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) 89-99.
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) 89-99.
5. 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.
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):442-73.
8. CYP2D6 AND OTHER
ANTIDEPRESSANTS
paroxetine
m
ianserin
venlafaxine PM
IM
EM
UM
138 138
186
114
114 109
90 90
86
66 74
68
0
50
100
150
200
Percentage
of
standard
dose
Medications Genotypes
PM
IM
EM
UM
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.
aripiprazole
flupentixol
haloperidol
olanzapine
perazine
perphenazine
risperidone
thioridazine
zuclopenthixol
PM
IM
EM
UM
134146
126 139
117
178
116
169
142
113116
107122
110
129
106
126
116
92 86 97 105 91
80 96
83 90
70 74 76
61
86
31
87
40 63
0
20
40
60
80
100
120
140
160
180
Percentage
of
standard
dose
Medications
PM
IM
EM
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
amitriptyline
clom
ipram
ine
doxepin
imipramine
trim
ipram
ine
citalopram
sertraline
moclobem
ide
PM
EM
109
110
105
108
107 108105 107
81
79
91
83
61
84 90
86
53 62
48 58
45 61
75
65
0
20
40
60
80
100
120
Percentage
of
standard
dose
TCAs SSRIs
PM
IM
EM
Kirchheiner J, Nickchen K, Bauer M, et el. Mol Psychiatry 2004 May; 9 (5):442-73.
11. 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.
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 (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.
13. CYP2C9
CYP2C9
CYP1A1
CYP1A1
CYP1A2
CYP1A2
CYP3A4
CYP3A4
R
R-
-warfarin
warfarin
S
S-
-warfarin
warfarin
Oxidized Vitamin K
Oxidized Vitamin K Reduced Vitamin K
Reduced Vitamin K
O
O2
2
Hypofunctional
Hypofunctional
F. II, VII, IX, X
F. II, VII, IX, X
Protein C, S, Z
Protein C, S, Z
Functional
Functional
F. II, VII, IX, X
F. II, VII, IX, X
Proteins C, S, Z
Proteins C, S, Z
γ-
-glutamyl
glutamyl
carboxylase
carboxylase
Vitamin K
Vitamin K
Reductase
Reductase
CO
CO2
2
Warfarin
Warfarin
R
R
-
-
w
a
r
f
a
r
i
n
w
a
r
f
a
r
i
n
S
S
-
-
w
a
r
f
a
r
i
n
w
a
r
f
a
r
i
n
Calumenin
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;352:2285-93.
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
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. 2005 Dec; 78(6):559-81.
Camptosar (irinotecan) package insert: http://www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Camptosar_PI.pdf
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: http://www.fda.gov/medwatch/SAFETY/2005/Jun_PI/Camptosar_PI.pdf
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%
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137.
22. TPMT
Azathioprine and 6-mercaptopurine are immunosuppressive antimetabolites.
Imuran (azathioprine) package insert: http://www.prometheuslabs.com/pi/Imuran.pdf
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.
Eichelbaum M, Ingelman-Sundberg M, Evans WE. Annu Rev Med. 2006.57:119-137.
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.
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
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: http://www.prometheuslabs.com/pi/Imuran.pdf
26. 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
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: http://pi.lilly.com/us/strattera-pi.pdf
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.
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