blood Oct 2005;106(7):2329-33
DOSING ALGORITHM 2006
PROPOSED
Linder MW Ph.D. DABCC, Manage the “Over-steer” in warfarin dose titration.
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
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Linder MW Ph.D. DABCC, Manage the “Over-steer” in warfarin dose titration.
UGT1A1
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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.
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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/Camptosar_PI.pdf
UGT1A1
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SN-38 is associated with neutropenia and lifethreatening diarrhea.
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Patients with homozygous UGT1A1*28 allele are at
increased risk for ADRs following the initiation of
therapy due to increased level of SN-38.
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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: http://www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Camptosar_PI.pdf
TPMT
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TPMT- normal metabolizer (homozygous
functional alleles): 90%
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TPMT- intermediate metabolizer (heterozygous
with one nonfunctional allele): 10%
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TPMT- deficient metabolizer (homozygous
nonfunctional alleles): 0.3%
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137.
TPMT
Azathioprine and 6-mercaptopurine are immunosuppressive antimetabolites.
Imuran (azathioprine) package insert: http://www.prometheuslabs.com/pi/Imuran.pdf
TPMT
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The active thiopurine metabolite, 6-TGN, can
eventually results in myelosuppresion, a dose
limiting factor for therapy.
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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. 2006.57:119-137.
TPMT
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Predominantly genotyping or phenotyping for
TPMT variant alleles is recommended before
thiopurine therapy.
TPMT- deficient metabolizers:
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give 6-10% of the standard dose of thiopurine and
monitor CBC carefully.
TPMT- intermediate metabolizers:
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usually start on full dose, but dose reduction is
recommended to avoid toxicity.
Imuran (azathioprine) package insert: http://www.prometheuslabs.com/pi/Imuran.pdf
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137
DDI
THIOPURINES VS ALLOPURINOL
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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
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
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: http://pi.lilly.com/us/strattera-pi.pdf
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.

QUESTIONS
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/Camptosar_PI.pdf
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Pharmcogenomics and individualized drug therapy. Annu Rev Med. 2006.57:119137. (16409140)
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
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
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)
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 antipsychotics: the contribution of allelic
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
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):249-53. (16432637)
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;352:2285-93. (15930419)
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
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 CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon
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.pdf
Weinshilboum RM. Pharmacogenomics: catechol O-methyltransferase to thiopurine S-methyltransferase. Cell Mol Neurobiol 2006 Jun
29. (16807786)
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