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When to Conduct a Renal Impairment Study

When to Conduct a Renal Impairment Study . dr shabeel pn. 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.” .

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When to Conduct a Renal Impairment Study

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  1. When to Conduct a Renal Impairment Study dr shabeel pn

  2. PrevalenceChronic 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

  3. When to Study Renal impairment? Renal impairment studies are considered necessary when- 1. Renal impairment is likely to significantly alter the PK (and PD) of the drug and its active metabolites 2. A dosage adjustment is likely to be required for safe and effective use of the drug in such patients 3. It is likely to be used in such patients • In particular, a study….with renal impairment is recommended when the drug (metabolites) .. • Narrow therapeutic index • Elimination primarily by renal mechanisms (excretion or metabolism) http://www.fda.gov/cder/guidance/1449fnl.pdf (guidance published in 1998) S Ibrahim, P Honig, S-M Huang, W Gillespie, LJ Lesko, RL Williams, J Clin Pharmacol, 2000;40:31

  4. Impact of the 1998 Renal Guidance *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 1. S Ibrahim, P Honig, S-M Huang, W Gillespie, LJ Lesko, RL Williams, J Clin Pharmacol, 2000;40:31 2. Huang, Abraham,Apparaju,Atkinson, Burckart, Lee, Roy, Strong, Xiao, Wu, Zhang, Zhang, Lesko, clin Pharmacol Ther (2008) S85, Orlando, April 2008

  5. NME’s Approved 2003-2007 • Determination of R or NR: • % fe: • %dose excreted unchanged in urine • (R: 70%; NR: 3%) • % bioavailability • - Radiolabeled ADME data • In vitro/in vivo metabolism/transport • Drug interaction • data R: Renal (%fe > 30%) NR: Non-renal: Metabolized/Transported 94 51 37 36 23 NR 14 13 NR R R # Oral # with renal study Total # NME

  6. NME’s Approved 2003-2007- Renal studies conducted- • Renal impairment had an effect on PK for drugs • renally eliminated (13/13) • metabolized or transported • (13/23) R: Renal (%fe>30%) 36 NR: Non-renal: Metabolized/Transported 26 23 19 13 13 13 13 R R R 6 NR NR NR PK Altered D/A Labeling Studied

  7. Renal impairment on Metabolism/Transport? • Decreased renal metabolism • Decreased renal elimination of metabolites • Decreased non-renal elimination • Uremic plasma • inhibited enzyme/transporter activity • decreased enzyme/transporter expression

  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. Selected efflux & uptake transporters in the gut wall (a), liver (b), and kidney (c) 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)

  10. Selected Metabolized/Transported Drugs with PK Altered in Renal Impairment Elimination Fold-change in Drug ADME Pathways AUC Cmax fe<1% %F>80% fe<0.3% fe<6% %F~20% fe<13% %F~57% fe<15% %F~90% Duloxetine Tadalafil Rosuvastatin Telithromycin Solifenacin 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 withStudies in Renal Impairment PK Altered PK NOT Altered CYP3A CYP3A CYP1A2 # of NME CYP1A2 CYP2C9 CYP2D6 CYP2D6 Transporter Non-CYP CYP2C19 CYP2C19 Transporter CYP2C9 Non-CYP

  12. Conclusion from the Survey (1) 1) The 1998 guidance had an impact on the determination of need to conduct a renal impairment study, study design and labeling: renal studies conducted in - 71% of oral NME (36/51) - 13 out of 14 NMEs with predominantly renal pathway (the remaining one post-marketing)

  13. Conclusion from the Survey (2) 2) More studies are needed for hemodialysis patients (44% studied in dialysis patients) 3) There appeared to be PK changes in renal impairment for NMEs that are predominantly metabolized and/or transported; the effect of renal impairment on drug metabolism and transport needs to be understood better

  14. Proposed Recommendations (1) When a study is needed? Renal Studies need to be conducted for drugs that are metabolized/transported, in addition to drugs that are renally eliminated

  15. Figure 1. Decision tree to determine when a renal impairment study is recommended Investigational Drug1 Single-dose use Volatile Inhalation Unlikely to be used in renal impaired patients Chronically administered oral, iv, sc and likely to be administered to target population Route of elimination No study required 1.Applied to metabolites (active/toxic) 2 To include both “pre dialysis” and “during dialysis” (unless large Vd) 3 Determinants of “positive”: - magnitude of PK change - exposure-response relationships - the target patient populations Non-renal (Metabolism/transport) Renal Reduced PK study (in ESRD patients)2 Full PK study Negative Positive3 Dose adjustment No dose adjustment Label Label Label

  16. Proposed Recommendations (2) Patient Stratification 1998 Guidance >80 50-80 30-50 <30 Dialysis

  17. Proposed Recommendations (3) Renal function be evaluated by the following: • MDRD (Modified Diet in Renal Disease) is the preferred method • Cockcroft-Gault equation should be used as a reference

  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 CommitteeMarch 19, 2008

  20. Does the committee agree that renal impairment can affect metabolism or transport of drugs that are substrates of metabolizing enzymes and transporters?

