Modeling of hypertension toxicity in response to anti-angiogenic therapy

1. Modeling of hypertensiontoxicity in response to anti-angiogenic therapy 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)

2. 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] Angiogenesis inhibitionin cancer treatment [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)

3. Angiogenesis inhibitionin 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)

4. Aim Develop a general model for hypertension and proteinuria in patients treated with angiogenesis inhibitors • Address clinical relevant questions • Optimize treatment

5. E7080:phase 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)

6. Example patient 200 systolic 150 diastolic Blood pressure (mmHg) 100 50 E7080 25 mg 0 50 100 150 200 Days

7. Dose reductions 200 systolic 150 diastolic Blood pressure (mmHg) 100 50 13 mg 19 mg E7080 25 mg 0 50 100 150 Days

8. AH medication 200 150 systolic Blood pressure (mmHg) diastolic 100 50 100 mg bid 100 mg qd Metoprolol 50 mg qd 30 mg qd Nifedipine 25 mg qd Hydrochlorothiazide 12.5 mg qd 2.5 mg qd Amiloride 8 mg 12 mg E7080 16 mg 0 50 100 150 200 Days

9. Dose E7080 Systolic BP kin kout Diastolic BP BP Central BP Conc Start E7080 Time Time AH AH Model:Structure Periph Pharmacokinetics

10. Model:Structure • Correlation between residuals BPsys and BPdia • Correlation between kin for BPsys and BPdia • No covariates

11. DDi = daily dose of AH-drug i DDD = defined* daily dose of AH-drug i Not enough data to assess difference in AH drugs AH medication • Some patients received antihypertensive meds. • “obscures” the hypertension toxicity of E7080 • Incorporate in model: DDD equivalents * Defined by WHO

12. AH medication + EffAH = θ · DDDE * Defined by WHO

13. Model:evaluation

14. 4 4 2 2 0 0 CWRES CWRES -2 -2 -4 -4 100 200 300 400 500 0 100 200 300 400 500 Time (days) Time (days) 4 4 2 2 CWRES CWRES 0 0 -2 -2 -4 -4 0 20 40 60 80 0 20 40 60 80 Time (days) Time (days) Model:evaluation Diastolic BP Systolic BP

15. 120 180 110 160 100 140 90 mmHg mmHg 80 120 70 100 60 50 80 0 20 40 60 80 0 20 40 60 80 Time (days) Time (days) Model:evaluationVisual predictive check Systolic BP Diastolic BP 90% 90% 50% 50% 10% 10%

16. Model:evaluationExample patient 200 150 Blood pressure (mmHg) Systolic 100 Diastolic 50 18 mg E7080 25 mg 0 20 40 60 80 Days

17. Simulations: 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

18. Simulations:summary

19. Intervention: None 120 AH: 1 DDDE AH: 2 DDDE 100 Dose 50% DBP (mmHg) 80 60 baseline After 12 weeks of treatment with E7080 Simulations:summary

20. Proteinurea • Categorical data: • From urinalysis, measured by `dipstick’ • Converted to toxicity grades (CTC) 0-3:

21. Dose E7080 Central AH AH Model:structure systolic BP kin kout Periph diastolic BP BP Pharmacokinetics

22. Dose E7080 Effect Central AH AH Model: structure systolic BP kin kout Periph diastolic BP BP Pharmacokinetics Pr(CTC) Proteinurea

23. Model: evaluation 100 Grade 0 80 Grade 1 Grade 2 60 % patients CTC grade Grade ≥ 3 40 20 0 0 20 40 60 80 100 Time (days)

24. Model: evaluation 100 Grade 0 80 Grade 1 Grade 2 60 % patients CTC grade Grade ≥ 3 40 20 0 0 20 40 60 80 100 Time (days)

25. Model: evaluation 100 Grade 0 80 Grade 1 Grade 2 60 % patients CTC grade Grade ≥ 3 40 20 0 0 20 40 60 80 100 Time (days)

26. Simulations: 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?

27. In 47% of patients only PU grade 0/1 In 39% of patients dose-limiting PU AH intervention: 35%dose-limiting 100 80 % patient PU 60 Grade 0 40 Grade 1 20 Grade 2 Grade 3 0 0 50 150 100 Days of treatment Simulationstreated @ 25 mg qd (MTD) for 3 months continuous

28. Conclusion / 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

29. Powered by and Piraña Acknowledgements Alwin Huitema Jos Beijnen Jan Schellens Anubha Gupta Mendel Jansen Jantien Wanders Mats Karlsson Pharmacometrics group