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Prop
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Modeling of Modeling of hypertensionhypertension toxicitytoxicity in response to anti-angiogenic in response to anti-angiogenic
therapytherapy
Ron Keizer, Anubha Gupta, Jantien Wanders, Mendel Jansen, Jos H Beijnen, Jan HM Schellens,
Mats O Karlsson, Alwin DR Huitema
Slotervaart Hospital / NKI-AvL, Amsterdam (NL) / Eisai Ltd, London (UK) / Uppsala University, Uppsala (SE)
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Angiogenesis inhibitionAngiogenesis inhibition in cancer treatmentin cancer treatment
● VEGF(R) is a major target● mAbs, e.g. bevacizumab
● TKI, e.g. sorafenib
● Hypertension occurs in:● 20-30% of patient on bevacizumab [1,2]
● 15-60% of patients on TKI [3]
● Proteinuria occurs in:
● 21-62% of patient on bevacizumab [4]
● 23–70% of patients on axitinib [5]
[1] Cobleigh, Semin. Oncol. (2003) [2] Sane et al. Angiogenesis (2004) [3] Sica, J. Clin. Oncol. (2006) [4] Zhu AmJKidneyDis (2007) [5] Rugo et al. JCO (2005)
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Angiogenesis inhibitionAngiogenesis inhibition in cancer treatmentin cancer treatment
● Hypertension is treatable and reversible
● Hypertension is not dose-limiting in most cases
● Anti-hypertensive medication (AH)
● Proteinuria is often dose-limiting
● Limited effect AH therapy
● Treatment interruptions → reduced efficacy[1,2]
● Hypertension correlated with efficacy[3-5]
[1] Harshman et al, Onkologie (2008) [2] Blay et al, ASCO (2008; #10554), [3-5] ASCO (2009; #3527,5045,8042)
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AimAim
Develop a general model for hypertension and proteinuria in patients treated with angiogenesis inhibitors
● Address clinical relevant questions
● Optimize treatment
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E7080E7080:: phase I drugphase I drug
● E7080: TKI of multiple receptors
• KDR (VEGFR-2), Flt-1 (VEGFR-1), bFGFR, PDGFR
● Data from phase I trial available (n=67)
• PK: 2 curves + sparse sampling
• BP data: weekly
• Proteinuria: urinanalysis weekly
• Available data: median 21 weeks (range 1-77 wks)
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0 50 100 150 200
Days
25 mg
50
10
01
50
20
0
Blo
od
pre
ssu
re (
mm
Hg)
Example patientExample patient
systolicdiastolic
E7080
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0 50 100 150Days
25 mg
19 mg
13 mg
50
10
01
50
20
0
Dose reductionsDose reductions
systolic
E7080
Blo
od
pre
ssu
re (
mm
Hg)
diastolic
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0 50 100 150 200
Days
16 mg
12 mg
8 mg
12.5 mg qd
Amiloride
50 mg qd
Hydrochlorothiazide
Nifedipine
Metoprolol
100 mg qd
50
10
01
50
20
0
Blo
od
pre
ssu
re (
mm
Hg)
100 mg bid
30 mg qd
25 mg qd
2.5 mg qd
E7080
systolicdiastolic
AH medicationAH medication
Prop
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nfor
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Model:Model: StructureStructure
Pharmacokinetics
CentralCentralPeriphPeriph
DoseDoseE7080E7080
kin kout
AH
AH
BP
SystolicSystolicBPBP
DiastolicDiastolicBPBP
Time
Con
c
Start E7080
Time
BP
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● Correlation between residuals BPsys and BPdia
● Correlation between kin for BPsys and BPdia
● No covariates
Model:Model: StructureStructure
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AH medicationAH medication
● Some patients received antihypertensive meds.