  21. Does the committee agree with the recommended methods of determining renal function and the proposed stratification of patients based on renal function?

  22. 3. What comments or recommendations does the committee have on applying the following decision tree (Figure 1) to the determination of when a renal impairment study is needed for an investigational drug?

  23. Figure 1. Decision tree to determine when a renal impairment study is recommended Investigational Drug1 Single-dose use Volatile Inhalation Unlikely to be used in renal impaired patients Chronically administered oral, iv, sc and likely to be administered to target population Route of elimination No study required 1.Applied to metabolites (active/toxic) 2 To include both “pre dialysis” and “during dialysis” (unless large Vd) 3 Determinants of “positive”: - magnitude of PK change - exposure-response relationships - the target patient populations Non-renal (Metabolism/transport) Renal Reduced PK study (in ESRD patients)2 Full PK study Negative Positive3 Dose adjustment No dose adjustment Label Label Label

  24. 4. What studies in hemodialysis patients does the committee recommend for drugs intended for chronic administration?

  25. Renal Working Group Office of Clinical Pharmacology Sophia Abrahm Sandhya Apparaju Shiew-Mei Huang Lawrence Lesko Kirk Roy Ta-Chen Wu Derek Zhang Lei Zhang Office of New Drugs Shen Xiao Office of Pharmaceutical Science John Strong FDA Scientific Sabbatical Program* Art Atkinson* Gilbert Burckart* Candace Lee* Kenneth Thummel* Steve Leeder*

  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

  27. Chronic Renal Disease (CKD): Public Health Problem in US • 26 million people currently have kidney damage, regardless of the cause, for three or more months (JAMA 298; 2047, 2007); • Risk factors included age>60y, hypertension, diabetes, cardiovascular disease, and family history • Outcome can be progression to kidney failure and premature death caused by cardiovascular disease. • CKD is diagnosed primarily as decreased GFR

  28. Outline • Definition and Stages of CKD • Definition of Impaired Renal Function • Measured Glomerular Filtration Rate (GFR) for Assessment of Kidney Function • Estimated GFR for Assessment of Kidney Function • Summary and Recommendation

  29. Normal values for GFR in Men and Women( Wesson LG, ed. Physiology of the Human Kidney1969: 96-108)

  30. Definition of CKD Either kidney damage (pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies) or GFR < 60 ml/min/1.73 m2 for ≥ 3 months by: NKF-K/DOQI ( Kidney Disease Outcomes Quality Initiative), 2002 KDIGO ( Kidney Disease Improving Global Outcomes), 2004, 2006

  31. Stages of CKD

  32. Definition of Impaired Renal Function • NKF/KDOQI guidelines: • GFR <60 mL/min/1.73 m2 for 3 months are classified as having chronic kidney disease, irrespective of the presence or absence of kidney damage. • GFR <90 mL/min/1.73 m2 would be abnormal in a young adult. On the other hand, a GFR of 60–89 mL/min/1.73 m2 could be normal from approximately 8 weeks to 1 year of age and in older individuals. • It is not certain whether individuals with chronically decreased GFR in the range of 60 to 89 mL/min/1.73 m2 without kidney damage are at increased risk for adverse outcomes, such as toxicity from drugs excreted by the kidney or acute kidney failure.

  33. GFR vs Urinary clearance For a substance (m) that is excreted in the Urine: Um x V = GFR x Pm–TRm+ TSm • GFR= (UmxV+TRm-TSm)/Pm • For an ideal filtration marker • TRm= 0; TSm= 0 • GFR= (Um xV)/Pm Um: urine concentration of substance m V: urine volume rate Pm: plasma concentration of m TRm: tubular reabsorption of m TSm: tubular secretion of m

  34. Ideal markers for GFR measurement GFR=Um x V/Pm (Pm and Um= plasma and urine concentrations of marker; V=urine flow rate) • Freely filterable at the glomerulus • Neither secreted nor reabsorbed by the tubules • Steady state concentrations in blood • No extrarenal route of excretion • Easily and accurately measured

  35. Exogenous marker: Inulin Exogenous marker: Inulin • Goldstandard • Constant infusion and bladder catheterization for good reproducibility • Significant blood sample volume • Assay is difficult to do • Expensive and time consuming • Limited to investigational research

  36. Exogenous markers: unlabeled markers andradio-labeled tracers (e.g. iothalamate, EDTA, iohexol, DTPA) • Low bias, high precision and reproducible measurement • Difficult to do in a routine clinical practice • Can be used when concomitant drugs (e.g. trimethoprim, cimetidine) interfere with elimination ofendogenous creatinine

