# Presentation: 928117

##  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**

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

## 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. KDOQITM Clinical Practice Guidelines and Clinical Practice Recommendations for Diabetes and Chronic Kidney Disease. Am J Kidney Dis 49:S1-S180, (suppl 2), February 2007 ***

**Notes:**
Older data as follows

(data from 1988- 1994)
An estimated 4.5 percent of adults 20 years of age and older have physiological evidence of chronic kidney disease (8 million adults) determined as a moderately or severely reduced glomerular filtration rate 

K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. American Journal of Kidney Disease. 2002;39(2, Suppl. 1):S1-S266. (data from 1988- 1994)

## When to Study Renal impairment?

**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)***

## Impact of the 1998 Renal Guidance

|  | CurrentSurvey2 | Previous
Survey1 |
| --- | --- | --- |
| 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***

**Notes:**
Results: A total of 94 new molecular entity drugs are included in the survey of which 51 are orally administered. 

## NME’s Approved 2003-2007

**Total # NME**

**  ****# Oral**

**  ****# with **
**renal study**

**R: Renal (%fe > 30%)**

**NR: Non-renal:**
**   ****Metabolized/Transported**

**R**

**NR**

**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**

## NME’s Approved 2003-2007- Renal studies conducted-

**R: Renal (%fe>30%)**

**R**

**NR**

**R**

**NR**

_**36**_

_**26**_

**13**

**13**

**23**

***Renal impairment had an effect on PK for drugs***
***renally eliminated ******(13/13)***
*** ******metabolized or transported***
***(13/23)***

**13**

**Studied**

**PK**
**Altered**

**D/A**
**Labeling**

**R**

**NR**

_**19**_

**13**

**6**

**NR: Non-renal:**
**Metabolized/Transported**

## 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**

## The percent contributions of individual P450 enzymes are based on total immunoquantified P450 content

**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 **

## 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 efflux & uptake transporters in the gut wall (a), liver (b), and kidney (c)**

## Selected Metabolized/Transported Drugs with PK Altered in Renal Impairment 

_**Drug**__**	**_

_**ADME**__**	**_

_**Pathways**__**	**_

_**AUC**__**	**_

_**Cmax**__**	**_

_**Fold-change in**_

_**Elimination**_

**Duloxetine**
**Tadalafil**
**Rosuvastatin**
**Telithromycin**
**Solifenacin**

**fe<1%**
**%F>80%**
**fe<0.3%**
**fe<6%**
**%F~20%**
** **
**fe<13%**
**%F~57%**
** ****fe<15%**
**%F~90% **

**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**

## Metabolized/Transported Drugs withStudies in Renal Impairment

**CYP1A2**

**CYP2C9**

**CYP2C19**

**CYP2D6**

**CYP3A**

**Transporter**

**Non-CYP**

**CYP1A2**

**CYP2C9**

**CYP2C19**

**CYP3A**

**Transporter**

**Non-CYP**

**CYP2D6**

**PK Altered**

**PK NOT Altered**

**# of NME**

## 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)**
** **

## 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 **

## 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?**

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

**Investigational Drug****1**

**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**

**Renal**

**Non-renal**
**(Metabolism/transport)**

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

**Full PK study **

**No dose adjustment**

**Dose adjustment**

**Negative**

**Positive****3**

**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**

## Proposed Recommendations (2)

| 
Stage | 
Description | GFR (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**

**1998**
_**Guidance**_
**>80**
**50-80**
**30-50**
**<30**
**Dialysis**

## 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 **

## 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)**

## Questions for the Clinical Pharmacology Advisory CommitteeMarch 19, 2008 

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

** **

##  
Does the committee agree with the recommended methods of determining renal function and the proposed stratification of patients based on renal function?

**Does the committee agree with the recommended **_**methods**_** of determining renal function and the proposed **_**stratification**_** of patients based on renal function?**

## 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? 

**  **

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

**Investigational Drug****1**

**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**

**Renal**

**Non-renal**
**(Metabolism/transport)**

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

**Full PK study **

**No dose adjustment**

**Dose adjustment**

**Negative**

**Positive****3**

**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**

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

**  **

## Renal Working Group

**Sophia Abrahm**
** ****Sandhya Apparaju **
**Shiew-Mei Huang**
** ****Lawrence Lesko  **

**Kirk Roy **
**Ta-Chen Wu**
**Derek Zhang**
** ****Lei Zhang**

_**Office of Clinical Pharmacology**_

**Candace Lee*  Kenneth Thummel***
**   ****Steve Leeder*  **

**John Strong**

**Shen Xiao**

_**Office of New Drugs**_

_**Office of Pharmaceutical Science**_

_**FDA Scientific Sabbatical Program***_

**Art Atkinson***
**Gilbert Burckart***

## 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

## 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

## 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

##  Normal values for GFR in Men and Women( Wesson LG, ed. Physiology of the Human Kidney1969: 96-108)

## 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

## 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) |

## 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.

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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 m**2**) = 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 m**__**2**__**) = 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 m**2**) = 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](http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g4.htm)_

## Cockcroft-Gault vs MDRD (4)

**(From **_[http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g4.htm](http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p5_lab_g4.htm)_
**prepared by Tom Greene, PhD.)**

## Cockcroft-Gault vs MDRD (5)

- Stevens al. NEJM 2006; 354: 2473-83

## 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

## 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

## 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](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)

- 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

## 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)

- 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 

- 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