When to conduct a renal impairment study
Download
1 / 52

When to Conduct a Renal Impairment Study - PowerPoint PPT Presentation


  • 181 Views
  • Updated On :

Clinical Pharmacology Advisory Committee Meeting March 19, 2008 Rockville, MD. When to Conduct a Renal Impairment Study . Shiew-Mei Huang, Ph.D. Deputy Director Office of Clinical Pharmacology Center for Drug Evaluation and Research Food and Drug Administration

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'When to Conduct a Renal Impairment Study' - bibiane


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
When to conduct a renal impairment study l.jpg

Clinical Pharmacology Advisory Committee Meeting

March 19, 2008

Rockville, MD

When to Conduct a Renal Impairment Study

Shiew-Mei Huang, Ph.D.

Deputy Director

Office of Clinical Pharmacology

Center for Drug Evaluation and Research

Food and Drug Administration

shiewmei.huang@fda.hhs.gov


Slide2 l.jpg

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


Slide3 l.jpg

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


Slide4 l.jpg

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


Nme s approved 2003 2007 l.jpg
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


Nme s approved 2003 2007 renal studies conducted l.jpg
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


Slide7 l.jpg

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


Slide8 l.jpg

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


Slide9 l.jpg

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)


Selected metabolized transported drugs with pk altered in renal impairment l.jpg
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


Slide11 l.jpg

Metabolized/Transported Drugs with Renal Impairment Studies 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


Conclusion from the survey 1 l.jpg
Conclusion from the Survey (1) Renal Impairment

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)


Conclusion from the survey 2 l.jpg
Conclusion from the Survey (2) Renal Impairment

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


Proposed recommendations 1 l.jpg
Proposed Recommendations (1) Renal Impairment

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


Slide15 l.jpg

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


Proposed recommendations 2 l.jpg
Proposed Recommendations (2) impairment study is recommended

Patient Stratification

1998

Guidance

>80

50-80

30-50

<30

Dialysis


Proposed recommendations 3 l.jpg
Proposed Recommendations (3) impairment study is recommended

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


Proposed recommendations 4 l.jpg
Proposed Recommendations (4) impairment study is recommended

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)


Slide19 l.jpg

Questions for the impairment study is recommended Clinical Pharmacology Advisory CommitteeMarch 19, 2008


Slide20 l.jpg


Slide21 l.jpg

  • Does the committee agree with the recommended metabolism or transport of drugs that are substrates of metabolizing enzymes and transporters? methods of determining renal function and the proposed stratification of patients based on renal function?


Slide22 l.jpg

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?


Slide23 l.jpg

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


Slide24 l.jpg

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


Slide25 l.jpg

Renal Working Group recommend for drugs intended for chronic administration?

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*


Methods of evaluation of renal function l.jpg

Methods of Evaluation of Renal Function recommend for drugs intended for chronic administration?

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


Chronic renal disease ckd public health problem in us l.jpg
Chronic Renal Disease (CKD): Public Health Problem in US recommend for drugs intended for chronic administration?

  • 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


Outline l.jpg
Outline recommend for drugs intended for chronic administration?

  • 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


Normal values for gfr in men and women wesson lg ed physiology of the human kidney1969 96 108 l.jpg
Normal values for GFR in Men and Women recommend for drugs intended for chronic administration?( Wesson LG, ed. Physiology of the Human Kidney1969: 96-108)


Definition of ckd l.jpg
Definition of CKD recommend for drugs intended for chronic administration?

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


Stages of ckd l.jpg
Stages of CKD recommend for drugs intended for chronic administration?


Definition of impaired renal function l.jpg
Definition of Impaired Renal Function recommend for drugs intended for chronic administration?

  • 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.


Gfr vs urinary clearance l.jpg
GFR vs Urinary clearance recommend for drugs intended for chronic administration?

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


Ideal marker s for gfr measurement l.jpg
Ideal marker recommend for drugs intended for chronic administration?s 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


Exogenous marker inulin l.jpg
Exogenous marker: Inulin recommend for drugs intended for chronic administration?

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


Exogenous markers unlabeled markers and radio labeled tracers e g iothalamate edta iohexol dtpa l.jpg
Exogenous markers: unlabeled markers and recommend for drugs intended for chronic administration?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 ofendogenous creatinine


Endogenous marker cystatin c l.jpg
Endogenous marker: Cystatin C recommend for drugs intended for chronic administration?

  • 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


Endogenous markers c reatinine ccr l.jpg
Endogenous markers: recommend for drugs intended for chronic administration?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


Equations used to estimate gfr egfr l.jpg
Equations Used to Estimate GFR (eGFR) recommend for drugs intended for chronic administration?

  • 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


Nkf kdoqi recommendation l.jpg
NKF-KDOQI recommendation recommend for drugs intended for chronic administration?

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


Cockcroft gault vs mdrd 1 l.jpg
Cockcroft-Gault vs MDRD (1) recommend for drugs intended for chronic administration?

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


Cockcroft gault vs mdrd 2 l.jpg
Cockcroft-Gault vs MDRD (2) recommend for drugs intended for chronic administration?

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


Cockcroft gault vs mdrd 3 l.jpg
Cockcroft-Gault vs MDRD (3) recommend for drugs intended for chronic administration?

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


Cockcroft gault vs mdrd 4 l.jpg
Cockcroft-Gault vs MDRD (4) recommend for drugs intended for chronic administration?

(From http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g4.htm

prepared by Tom Greene, PhD.)


Cockcroft gault vs mdrd 5 l.jpg
Cockcroft-Gault vs MDRD (5) recommend for drugs intended for chronic administration?

Stevens al. NEJM 2006; 354: 2473-83


Cockcroft gault vs mdrd 6 l.jpg
Cockcroft-Gault vs MDRD (6) recommend for drugs intended for chronic administration?

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


Cockcroft gault vs mdrd 7 l.jpg
Cockcroft- Gault vs MDRD (7) recommend for drugs intended for chronic administration?

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


Cockcroft gault vs mdrd 8 l.jpg
Cockcroft- Gault vs MDRD (8) recommend for drugs intended for chronic administration?

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)


When clearance measurements may be necessary to estimate gfr recommended by kdigo l.jpg
When Clearance Measurements May Be recommend for drugs intended for chronic administration?Necessaryto 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


Summary and recommendation for pk study in patients with impaired renal function 1 l.jpg
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.


Summary and recommendation for pk study in patients with impaired renal function 2 l.jpg
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?


Acknowledgement l.jpg
Acknowledgement impaired renal function

  • 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