  37. Endogenous marker: Cystatin C • May have possible advantages over serum creatinine due to constant rate of production and its intrarenal handling • Sensitive marker for early and mild changes of GFR • Greater intra-individual variability than Scr • Urinary clearance can not be measured • Influenced by age, gender, weight, height, smoking status, the level of c-reactive protein and corticosteroid use • Not recommend currently for CKD • CystatinC equations may be accepted in the future

  38. Endogenous markers: Creatinine/Ccr • Secreted by proximal tubular cells as well as filtered by the glomerulus • Generation primarily determined by muscle mass and dietary intake • Need 24-hour urine collection and blood sampling during the collection period • Cumbersome for timed urinary collection • Susceptible to error

  39. Equations Used to Estimate GFR (eGFR) • Derived with the use of regression techniques to model the observed relation between the serum level of creatinine and the measured GFR • Included several variables such as age, gender, race, and body size (overcome the limitations of the use of serum creatinine) • Study populations consisting predominantly of patients with CKD and reduced GFR

  40. NKF-KDOQI recommendation Adults Cockcroft-Gault equation: GFR (ml/min) = (140-age) X Weight /72 x Scr X(0.85 if female) MDRD (modification of diet in renal disease) equation: GFR (ml/min/1.73 m2) = 186 X (SCr) -1.154 X (Age) -0.203 X (0.742 if female) X (1.210 if black) Children Schwartz equation: GFR (ml/min) = 0.55 x length/Scr Counahan-Barratt equation: GFR (ml/min/1.73m2)= 0.43 X Length/Scr

  41. Cockcroft-Gault vs MDRD (1) Equation Development of eGFR • Cockcroft-Gault: Derived from 249 men with Ccr from 30 to 130 ml/min in 1973. • MDRD: Derived from 1628 patients with CKD in 1999 and re-expressed in 2005 for use with a standard serum creatinine assay

  42. Cockcroft-Gault vs MDRD (2) Studied Populations • Gender: Males and Females • Race: blacks, whites and Asians • Diseases: Healthy, CKD, Diabetes with and without kidney disease, Kidney-transplant recipients, and potential kidney donors

  43. Cockcroft-Gault vs MDRD (3) Variables • Cockcroft-Gault: Age, gender, and body mass GFR (ml/min) = (140-age) X Weight/72 xScrX(0.85 if female) • MDRD: Age, gender, race, and body mass (albumin and urea) GFR (ml/min/1.73 m2) = 170 X (SCr) -0.999 X (Age) -0.175 X (0.762 if female) X (1.1800 if black) X (BUN) -0.270 X (Alb) +0.318 (Equation 7) GFR (ml/min/1.73 m2) = 186 X (SCr) -1.154 X (Age) -0.203 X (0.742 if female) X (1.210 if black) (Abbreviated equation) GFR (ml/min/1.73 m2) = 175 X (SCr) -1.154 X (Age) -0.203 X (0.742 if female) X (1.210 if black) (will be used after creatinine standardization) http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g4.htm

  44. Cockcroft-Gault vs MDRD (4) (From http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g4.htm prepared by Tom Greene, PhD.)

  45. Cockcroft-Gault vs MDRD (5) Stevens al. NEJM 2006; 354: 2473-83

  46. Cockcroft-Gault vs MDRD (6) Accuracy • Overall, MDRD are more accurate than the Cockcroft- Gault in some studies whereas the two are similar in other studies • MDRD is reasonably accurate in non-hospitalized patients with CKD • Cockcroft-Gault is less accurate than the MDRD in older and obese people • Both are less accurate than the measured GFR in population without CKD (GFR > 60 ml/min/1.73m2) such as type I diabetes without microalbuminuria and potential kidney donors

  47. Cockcroft- Gault vs MDRD (7) Major Limitations for both equations • Unusual body habitus or diet: e.g.Overestimation of eGFR in patients with low muscle mass or low meat diet • In non-steady state (rapidly changing kidney function) • Patients with estimated GFR > 60 ml/min/1.73m2 • Medication

  48. Cockcroft- Gault vs MDRD (8) Recommendation from Scientific Communities • National Kidney foundation: Among adults, the MDRD Study equation may perform better than the Cockroft-Gault equation. (http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p5_lab_g4.htm) • American Society of Nephrology; American Association for Clinical Chemistry; American Diabetes Association; College of American Pathologists; and National Kidney Disease Educational Program: MDRD (http://nkdep.nih.gov/labprofessionals/index.htm)

  49. When Clearance Measurements May BeNecessaryto Estimate GFR (recommended by KDIGO) • Extremes of age (elderly, children) • Extremes of body size (obesity, type 2 diabetes, lowbody mass index, ie, <18.5 kg/m2) • Severe malnutrition (cirrhosis, end-stage renal failure) • Grossly abnormal muscle mass (amputation, paralysis) • High or low intake of creatinine of creatine (vegetariandiet, dietary supplements) • Pregnancy • Rapidly changing kidney function • Prior to dosing (high toxicity drugs, excreted by thekidney) • Prior to kidney donation

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