Farmacogenetica bij targeted therapies
Henk-Jan Guchelaar Klinische Farmacie & Toxicologie Amersfoort – 8 april 2010
Farmacogenetica
Mahgoub, A., R. & Smith, R. L. Lancet 1977(2): 584–586 Polymorphic hydroxylation of debrisoquine in man
CYP2D6 fenotype
debrisoquine/4-OH-debrisoquine
CYP2D6 genotype Allel
Enzym activiteit
Genetische variant
Allel frequentie (%) Caucasisch (Europa)
Japan
Tanzania
*1
Normaal
Wild-type
32.2-36.4
43
27.8
*2
Normaal
2850C>T, 4180G>C
28.5-32.4
12.3
40
*2x2
Hoog
Duplicatie
1-1.3
*3
Absent
2549delA
1-2
*4
Absent
1846G>A
17.2-20.7
.2
.9
*5
Absent
CYP2D6 deletie
2-6.9
4.5
6.3
*6
Absent
1707delT
.9-1.3
*9
Laag
2615_2617delAAG
1.8-2.7
*10
Laag
100C>T
1.5-2
*17
Laag
1023C>T, 2850C>T
*41
Laag
2988G>A
Fenotype:
0
0
38.1
3.8 17
8.4
Poor Metabolizer (5-10%) Intermediate Metabolizer (10-15%)
http://www.cypalleles.ki.se/
CYP2D6/2C19 varianten en chip technologie
• 33 CYP2D6 varianten • 3 CYP2C19 varianten
Van genotype naar phenotype
E
Roche, AmpliChip CYP450 Test, manual
Concept: concentratie-effect relatie Distributie, metabolisme, eliminatie absorptie
Concentratie-effect relatie
6 studies: 639 pt PD en 443 pt PK (sunitinib + SU12662) 2 studies “any solid tumor”; 2 studies GIST; 2 studies mRCC 25-150 mg/dag of om de dag in een 4/2, 2/2 en 2/1 week-schema Houk, Cancer Chemother Pharmacol, Dec 2009
Concentratie-effect relatie • Blootstelling (AUC)
~ TTP en OS ~ response ~ incidentie vermoeidheid
• Plasmaconcentratie
~ DBP
• Cum. Blootstelling
~ absolute aantal neutrofielen
mediane AUCss (> 0.8 ug*hr/mL) Houk, Cancer Chemother Pharmacol, Dec 2009
Concentratie-effect relatie
10
Houk, Cancer Chemother Pharmacol, Dec 2009
Orale cytostatica: transporters
Oostendorp, Cancer Treat Rev 2009;35(2):137-147
Resorptie: grote interpatient variabiliteit Mecano-studie: nierttransplantatie
Everolimus blood concentration (µg/L)
40
35
30
25
≈ 5-voud 20
15
10
5
0 -1
0
1
2
3
4
5
6
7
Time (Hours)
Unpublished data D.J. Moes
Variabiliteit in DNA • Farmacokinetiek geneesmiddelen • Transporters • Metabolisme
3% 3% 4% 12%
CYP1A2 CYP2E1 CYP2C19 CYP2C9
53% 25%
CYP2D6 CYP3A4
13
“drug targets” RCC
Rini , Lancet Oncology 2009 (modified)
Monogenetische eigenschap versus “complex” fenotype
Nebert, Drug Metab Rev 2008:187-224
15
Respons mRCC Drug
Patients
PFS
(number)
(months
RECIST SD response
median)
(%)
Withdrawal due adverse events
Previous
MSKCC
ECOG
Therapy
score >0
score 0
Disease sites ≥ 3
(%)
(%)
(%)
(%)
(%) sunitinib
375
11
48
8
no
62
62
57
sorafinib
97
5.7
74.5 (≥ 6 weeks)
11.3
no
44
57.7
-
pazopanib
225
12
44.9
15
yes- 31 cy
43
65
-
axitinib
62
7.4
17.7
35.5
yes-100 so
-
33.9
-
lapatinib
209
3.8 TTP
32
13
yes-100 cy
59
-
-
gefitinib
21
2.7
38.1
0
yes-100 cy
52.4
57
42.9
erlotinib
45
-
31
-
no
-
-
-
everolimus
41
11.2
