Guidance for Industry 
Pharmacokinetics  in Patients 
with Impaired Renal Function  
Study Design, Data Analysis, 
and Impact on Dosing 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 90 days of 
publication  in the Federal Register of the notice announcing  the availability  of the draft 
guidance.  Submit electronic comments to http://www.regulations.gov.   Submit  written 
comments to the Division  of Dockets Management (HFA-305), Food and Drug Administration, 
5630 Fishers Lane, rm. 1061, Rockville,  MD  20852.  All comments should be identified  with 
`the docket number listed in the notice of availability  that publishes  in the Federal Register. 
 
For questions regarding this draft document contact the CDER, Office of Clinical 
Pharmacologys Guidance and Policy Team at CDER_OCP_GPT@fda.hhs.gov. 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
September 2020 
Clinical Pharmacology 
Revision 2 
 
Draft Guidance Temp 
09/03/20  Guidance for Industry 
Pharmacokinetics  in Patients 
with Impaired Renal Function  
Study Design, Data Analysis, 
and Impact on Dosing 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 September 2020 
Clinical Pharmacology 
 
Revision 2 
 
Draft Guidance Temp 
09/03/20  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION.......................................................................................................... 1 
II.  BACKGROUND ............................................................................................................ 2 
III.  CONSIDERATIONS FOR RENAL IMPAIRMENT STUDIES ............................... 3 
A.  CIRCUMSTANCES WHERE A DEDICATED STUDY IS RECOMMENDED ................................................................... 3 
B.  CIRCUMSTANCES WHERE A DEDICATED STUDY CAN BE CONSIDERED .............................................................. 4 
C.  CIRCUMSTANCES WHERE A DEDICATED STUDY MAY NOT BE IMPORTANT OR PRACTICAL ............................. 4 
IV.  STUDY DESIGN ........................................................................................................ 5 
A.  DETERMINATION OF RENAL FUNCTION................................................................................................................. 5 
B.  FULL PHARMACOKINETIC STUDY DESIGN ............................................................................................................ 7 
C.  REDUCED PHARMACOKINETIC STUDY DESIGN................................................................................................... 10 
D.  CHARACTERIZING THE IMPACT OF RENAL FUNCTION IN PHASE 2 AND PHASE 3 TRIALS ................................. 10 
E.  EFFECT OF DIALYTIC THERAPIES ON THE PK OF A DRUG .................................................................................. 11 
F.  CONSIDERATIONS FOR PHARMACODYNAMIC ASSESSMENTS ............................................................................. 13 
V.  DATA ANALYSIS ....................................................................................................... 13 
A.  ESTIMATING PHARMACOKINETIC PARAMETERS ................................................................................................. 13 
B.  MODELING THE RELATIONSHIP BETWEEN RENAL FUNCTION AND PHARMACOKINETIC PARAMETERS........... 13 
C.  DEVELOPING DOSING RECOMMENDATIONS........................................................................................................ 14 
VI.  LABELING .............................................................................................................. 14 
 
 
 
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1  Pharmacokinetics in Patients with Impaired  Renal Function   Study 
2  Design, Data Analysis, and Impact on Dosing 
3  Guidance for Industry1 
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14   
15  I.  INTRODUCTION  
16   
17  This guidance assists sponsors in the design and analysis of studies2 that assess the influence of 
18  impaired renal function on the pharmacokinetics  (PK) and/or pharmacodynamics (PD) of an 
19  investigational  drug and addresses how such information  can inform the labeling.  This version3 
20  revises and replaces the draft guidance entitled Pharmacokinetics in Patients With Impaired 
21  Renal Function  Study Design, Data Analysis and Impact on Dosing and Labeling (March 
22  2010) and provides updated recommendations on the following  topics: 
23   
24    When a standalone study of a drugs PK in subjects with impaired renal function is 
25  recommended and when it may not be needed 
26   
27    The design and conduct of pharmacokinetic  studies in subjects with impaired renal 
28  function 
29   
30    Considerations  for characterizing a drugs PK in patients undergoing  intermittent  or 
31  continuous  dialytic therapies 
32   
                                              
1 This guidance has been prepared by the Renal Impairment Guidance Working Group in the Center for Drug 
Evaluation and Research (CDER) at the Food and Drug Administration (FDA). 
 
