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When to Conduct a Renal
Impairment Study
1
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
2 Shiew-Mei Huang
When to Study Renal impairment?
Renal impairment studies are considered necessary when1. 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 index
2. Elimination primarily by renal
mechanisms (excretion or
metabolism)
http://www.fda.gov/cder/guidance/1449fnl.pdf (guidance published in 1998)
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S Ibrahim, P Honig, S-M Huang, W Gillespie, LJ Lesko, RL Williams, J Clin Pharmacol, 2000;40:31
Shiew-Mei Huang
Impact of the 1998 Renal Guidance
Current
Survey2
Renal
Impairment 71% (36/51)
Study
Full Study
67% (24/36)
Design
Hemodialysis 44% (16/36)
Previous
Survey1
55% (39/71)
44% (17/39)
15% (6/39)
*Note that the “current survey” includes NME NDAs for oral dosing only from 2003July 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,
4 Shiew-Mei Huang
Zhang, Lesko, clin Pharmacol Ther (2008) S85, Orlando, April 2008
NME’s Approved 2003-2007
100
90
80
70
60
50
40
30
20
10
0
94
R: Renal (%fe > 30%)
NR: Non-renal:
Metabolized/Transported
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37
14NR
R
36
23
13 NR
R
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 5 Shiew-Mei Huang
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35
30
NME’s Approved 2003-2007
- Renal studies conducted36
R: Renal (%fe>30%)
NR: Non-renal:
Metabolized/Transported
25
20
23
15
10
5
13
R NR
0
Studied
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19
13 13
R
NR
PK
Altered
13
R 6
NR
D/A
Labeling
Renal
impairment had
an effect on
PK for drugs
-renally
eliminated
(13/13)
- metabolized
or transported
(13/23)
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Shiew-Mei Huang
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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Shiew-Mei Huang
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 8 Shiew-Mei Huang
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,
9 Shiew-Mei Huang
Elsevier (publication date: 2008)
Selected Metabolized/Transported Drugs
with PK Altered in Renal Impairment
Drug
Duloxetine
ADME
fe<1%
%F>80%
Elimination
Pathways
CYP1A2
CYP2D6
Tadalafil
fe<0.3%
CYP3A4
2.7-4.1
2.0
OATP1B1*
BCRP*
CYP2C9
3.0
-
1.9
1.4
2.1(1.0)*
1.2
Rosuvastatin fe<6%
%F~20%
Telithromycin fe<13%
%F~57%
Solifenacin
fe<15%
%F~90%
CYP3A4
CYP3A4
Fold-change in
AUC
Cmax
2.0*
2.0
Note: Comparisons between Severe vs.Normal; * information from the literature; *dialysis
fe: % dose excreted unchanged in urine; %F:% absolute bioavailability 10 Shiew-Mei Huang
Metabolized/Transported Drugs with
Studies in Renal Impairment
PK Altered
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PK NOT Altered
CYP3A
CYP3A
# of NME
6
5
4
3
CYP1A2
CYP1A2
2
1
0
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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 postmarketing)
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Shiew-Mei Huang
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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Shiew-Mei Huang
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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Shiew-Mei Huang
Figure 1. Decision tree to determine when
a renal impairment study is recommended
Investigational Drug1
Chronically administered oral, iv, sc
and likely to be administered to
target population
Single-dose use
Volatile Inhalation
Unlikely to be used in renal
impaired patients
Route of elimination
Non-renal
(Metabolism/transport)
Reduced PK study
(in ESRD patients)2
Negative
Label
Positive3
No study required
Renal
Full PK study
Dose adjustment
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
No dose adjustment
Label
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Shiew-Mei Huang
Proposed Recommendations (2)
Patient Stratification
GFR
(ml/min/1.73m2)
1998
Guidance
Stage
Description
1
≥ 90
>80
2
Control (normal)
GFR
Mild ↓ GFR
60-89
50-80
3
Moderate ↓ GFR
30-59
30-50
4
Severe ↓ GFR
15-30
<30
5
Kidney failure
(ESRD)
<15 or Requiring
dialysis
Dialysis
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Shiew-Mei Huang
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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Shiew-Mei Huang
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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Shiew-Mei Huang
Questions for the
Clinical Pharmacology
Advisory Committee
March 19, 2008
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Shiew-Mei Huang
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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Shiew-Mei Huang
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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Shiew-Mei Huang
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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Shiew-Mei Huang
Figure 1. Decision tree to determine when
a renal impairment study is recommended
Investigational Drug1
Chronically administered oral, iv, sc
and likely to be administered to
target population
Single-dose use
Volatile Inhalation
Unlikely to be used in renal
impaired patients
Route of elimination
Non-renal
(Metabolism/transport)
Reduced PK study
(in ESRD patients)2
Negative
Label
Positive3
No study required
Renal
Full PK study
Dose adjustment
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
No dose adjustment
Label
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Shiew-Mei Huang
4. What studies in hemodialysis
patients does the committee
recommend for drugs intended
for chronic administration?
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Shiew-Mei Huang
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*
Candace Lee* Kenneth Thummel*
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Gilbert Burckart* Steve Leeder*
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
1
2
Description
GFR
(ml/min/1.73m2)
≥ 90
Kidney damage with normal
or ↑GFR
Kidney damage with mild ↓
60-89
GFR
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 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
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 and
radio-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/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.htm
prepared by Tom Greene, PhD.)
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Cockcroft-Gault vs MDRD (5)
Stevens al. NEJM 2006; 354: 2473-83
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Cockcroft-Gault vs MDRD (6)
Accuracy
• Overall, MDRD are more accurate than the CockcroftGault 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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