57
-
63.4
-
34
temsirolimus
209
5.5
32.1
14
no
100
-
-
bevacizumab
50
11
58
20
no
100
-
38
(≥ 8 weeks)
yes- 83 cy
50% erlotinib
Farmacogenetica studies Drug
Disease
Gene
sunitinib
imatinib
danusertib
telatinib
Toxicity / response
Pharmacokinetic paramater
Study data will be presented
GIST
ABCB1
↓ oral clearance; no association CL
GIST
ABCG2
no association CL; ↓ clearance HT
Various solid tumors
ABCB1;
Various solid tumors
ABCB1;
no association neutropenia
no association CL
no association transporters with any toxicity grade 1-4
no association with exposure AUC
ABCG2
ABCG2
no association toxicity with VEGFR2 and VEGFR3 gefitinib
erlotinib
NSCLC
ABCB1
no association skin toxicity and diarrhoea
NSCLC
ABCG2
↑ diarrhoea HT
Various solid tumors
ABCG2;
HNSCC
ABCB1
HNSCC;
ABCG2
no association with diarrhoea
VEGFR2;
VEGR associates with OS and
VEGF
less grade 3 and 4 hypertension
no association with exposure
ABCB1 no association CL no association AUC; ↓ clearance HT
NSCLC bevacizumab
breastcancer
Pander, Curr Opin Mol Ther 2010 (submitted)
Metabolisme en transporters TKIs
Enzymen fase I
Sunitinib
CYP3A4
Sorafenib
CYP3A4
Axitinib
Pazopanib
Enzymen fase II
Transporters
ABCB1, ABCG2 UGT1A9
ABCB1, ABCG2
Major CYP3A4 Minor CYP1A2
unknown
Major CYP3A4 Minor CYP1A2, CYP2C8
ABCB1, ABCG2 Van Erp, Cancer Treat Rev 2009;35(8):692-706 Hurwitz, Clin Cancer Res 2009;15(12):4220-4227 Rugo, J Clin Oncol 2005;23(24):5474 – 5483 FDA registration information
Farmacogenetica sunitinib toxiciteit • Identificeren genetische markers die voorspellen voor sunitinib toxiciteit • 219 patienten behandeld met sunitinib (UMCG, VUMC, ErasmusMC, NKI, LUMC)
• mRCC (159), GIST (50), overig (10) • Toxiciteit geevalueerd in eerste cyclus (6 wk) NCI–CTC-AE versie 3.0 • Univariate associatie; gevolgd door multivariate logistische regressie analyse; correctie voor leeftijd, geslacht, ECOG; p- value < 0.05 • 31 ‘single nucleotide polymorphisms’ in 12 kandidaat genen – PK en PD sunitinib
19
Van Erp, J Clin Oncol 2009:27(26):4406-12
Selectie PK gerelateerde SNPs ABCG2 (BCRP) (421C/A, 34G/A, -15622C/T, 1143C/T) ABCB1 (Pgp) (3435C/T, 1236C/T, 2677G/T)
NR1I2 (-25385C/T, -24113G/A, 7635A/G, 8055C/T, 10620C/T, 10799G/A ) NR1I3 (5719C/T, 7738A/C, 7837T/G)
CYP3A4 (
Metabolieten
Sunitinib CYP3A5 (6986A/G)
SU12662 (actief) en inactieve metabolieten
CYP1A1 (2455A/G) CYP1A2 (-163A/C) O
N N H
N H O
F N H
20
Van Erp, J Clin Oncol 2009:27(26):4406-12
Selectie PD gerelateerde SNPs RET
1580T/C
738T/C
2251G/A
-604T/C
-1171C/G
-92G/A
-735G/A
54T/C
-573G/T
1191C/T
1501A/G 1501A/G
1718T/A
Van Erp, J Clin Oncol 2009:27(26):4406-12
21
‘Any toxicity’
% with any toxicity > grade 2 ABCG2 haplotype
% with any toxicity > grade 2 VEGFR genotype OR=2.39 P=0.046
