1. Practice and Research on Cancer & the Kidney
Brussels, Belgium
April 2015
Parallel Session 2
Practice and Research on Cancer & the Kidney

2. New Guidelines and Regulations regarding Drugs & CKD
Dr. Vincent LAUNAY-VACHER, PharmD
Service ICAR
Pitié-Salpêtrière University Hospital
Paris, France

3. Disclosure Past 3 years
Pharmaceutical industry: Amgen, Bayer-Schering, Boehringer-Ingelheim, Daiichi-Sankyo, Gilead, Helsinn, Hospira, Ipsen, Leo Pharma, Roche, TEVA, Vifor Pharma (direct and/or indirect)
French Health Authorities: Haute Autorité de Santé (HAS), Institut National du Cancer (INCa) (direct)
Principles and definitions1:
Links of interest can generate conflicts of interest
Every link of interest does not necessarily result in a conflict of interest
1Haute Autorité de Santé. Guide des déclarations d’intérêts et de gestion des conflits d’intérêts. Juillet 2013

4. Example 2003: Approval of Zometa* (zoledronic acid)
Therapeutic indications:
Prevention of skeletal-related events in adult patients with advanced malignancies involving bone
Treatment of adult patients with tumour-induced hypercalcaemia (TIH)
Dosage: 4 mg IV infusion
Initial SmPC:
No renal toxicity
No need for dosage adjustment in patients with renal impairment
: First marketing authorization (EMA and FDA) :
Chang JT, et al. N Engl J Med 2003

5. Example Letter from the FDA
72 cases of acute renal failure following Zometa* administration
Outcomes:
48/72 were hospitalized: 66.7%
27/72 required dialysis: 37.5%
18/72 died: 25%
Dear Doctor letter sent out
FDA and EMA SmPC were modified (2006):
Warning on renal toxicity
Dosage adjustment recommendations
Chang JT, et al. N Engl J Med 2003

6. Example 2005: Approval of Aclasta* (zoledronic acid)
Treatment of osteoporosis:
In post-menopausal women and in adult men
Treatment of osteoporosis associated with long-term systemic glucocorticoid therapy
Dosage: 5 mg IV infusion
Initial SmPC:
No renal toxicity
No need for dosage adjustment in patients with renal impairment
: First marketing authorization (EMA and FDA)

7. Example Mid-2010: Dear Dr letter reporting Acute renal failure
Need for dosage adjustment
FDA and EMA SmPC were modified (2010):
Warning on renal toxicity
Dosage adjustment recommendations

8. What can be learnt ? How is this possible ?
Zometa* file was reviewed by oncologists and hematologists
Aclasta* file was reviewed by rheumatologists
Agencies (FDA & EMA) lack expertise on:
Drugs renal safety
Drugs dosage adjustment in renal insufficiency patients
Pharmaceutical firms lack expertise also
This must be improved !

9. Agencies initiatives Food & Drug Administration May 1998 !
17 years ago…
March 2010 but…
not approved yet…
May 1998 !

10. Agencies initiatives European Medicines Agency 11 years ago…
Not approved yet…

11. EMA Guidance to be released…
EMA has been invited to present these guidelines today
They did not accept our invitation
Let’s see together what’s in these guidelines

12. EMA Guidance to be released…

13. Impact of CKD on Drugs PK
Kidney disease induces:
Decreased renal excretion
Modified oral absorption
Altered drug distribution
Decreased drug hepatic metabolism

14. Reduced hepatic metabolism in CKD
uptake of drugs
Reduced CYP
activity
Uremic
toxins
Drug
CYP
Hepatocyte
Circulation
Vanholder R, et al. Kidney Int. 2003; Dowling TC, et al. Clin Pharmacol Ther. 2003; Leblond F, et al. J Am Soc Nephrol. 2001; Leblond F, et al. J Am Soc Nephrol. 2002; Yeung CK, et al. Kidney Int. 2014

15. Impact of CKD on Drugs PK
Example of Vandetanib:
Oral tyrosine kinase inhibitor
Targets VEGFR-2, EGFR, and RET
Renal excretion accounts for less than 25%
Hepatic metabolism/biliary excretion are the main routes of elimination
Caprelsa®. Summary of product characteristics. EMA, 2012

