1 When to Conduct a Renal Impairment Study Shiew-Mei Huang, Ph.D. Deputy Director Office of Clinical Pharmacology Center for Drug Evaluation and Research.

1

When to Conduct a Renal Impairment Study

Shiew-Mei Huang, Ph.D.Deputy Director

Office of Clinical PharmacologyCenter for Drug Evaluation and Research

Food and Drug Administration

[email protected]

Clinical Pharmacology Advisory Committee Meeting March 19, 2008Rockville, MD

2 Shiew-Mei Huang

PrevalenceChronic Kidney

Disease

PrevalenceChronic Kidney

Disease

“Chronic kidney disease is a worldwidepublic 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 Shiew-Mei HuangS Ibrahim, P Honig, S-M Huang, W Gillespie, LJ Lesko, RL Williams, J Clin Pharmacol, 2000;40:31

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) ..

1. Narrow therapeutic index2. Elimination primarily by renal

mechanisms (excretion or metabolism)

http://www.fda.gov/cder/guidance/1449fnl.pdf (guidance published in 1998)

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CurrentSurvey2

PreviousSurvey1

Renal Impairment Study

71% (36/51)

55% (39/71)

Full Study Design

67% (24/36)

44% (17/39)

Hemodialysis

44% (16/36)

15% (6/39)

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

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NME’s Approved 2003-2007

0

10

20

30

40

50

60

70

80

90

100

Total #

NM

E

# O

ral

# w

ith

renal s

tudy

R: Renal (%fe > 30%)NR: Non-renal: Metabolized/Transported

RNR

R NR

94

51

36

14

37

13

23

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

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NME’s Approved 2003-2007

- Renal studies conducted-

0

5

10

15

20

25

30

35

40R: Renal (%fe>30%)

RNR

R NR

36

26

1313

23

Renal impairment had an effect on PK for drugs

-renally eliminated (13/13)

- metabolized or transported(13/23)

13

Studied PKAltered

D/ALabeling

RNR

19

13

6

NR: Non-renal:Metabolized/Transported

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Renal impairment on Metabolism/Transport?

• Decreased renal metabolism

- Uremic plasma - inhibited enzyme/transporter activity- decreased enzyme/transporter expression

• Decreased non-renal elimination

• Decreased renal elimination of metabolites

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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

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 Shiew-Mei Huang

Selected Metabolized/Transported Drugs with PK Altered in Renal

Impairment

Drug ADME Pathways AUC CmaxFold-change inEliminatio

nDuloxetine

Tadalafil

Rosuvastatin

Telithromycin

Solifenacin

fe<1%%F>80%

fe<0.3%

fe<6%%F~20%

fe<13%%F~57%

fe<15%%F~90%

CYP1A2CYP2D6

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; *dialysisfe: % dose excreted unchanged in urine; %F:% absolute bioavailability

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Metabolized/Transported Drugs with

Studies in Renal Impairment

0

1

2

3

4

5

6

7

CYP1A2

CYP2

C9

CYP2

C19

CYP2

D6

CYP3ATr

ansp

orte

r

Non

-CYP

CYP1A2CY

P2C9

CYP2

C19

CYP3A

Tran

spor

ter

Non

-CYP

CYP2

D6

PK Altered PK NOT Altered

# o

f N

ME

12 Shiew-Mei Huang

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)

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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

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Proposed Recommendations (1)

Renal Studies need to be conducted for drugs that are metabolized/transported, in addition to drugs that are renally eliminated

When a study is needed?

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Figure 1. Decision tree to determine when a renal impairment study is recommended

Investigational Drug1

Single-dose useVolatile Inhalation

Unlikely to be used in renal impaired patients

Chronically administered oral, iv, sc and likely to be

administered to target population

No study requiredRoute of elimination

RenalNon-renal(Metabolism/transport)

Reduced PK study(in ESRD patients)2 Full PK study

No dose adjustmentDose adjustmentNegative Positive3

Label

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

Label Label

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Stage

DescriptionGFR

(ml/min/1.73m2

)

1 Control (normal) GFR

≥ 90

2 Mild ↓ GFR 60-89

3 Moderate ↓ GFR

30-59

4 Severe ↓ GFR 15-30

5 Kidney failure (ESRD)

<15 or Requiring dialysis

Proposed Recommendations (2)

Patient Stratification

1998Guidance

>80

50-80

30-50

<30

Dialysis

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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

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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)

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Questions for the Clinical Pharmacology Advisory Committee

March 19, 2008

Questions for the Clinical Pharmacology Advisory Committee

March 19, 2008

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

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2. Does the committee agree

with the recommended methods of determining renal function and the proposed stratification of patients based on renal function?