2 For the purposes of this guidance, studies and trials are used interchangeably. 
 
3 The updates in this guidance are in part based on the discussion at an FDA Advisory Committee Meeting in May 
2019:  https://www.fda.gov/advisory-committees/advisory-committee-calendar/may-7-2019-meeting-
pharmaceutical-science-and-clinical-pharmacology-advisory-committee-meeting#event-materials. 
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33    The use of pharmacokinetic  information  from phase 2 and 3 studies to inform dosing 
34  recommendations for patients with impaired  renal function 
35   
36    The analysis and reporting of the results of studies that characterize the impact of 
37  impaired renal function and how these data inform dosing recommendations  in labeling 
38   
39  FDAs guidance documents, including  this guidance, do not establish legally  enforceable 
40  responsibilities.   Instead, guidances describe the Agencys current thinking  on a topic and are to 
41  be viewed only as recommendations,  unless specific regulatory or statutory requirements are 
42  cited.  The use of the word should in Agency guidances means that something is suggested or 
43  recommended, but not required.  
44   
45   
46  II.  BACKGROUND 
47   
48  Drugs are eliminated  from the body by a variety of mechanisms.  Most drugs are cleared by a 
49  combination  of some or all of the following  pathways: metabolism  and transport in the small 
50  intestine, metabolism  and transport in the liver, and glomerular  filtration  and tubular secretion of 
51  unchanged drug by the kidneys (i.e., renal excretion).  If a drug is eliminated  primarily  through 
52  renal excretion, then impaired renal function usually alters the drugs PK to an extent that a 
53  change in the dosage regimen from that used in patients with normal renal function should be 
54  considered. 
55   
56  The most obvious type of change in the PK of a drug arising from impaired renal function is a 
57  decrease in renal excretion of the drug or its metabolites.  However, impaired renal function has 
58  also been associated with changes in the absorption,  plasma protein binding,  and/or tissue 
59  distribution  of a drug.  Literature reports indicate that impaired renal function can alter some 
60  drug metabolism  and transport pathways in the liver and gut.4,5  These changes can be 
61  particularly  prominent in patients with severely impaired renal function.  These topics are an area 
62  of active research, and the findings  from this research could inform FDA guidance in the future.   
63   
64  As a result of the above considerations,  for most drugs that are likely  to be administered to 
65  patients with impaired renal function, it is important to characterize a drugs PK in subjects with 
66  impaired renal function to provide appropriate dosing recommendations.  Exceptions to this 
67  recommendation  are described in section I.C. 
68   
                                              
4 Sun, H, L Frassetto, and LZ Benet, 2006, Effects of Renal Failure on Drug Transport and Metabolism, Pharmacol 
Ther, 109:111. 
 
5 Nolin, TD, J Naud, FA Leblond, and V Pichette, 2008, Emerging Evidence of the Impact of Kidney Disease on 
Drug Metabolism and Transport, Clin Pharmacol Ther, 83:898903. 
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69   
70  III.  CONSIDERATIONS FOR RENAL IMPAIRMENT STUDIES 
71   
72  The safety and effectiveness of a drug are generally established for specific dosage regimens in 
73  late-phase clinical trials that enroll patients from the target patient population.   Frequently, 
74  individuals  with advanced renal disease are explicitly  excluded from participation  in these trials.  
75  Drug development programs should include an early characterization of the expected effect of 
76  impaired renal function on a drugs PK, with the goal of enabling the inclusion  of this population 
77  in late-phase trials by allowing  appropriate prospective dosage adjustment. 
78   
79  Early characterization can be based on data obtained from phase 1 and/or phase 2 studies. 
80  Alternatively,  this information  can be obtained by utilizing  modeling  and simulation  strategies, 
81  for example, physiologically  based pharmacokinetic modeling  and simulation.   Such approaches 
82  allow sponsors to obtain clinical  experience using the proposed dosing regimen in patients with 
83  impaired renal function and thus better ensure that the trial findings  will be applicable to the 
84  population  likely  to use the drug, should it be approved.6,7 
85   
86  Alternative enrollment  designs, such as sequential or adaptive enrollment  of patients with 
87  progressively  worsening categories of renal function can also be considered to support the safe 
88  enrollment  of patients.  The exclusion of patients with impaired renal function from clinical 
89  studies conducted for a development  program should be justified  and discussed with the relevant 
90  review divisions. 
91   
92  A.  Circumstances Where a Dedicated Study Is Recommended 
93   
94  1.  Drugs Excreted Primarily Via Renal Mechanisms 
95   
96  A dedicated renal impairment study is generally recommended: (1) when the drug is likely  to be 
97  used in such patients; and (2) when impaired renal function is likely  to alter the PK of the drug or 
98  its active metabolites because they are substantially  eliminated  by the renal route.  A drug is 
99  considered to be substantially  eliminated  by the renal route when the fraction of systemically 
100  available drug or active metabolite that is eliminated  unchanged in the urine (f ) is 0.3 or greater.    
e
101   
                                              
6 See the FDA draft guidance entitled Enhancing the Diversity of Clinical Trial Populations  Eligibility Criteria, 
Enrollment Practices, and Trial Designs (June 2019).  When final, this guidance will represent the FDAs current 
thinking on this topic.  We update guidances periodically.  For the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. 
 
7 See the FDA final guidance entitled Cancer Clinical Trial Eligibility Criteria: Patients with Organ Dysfunction or 
Prior or Concurrent Malignancies Guidance for Industry (July 2020). 
 