16. x 1.08
x 0.93
Clearance
AUC
x 1.41
x 0.71
Weil A, et al. Clin Pharmacokinet. 2010

17. Impact of CKD on Drugs PK
Example of Vandetanib:
Oral tyrosine kinase inhibitor
Targets VEGFR-2, EGFR, and RET
Renal excretion accounts for less than 25%
Hepatic metabolism/biliary excretion are the main routes of elimination
However, vandetanib pharmacokinetics are altered in the presence of reduced renal function:
Clearance reduced by 30% and AUC increased by 40%1
AUC increased from 1.5 to 2-fold in mild to severe renal impairment2
Dosage adjustment is required2
1Weil A, et al. Clin Pharmacokinet. 2010; 2Caprelsa®. Summary of product characteristics. EMA, 2012

18. EMA Guidance to be released…
All drugs should be studied in CKD patients,
including these which are metabolized in the liver

19. EMA Guidance to be released…
The groups must be the same as the international definition of CKD

20. EMA Guidance to be released…
Several very important points

21. EMA Guidance to be released…
Measuring the GFR:
« The gold standard for assessment of kidney function is a measured GFR using an exogenous substance as a filtration marker (e.g. inulin, 51Cr-EDTA, 99mTc-DTPA, iothalamate, iohexol). »
« Methods for estimating GFR using endogenous markers have drawbacks and are not as accurate as measured GFR. »
« Therefore, it is recommended that a method accurately measuring GFR using an exogenous marker is used in pharmacokinetic studies in subjects with decreased renal function. « 
No more measured Creatinine Clearance

22. EMA Guidance to be released…
Presenting data for dosage adjustments:
« In addition to measured GFR, presentation and modelling of data (see section 6.3) should preferably be made also using estimated GFR  »
To be easily put into practice, dosage adjustment recommendations should be presented also according to estimated GFR

23. EMA Guidance to be released…
Presenting data for dosage adjustments:
« GFR should be measured and expressed as ml/min. Dose adjustment in decreased renal function should be based on the subject’s absolute GFR and not on a GFR adjusted to body surface area (BSA) of 1.73 m2. »
« Hence for formulas providing BSA-adjusted GFR (ml/min/1.73 m2) this should be recalculated to the absolute GFR in ml/min in each individual. »
Diagnosis of CKD: mL/min/1.73m2
Dose adjustment : mL/min

24. EMA Guidance to be released…
Elaboration of dosage adjustments:
« Dosing recommendations should be based on absolute and not body-surface area-adjusted GFR. »
« If there are active metabolites, the increase in total active moiety (sum of clinically relevant active entities, taking into account the potency and unbound exposure of each active entity) should guide the dosing recommendation. »
Active metabolites that may also accumulate should be considered

25. EMA Guidance to be released…
Elaboration of dosage adjustments:
«  Based on the mathematical model, calculations can be made to identify doses and dosing intervals that will lead to exposure or concentrations within the target range in patients with decreased renal function. »
« This may be achieved by a reduced dose, prolonged dose interval or a combination of both.  »
The objective of dosage adjustment is to be in the therapeutic range:
Optimal Benefit/Risk ratio

26. EMA Guidance to be released…
Elaboration of dosage adjustments:
«  it is recommended to present data and evaluate dosing recommendations also applying other methods such as estimation of GFR from serum creatinine (by e.g. the MDRD or CKD-EPI formulas) or from Cystatin C, or estimation of creatinine clearance (by e.g. the Cockcroft-Gault formula).  »
Don’t agree:
MDRD and CKD-EPI are recommended in clinical practice
Clinicians should not have to calculate an additional Cockcroft-Gault only to adjust drugs dosages

27. EMA Guidance to be released…
There are several very important improvements in the future version of EMA Guidance to the Industry
They need to be released as soon as possible
How to make sure the Industry will conduct these studies ?
We do need data, not contra-indications or « warnings » which are of no use for clinical practice

28. Thank you for your attention!
Vincent Launay-Vacher
Service ICAR
Pitié-Salpêtrière University Hospital