Practice and Research on Cancer & the Kidney Brussels, Belgium 14 - 15 April 2015 Parallel Session 2 Practice and Research on Cancer & the Kidney

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

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

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 24.03.2003: First marketing authorization (EMA and FDA) 23.10.2003: Chang JT, et al. N Engl J Med 2003

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

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 15.04.2005: First marketing authorization (EMA and FDA)

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

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 !

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

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

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

EMA Guidance to be released…

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

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

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

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

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

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

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

EMA Guidance to be released… Several very important points

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

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

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

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

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

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

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

Thank you for your attention! Vincent Launay-Vacher Service ICAR Pitié-Salpêtrière University Hospital vincent.launay-vacher@aphp.fr