When to Conduct a Renal Impairment Study

1
When to Conduct a Renal Impairment Study
Clinical Pharmacology Advisory Committee Meeting
March 19, 2008 Rockville, MD

• Shiew-Mei Huang, Ph.D.
• Deputy Director
• Office of Clinical Pharmacology
• Center for Drug Evaluation and Research
• Food and Drug Administration
• shiewmei.huang_at_fda.hhs.gov

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 49S1-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, 20004031
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, 20004031
2. Huang, Abraham,Apparaju,Atkinson, Burckart,
Lee, Roy, Strong, Xiao, Wu, Zhang, Zhang, Lesko,
clin Pharmacol Ther (2008) S85, Orlando, April
2008
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NMEs 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 gt 30)
NR Non-renal Metabolized/Transported
94
51
36
37
23
NR
14
13
NR
R
R
Oral
with renal study
Total NME
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NMEs 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 (fegt30)
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

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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
34880-886
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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)
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Selected Metabolized/Transported Drugs with PK
Altered in Renal Impairment
Fold-change in
Elimination
Drug
ADME
Pathways
AUC
Cmax
felt1 Fgt80 felt0.3 felt6 F20
felt13 F57 felt15 F90
Duloxetine Tadalafil Rosuvastatin Telithromyc
in 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
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Metabolized/Transported Drugs withStudies in
Renal Impairment
PK Altered
PK NOT Altered
CYP3A
CYP3A
CYP1A2
of NME
CYP1A2
CYP2C9
CYP2D6
CYP2D6
Transporter
CYP2C19
Non-CYP
CYP2C19
Transporter
CYP2C9
Non-CYP
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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)
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

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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
No study required
Route of elimination
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
No dose adjustment
Dose adjustment
Negative
Positive3
Label
Label
Label
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Proposed Recommendations (2)
Patient Stratification
1998 Guidance gt80 50-80 30-50 lt30 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 CommitteeMarch 19, 2008
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• 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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• 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 use Volatile Inhalation Unlikely to
be used in renal impaired patients
Chronically administered oral, iv, sc and likely
to be administered to target population
No study required
Route of elimination
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
No dose adjustment
Dose adjustment
Negative
Positive3
Label
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
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
Candace Lee Kenneth Thummel Steve Leeder
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 agegt60y, 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 lt 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
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Definition of Impaired Renal Function

• NKF/KDOQI guidelines
• GFR lt60 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 lt90 mL/min/1.73 m2 would be abnormal in a
  young adult. On the other hand, a GFR of 6089
  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 PmTRm TSm
• GFR (UmxVTRm-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

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Ideal markers for GFR measurement

• GFRUm x V/Pm
• (Pm and Um plasma and urine concentrations of
  marker Vurine 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 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

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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 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/guidelin
  es_ckd/p5_lab_g4.htm

44
Cockcroft-Gault vs MDRD (4)
45
Cockcroft-Gault vs MDRD (5)
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 gt 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 gt 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/guideli
  nes_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, lt18.5 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)

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