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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?

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Figure 1. Decision tree to determine when a renal impairment study is recommended

Investigational Drug1

Single-dose useVolatile Inhalation

Unlikely to be used in renal impaired patients

Chronically administered oral, iv, sc and likely to be

administered to target population

No study requiredRoute of elimination

RenalNon-renal(Metabolism/transport)

Reduced PK study(in ESRD patients)2 Full PK study

No dose adjustmentDose adjustmentNegative Positive3

Label

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

Label Label

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

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Renal Working Group

Sophia Abrahm Sandhya Apparaju

Shiew-Mei Huang Lawrence Lesko

Kirk Roy Ta-Chen WuDerek Zhang Lei Zhang

Office of Clinical Pharmacology

Candace Lee* Kenneth Thummel*

Steve Leeder*

John Strong

Shen XiaoOffice of New Drugs

Office of Pharmaceutical Science

FDA Scientific Sabbatical Program*Art Atkinson*

Gilbert Burckart*

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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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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

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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

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Normal values for GFR in Men and Women

( Wesson LG, ed. Physiology of the Human Kidney1969: 96-108)

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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

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Stages of CKD

Stage Description GFR (ml/min/1.73m2

)

1 Kidney damage with normal or ↑GFR

≥ 90

2 Kidney damage with mild ↓ GFR

60-89

3 Moderate ↓ GFR 30-59

4 Severe ↓ GFR 15-29

5 Kidney failure < 15 (or dialysis)

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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.

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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 mV: urine volume rate

Pm: plasma concentration of m

TRm: tubular reabsorption of m

TSm: tubular secretion of m

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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

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Exogenous marker: Inulin

Exogenous marker: Inulin • Gold standard• 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

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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 of endogenous creatinine

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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

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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

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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

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NKF-KDOQI recommendationAdults

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)

ChildrenSchwartz equation: GFR (ml/min) = 0.55 x length/Scr Counahan-Barratt equation: GFR (ml/min/1.73m2)= 0.43 X Length/Scr

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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

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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

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Cockcroft-Gault vs MDRD (3)Variables

• Cockcroft-Gault : Age, gender, and body massGFR (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

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Cockcroft-Gault vs MDRD (4)

(From http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g4.htmprepared by Tom Greene, PhD.)

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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

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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

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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)

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When Clearance Measurements May Be Necessary to Estimate GFR (recommended by KDIGO)

• Extremes of age (elderly, children)• Extremes of body size (obesity, type 2 diabetes, low

body 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 (vegetarian

diet, dietary supplements)• Pregnancy• Rapidly changing kidney function• Prior to dosing (high toxicity drugs, excreted by the

kidney)• Prior to kidney donation

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Summary and Recommendation for PK study in patients with impaired renal function

(1)

1.PK studies conducted in patients with impaired renal function should start with GFR ≤ 60 ml/min/1.73m2

2.Considering the MDRD may provide a more accurate estimate of GFR than the Cockcroft-Gault equation, MDRD should be recommended for PK study in patients with impaired renal function.

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Summary and Recommendation for PK study in patients with impaired renal function

(2)3.Since the Cockcroft-Gault equation has been mainly

used in previous PK studies, the sponsor should be encouraged to provide the data based on the Cockcroft-Gault equation as well.

4.Both equations are derived from the serum level of creatinine. In conditions of interference with creatinine elimination caused either by the diseases or test products, the clearance of other filtration markers such as iothalamate, EDTA, DTPA, or iohexol should be used to estimate renal function.

5. A better estimation equation for GFR for use in PK modeling to cover all populations is needed: new creatinine equations? Cystatin C equations? New filtration markers?

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Acknowledgement

• Renal working group

Sophia Abrahm Sandhya Apparaju

Gibert Burckart Shiew-Mei Huang

Kirk Roy John Strong

Ta-Chen Wu Derek Zhang

Lei Zhang Lawrence Lesko• Norman Stockbridge• Tomas Marciniak