2. Prevalence Chronic Kidney Disease “ Chronic kidney disease is a worldwide public health problem affecting more than 50 million people, and more than 1 million of them are receiving kidney replacement therapy.” National Kidney Foundation. KDOQI™ Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 49:S1-S180, (suppl 2), February 2007
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4. Impact of the 1998 Renal Guidance 2. Huang, Abraham,Apparaju,Atkinson, Burckart, Lee, Roy, Strong, Xiao, Wu, Zhang, Zhang, Lesko, clin Pharmacol Ther (2008) S85, Orlando, April 2008 1. S Ibrahim, P Honig, S-M Huang, W Gillespie, LJ Lesko, RL Williams, J Clin Pharmacol, 2000;40:31 *Note that the “current survey” includes NME NDAs for oral dosing only from 2003-July 2007; while “previous survey” includes all NDAs from Oct 1996 to Sept 1997 15% (6/39) 44% (16/36) Hemodialysis 44% (17/39) 67% (24/36) Full Study Design 55% (39/71) 71% (36/51) Renal Impairment Study Previous Survey 1 Current Survey 2
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8. The percent contributions of individual P450 enzymes are based on total immunoquantified P450 content Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC: The Human Intestinal Cytochrome P450 "Pie". Drug Metab Disp 2006; 34:880-886
9. Shiew-Mei Huang, Lawrence J Lesko, and Robert Temple, "Adverse Drug Reactions and Pharmacokinetic Drug Interactions", Chapter 21, Adverse Drug Reactions and Drug Interactions in Part 4, FUNDAMENTAL PRINCIPLES: Clinical Pharmacology, “Pharmacology and Therapeutics: Principles to Practice,” Ed. Waldman & Terzic, Elsevier (publication date: 2008) Selected efflux & uptake transporters in the gut wall (a), liver (b), and kidney (c)
10. Selected Metabolized/Transported Drugs with PK Altered in Renal Impairment Drug ADME Pathways AUC Cmax Fold-change in Elimination Duloxetine Tadalafil Rosuvastatin Telithromycin Solifenacin fe<1% %F>80% fe<0.3% fe<6% %F~20% fe<13% %F~57% fe<15% %F~90% CYP1A2 CYP2D6 CYP3A4 OATP1B1* BCRP* CYP2C9 CYP3A4 CYP3A4 2.0* 2.7-4.1 3.0 1.9 2.1(1.0)* 2.0 2.0 - 1.4 1.2 Note: Comparisons between Severe vs.Normal; * information from the literature; *dialysis fe: % dose excreted unchanged in urine; %F:% absolute bioavailability
11. Metabolized/Transported Drugs with Studies in Renal Impairment CYP1A2 CYP2C9 CYP2C19 CYP2D6 CYP3A Transporter Non-CYP CYP1A2 CYP2C9 CYP2C19 CYP3A Transporter Non-CYP CYP2D6 PK Altered PK NOT Altered # of NME
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16. Proposed Recommendations (2) Patient Stratification 1998 Guidance >80 50-80 30-50 <30 Dialysis <15 or Requiring dialysis Kidney failure (ESRD) 5 15-30 Severe ↓ GFR 4 30-59 Moderate ↓ GFR 3 60-89 Mild ↓ GFR 2 ≥ 90 Control (normal) GFR 1 GFR (ml/min/1.73m 2 ) Description Stage
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18. Proposed Recommendations (4) ESRD (hemodialysis) patients ESRD patients need to be studied for most investigational drugs - Pre-dialysis to evaluate the effect of renal impairment on drug clearance [considered as the worst case scenario] - During dialysis to evaluate the effect of dialysis on drug removal (unless the drug has a large Vd)
19. Questions for the Clinical Pharmacology Advisory Committee March 19, 2008
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25. Renal Working Group Sophia Abrahm Sandhya Apparaju Shiew-Mei Huang Lawrence Lesko Kirk Roy Ta-Chen Wu Derek Zhang Lei Zhang Office of Clinical Pharmacology Candace Lee* Kenneth Thummel* Steve Leeder* John Strong Shen Xiao Office of New Drugs Office of Pharmaceutical Science FDA Scientific Sabbatical Program* Art Atkinson* Gilbert Burckart*
26. Methods of Evaluation of Renal Function Clinical Pharmacology Advisory Committee (CPAC) March 18-19, 2008 Shen Xiao, M.D., Ph.D. Medical Officer Division of Cardiovascular and Renal Products OND/CDER/FDA
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29. Normal values for GFR in Men and Women ( Wesson LG, ed. Physiology of the Human Kidney1969: 96-108)
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31. Stages of CKD < 15 (or dialysis) Kidney failure 5 15-29 Severe ↓ GFR 4 30-59 Moderate ↓ GFR 3 60-89 Kidney damage with mild ↓ GFR 2 ≥ 90 Kidney damage with normal or ↑GFR 1 GFR (ml/min/1.73m2) Description Stage
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Editor's Notes
Older data as follows (data from 1988- 1994) An estimated 4.5 percent of adults 20 years of age and older have physiological evidence of chronic kidney disease (8 million adults) determined as a moderately or severely reduced glomerular filtration rate K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. American Journal of Kidney Disease. 2002;39(2, Suppl. 1):S1-S266. (data from 1988- 1994)
Results: A total of 94 new molecular entity drugs are included in the survey of which 51 are orally administered.