OR=0.38 P=0.016 50 45 40 35 30 25 20 15 10 5 0
31,1 22,2 14,3
population
at least 1 copy of TT
no copy of TT
100 90 80 70 60 50 40 30 20 10 0
66,7
30,3
22,2
19
population
CC
CT
TT
Van Erp, J Clin Oncol 2009:27(26):4406-12
Leukopenie
% with leucopenia at 4 weeks OR= 6.24 P= 0.029
100
OR=1.74 P=0.041
100
86,7
80 60
59,5
54,9
40 20 0 population
AA
AG
GG
Cyp1A1 genotype
Van Erp, J Clin Oncol 2009:27(26):4406-12
Leukopenie % with leucopenia at 4 weeks OR= 0.36 P= 0.008
100 80 60
71 59,5 51,5
52,3
CT
CC
40 20 0
population
TT
FLT3 genotype 24
Van Erp, J Clin Oncol 2009:27(26):4406-12
Hand-foot syndroom en mucositis % hand-foot syndrome ABCB1 haplotype
% mucosal inflammation CYP1A1 genotype
OR=0.39 P=0.035
30 25 20 15 10 5 0
OR=4.03 P=0.021 86,7
100
25,5
80
19
60
10,5
44
40
40,7
20
0
0
population at least 1 copy no copy of of TTT TTT
population
AA
AG
GG
Van Erp, J Clin Oncol 2009:27(26):4406-12
Associaties toxiciteit met SNPs • Leukopenie • CYP1A1 2455A/G
OR= 6.24
• FLT3 738T/C
OR= 2.8
• NR1I3 haplotype
OR= 1.74
• Any toxicity > graad 2 • VEGFR2 1191C/T
OR= 2.39
• ABCG2 haplotype
OR= 2.63
• Mucositis • CYP1A1 2455A/G
OR= 4.03
• Handfoot syndroom • ABCB1 haplotype
OR= 2.56
26
Van Erp, J Clin Oncol 2009:27(26):4406-12
Leukopenie
27
Farmacogenetica sunitinib effectiviteit • Identificeren genetische markers die voorspellen voor sunitinib effectiviteit • PFS/OS • 136 mRCC ‘clear cell’
• 31 ‘single nucleotide polymorphisms’ in 12 kandidaat genen – PK en PD sunitinib • Klinische karakteristieken
28
Farmacogenetica sunitinib effectiviteit
29
Kiemcel versus Somatische mutaties: Cetuximab
k-ras wild type
mutant
growth-signals 30
Karapetis, N Engl J Med 2008;359(17):1757-65
Cairo-2 studie • Multicenter DCCG studie eerstelijns behandeling gemetastaseerd colorectaal carcinoom (mCRC) – PI: Prof. C.J.A. Punt, UMC St. Radboud, Nijmegen • Toevoeging cetuximab aan capecitabine + oxaliplatin + bevacizumab (Tol et al. NEJM 2009) • Blood samples: 564 van de 732 patienten • Doel: farmacogenetische markers voor cetuximab effictiviteit
31
FCGR3A 818A>C (Phe158>val) Median PFS (mo; 95% CI): Phe/Phe = 12.1 (10.3-13.2) Val-allele carrier = 7.8 (7.2-9.4) (P = 0.003, log rank test)
32
Pander, Eur J Cancer 2010 (in press)
FCGR3A 818A>C plus KRAS status Median PFS (mo): KRAS WT AC+CC AA p KRAS MT AC+CC AA p
33
Conclusies • Targeted therapies vertonen variabele respons • Variabiliteit • Farmacokinetiek • Farmacodynamiek • Niet-genetische determinanten
• Exploratieve farmacogenetische associatiestudies • Transporters en metabolisme • ‘Drug targets’
• (Nog) geen toepassing in kliniek
34
=8.2 =12.8 =0.025 =7.8 =12.1 =0.006
Dank aan
Dr Hans Gelderblom
Dr Nielka van Erp
Dr Tahar van der Straaten Laboratory for Experimental and Clinical Pharmacogenetics
Dr Judith Wessels 35