● “obscures” the hypertension toxicity of E7080
● Incorporate in model: DDD equivalents
AH DDiDDDii1
n
DDi = daily dose of AH-drug iDDD = defined* daily dose of AH-drug i
Not enough data to assess difference in AH drugs
* Defined by WHO
Prop
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AH medicationAH medication
* Defined by WHO
AH medication DDD* DDDE
Metoprolol 50 mg qd 150 mg 0.33
Furosemide 20 mg qd 40 mg 0.5
Lisinopril 10 mg qd 10 mg 1
1.83
+
EffAH = θ · DDDE
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Model:Model: evaluationevaluation
Diagnostic Value
%RSE Θ < 25%
%RSE Ω < 20%
%RSE Σ < 5%
Shrinkage ηBP_bas 6%
Shrinkage ηk_in 45%
Shrinkage ηε 33%
Shrinkage ε 28%
Cond. Number 62
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100 200 300 400 500
Time (days)
02
4-4
-2
CW
RE
S
0 100 200 300 400 500
Time (days)
CW
RE
S0
24
-4-2
Model:Model: evaluationevaluationSystolic BP Diastolic BP
Time (days)
CW
RE
S
0 20 40 60 80
02
4-4
-2
Time (days)
CW
RE
S
0 20 40 60 80
02
4-4
-2
Prop
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nfor
mat
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Can
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5060
7080
9010
011
012
0
Time (days)
mm
Hg
0 20 40 60 800 20 40 60 80
8010
012
014
016
018
0
Time (days)
mm
Hg
Model:Model: evaluationevaluationVisual predictive checkVisual predictive check
Systolic BP Diastolic BP
90%
50%
10%
90%
50%
10%
Prop
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0 20 40 60 80Days
50
10
01
50
20
0
Blo
od
pre
ssu
re (
mm
Hg)
25 mg
18 mg
Systolic
Diastolic
E7080
Model:Model: evaluationevaluationExample patientExample patient
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Simulations: Simulations: questions questions
When treated at the MTD:
● % of patients experiencing dose limiting hypertension
• Hypertension = increase in BPdia ≥20 mmHg from baseline
● In what % of patients can BP be normalized, when:
• Treating with AH medication
• Dose reduction
Prop
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nfor
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Simulations:Simulations: summarysummary
Intervention Median ΔBPdia
(RSE) % remain on treatment
(RSE)
None 0 43.3% (15%)
AH: 1 DDDE -2.6 mmHg (84%) 63.7% (13%)
AH: 2 DDDE -4.8 mmHg (39%) 68.8% (13%)
50% dose reduction -7.0 mmHg (29%) 82.1% (7%)
Prop
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isai I
nfor
mat
ion.
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Simulations:Simulations: summarysummary
baseline
6080
100
120
DB
P (
mm
Hg)
After 12 weeks of treatment with E7080
None
Intervention:
AH: 1 DDDE
AH: 2 DDDE
Dose 50%
Prop
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nfor
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ProteinureaProteinurea
● Categorical data:
• From urinalysis, measured by `dipstick’
• Converted to toxicity grades (CTC) 0-3:
Observation CTC grade
‘Negative’, ‘Trace’ 0
1+, 2+ 1
3+ 2
4+ 3
Prop
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nfor
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Model:Model: structurestructure
kin kout
Pharmacokinetics
AH
AH
BP
CentralCentralPeriphPeriph
DoseDoseE7080E7080
systolicsystolicBPBP
diastolicdiastolicBPBP
Prop
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nfor
mat
ion.
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Model: Model: structurestructure
kin kout
Pharmacokinetics
AH
AH
BP
Proteinurea
Pr(CTC)Pr(CTC)
CentralCentralPeriphPeriph
DoseDoseE7080E7080
systolicsystolicBPBP
diastolicdiastolicBPBP
EffectEffect
Prop
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nfor
mat
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Model:Model: evaluation evaluation
0 20 40 60 80 100
Time (days)
% p
atie
nts
CT
C g
rad
e0
20
40
60
80
10
0
Grade 0
Grade 1
Grade 2
Grade ≥ 3
Prop
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nfor
mat
ion.
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Model:Model: evaluation evaluation
0 20 40 60 80 100
Time (days)
% p
atie
nts
CT
C g
rad
e0
20
40
60
80
10
0
Grade 0
Grade 1
Grade 2
Grade ≥ 3
Prop
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ry E
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nfor
mat
ion.
Can
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Model:Model: evaluation evaluation
0 20 40 60 80 100
02
04
06
08
01
00
Time (days)
% p
atie
nts
CT
C g
rad
e
Grade 0
Grade 1
Grade 2
Grade ≥ 3
Prop
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ry E
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nfor
mat
ion.
Can
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e re
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uced
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Simulations: Simulations: questions questions
When treated at the MTD:
● What is the % of patients experiencing dose-limiting proteinuria
• Proteinuria = multiple occurrences of grade 2, or once grade 3 or 4
● What is the protective effect of AH therapy on dose limiting proteinuria?
Prop
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ry E
isai I
nfor
mat
ion.
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0 50 100 150
02
04
06
08
01
00
Days of treatment
% p
atie
nt P
U
Grade 0
Grade 1Grade 2
Grade 3
SimulationsSimulationstreated @ 25 mg qd (MTD) for 3 months continuoustreated @ 25 mg qd (MTD) for 3 months continuous
• In 47% of patients only PU grade 0/1
• In 39% of patients dose-limiting PU
• AH intervention: 35% dose-limiting
Prop
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nfor
mat
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Conclusion / ProspectsConclusion / Prospects
● Combined model describing hypertension and proteinuria following anti-VEGF treatment
• General: applicable to other VEGF inhibitors
• Use in phase II development of E7080
● Update model: data from other studies / drugs
• Gain insight into concentration effect relationships
• Obtain more info on AH effect
• Investigate possible role of hypertension as biomarker for efficacy
Prop
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nfor
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AcknowledgementsAcknowledgements
Mats KarlssonPharmacometrics group
Anubha GuptaMendel JansenJantien Wanders
Alwin HuitemaJos BeijnenJan Schellens
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