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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

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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

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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

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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%

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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

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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%)

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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%

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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

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Model:Model: structurestructure

kin kout

Pharmacokinetics

AH

AH

BP

CentralCentralPeriphPeriph

DoseDoseE7080E7080

systolicsystolicBPBP

diastolicdiastolicBPBP

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Model: Model: structurestructure

kin kout

Pharmacokinetics

AH

AH

BP

Proteinurea

Pr(CTC)Pr(CTC)

CentralCentralPeriphPeriph

DoseDoseE7080E7080

systolicsystolicBPBP

diastolicdiastolicBPBP

EffectEffect

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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

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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

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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

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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?

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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

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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

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AcknowledgementsAcknowledgements

Mats KarlssonPharmacometrics group

Anubha GuptaMendel JansenJantien Wanders

Alwin HuitemaJos BeijnenJan Schellens

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