Title: When to Conduct a Renal Impairment Study
1 When to Conduct a Renal Impairment Study
dr shabeel pn
2PrevalenceChronic 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
3When 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
4Impact 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
5NMEs 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
6NMEs 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
7Renal 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
34880-886
9Selected 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)
10Selected 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
11Metabolized/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
12Conclusion 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) -
13Conclusion 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
14Proposed 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 -
15Figure 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
16Proposed Recommendations (2)
Patient Stratification
1998 Guidance gt80 50-80 30-50 lt30 Dialysis
17Proposed 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
18Proposed 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)
19Questions 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? -
23Figure 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
24- 4. What studies in hemodialysis patients does the
committee recommend for drugs intended for
chronic administration? -
25Renal 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
26Methods 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
27Chronic 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
28Outline
- 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)
30Definition 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
31Stages of CKD
32Definition 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.
33GFR 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
34Ideal 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
35Exogenous 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
36Exogenous 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
37Endogenous 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
38Endogenous 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
39Equations 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
40NKF-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
41Cockcroft-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
42Cockcroft-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
43Cockcroft-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
44Cockcroft-Gault vs MDRD (4)
45Cockcroft-Gault vs MDRD (5)
46Cockcroft-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
47Cockcroft- 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
48Cockcroft- 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)
49When 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