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102  2.  Certain Biologic Drugs (Therapeutic Proteins and Peptides) 
103   
104  Data from biologics  license application  reviews indicate that impaired renal function decreased 
105  the renal clearance of therapeutic proteins and peptides that have a molecular weight of less than 
106  69 kDa.  In some cases, a dose adjustment was necessary to reduce the risk of exposure-related 
107  toxicity  in patients with impaired renal function.  Therefore, pharmacokinetic  studies in patients 
108  with impaired renal function are recommended for therapeutic proteins and peptides with a 
109  molecular weight less than 69 kDa. 
110   
111  3.  Evaluating the Influence of Dialytic Therapies 
112   
113  The PK of drugs that are likely  to be used in patients with end-stage renal disease (ESRD) 
114  undergoing  dialysis  should be evaluated both while the patient is on dialysis  and off dialysis  to 
115  determine the contribution  of the dialytic  method to the elimination  of the drug and its 
116  potentially  active metabolites (see section I.E).  Dialytic therapies can remove a significant 
117  fraction of a drug or its active metabolites,  leading to clinically  significant  exposure changes.  In 
118  such cases, a change in the dosage regimen, such as a supplemental  dose following  the dialysis 
119  procedure, could be appropriate. 
120   
121  Intermittent hemodialysis  (IHD) is the most common dialytic  modality used in patients with 
122  ESRD in the United States.  Therefore, to evaluate the impact of dialysis on the PK of a drug, we 
123  recommend that sponsors conduct these studies in patients undergoing IHD.  When relevant to 
124  the intended patient population,  similar principles  can be applied to characterize the impact of 
125  peritoneal dialysis or continuous renal replacement therapy (CRRT) on the disposition  of the 
126  drug and/or its metabolites. 
127   
128  A study of the effect of dialytic  therapies on the PK of a drug can be omitted if the dialytic 
129  procedure is unlikely  to result in significant  elimination  of the drug or its active metabolites, for 
130  example, if the drug: 
131   
132    Has a molecular weight that makes it unlikely  to be cleared by dialytic  modalities 
133    Exhibits  high plasma protein binding  that is not affected by impaired renal function 
134   
135  B.  Circumstances Where a Dedicated Study Can Be Considered 
136   
137  As mentioned in section II, it is often important to characterize the impact of impaired renal 
138  function on the PK of drugs that are eliminated  predominantly  via nonrenal routes.  In such 
139  situations,  a reduced pharmacokinetic study design (described in section I.C) can be considered. 
140   
141  C.  Circumstances Where a Dedicated Study May Not Be Important  
142   
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143  For some drugs, impaired renal function is not likely  to alter the PK of a drug enough to justify 
144  dosage adjustment.  In such cases, a dedicated study is generally not necessary.  Current 
145  knowledge suggests that the following  drug properties justify this approach: 
146   
147    Gaseous or volatile  drugs and active metabolites that are primarily  eliminated  through the 
148  lungs 
149   
150    Drugs intended only for single-dose  administration 
151   
152    Therapeutic proteins with a molecular weight greater than 69 kDa 
153   
154    Locally acting drugs (e.g., topical products) with limited  systemic absorption 
155   
156   
157  IV.  STUDY DESIGN 
158   
159  The primary goal is to characterize the impact of impaired renal function on the PK of the drug 
160  and determine whether the extent of the changes in the PK of the drug warrant a dose adjustment.  
161  Achieving this goal can be accomplished in a variety of ways, depending on the characteristics of 
162  the drug and the intended patient population.  This section discusses:  
163   
164    Determination of renal function in adults 
165   
166    Design of a full pharmacokinetic  study 
167   
168    Design of a reduced pharmacokinetic  study 
169   
170    Evaluation  of the impact of impaired renal function on the PK of a drug in phase 2 or 
171  phase 3 studies 
172   
173    Design of studies in patients receiving dialytic  therapies 
174   
175    Considerations  for pharmacodynamic  or other response assessments 
176   
177  A.  Determination of Renal Function 
178   
179  There are different ways to assess renal function.  Measurement of the glomerular  filtration  rate 
180  (GFR) using exogenous markers such as inulin,  iothalamate,  EDTA, diethylene triamine 
181  pentaacetic acid, and iohexol  provides a more accurate assessment of renal function than 
182  estimating equations.  In addition,  measured creatinine clearance (CLcr) using timed urine 
183  samples is sometimes used to assess renal function.  However, these methods are not routinely 
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184  used in clinical  practice and estimation of renal function using a widely accepted serum 
185  creatinine-based equation is usually sufficient for pharmacokinetic  studies.  
186   
187  Serum creatinine-based equations include: 
188   
189  (1) Estimated GFR (eGFR) calculated using a contemporary, widely accepted equation 
190  for the population  being studied.8,9  In clinical  practice, eGFR values are standardized to 
191  a body surface area (BSA) value of 1.73 m2 and expressed and reported in units of 
192  mL/min/1.73  m2.  Renal clearance of a drug is proportional  to individual  GFR (expressed 
193  as mL/min) and not BSA-standardized GFR, hence BSA-standardization  will not be 
194  appropriate in patients with BSAs different than the standard (1.73 m2).  To individualize 
195  GFR for drug dosing, multiply  the standardized GFR by the individuals  BSA calculated 
196  using an appropriate formula10,11 and divide by 1.73. 
197   
198  (2) Estimated creatinine clearance (CLcr) in mL/min calculated using the Cockcroft-
199  Gault (C-G) equation.12  In overweight or obese individuals,  use of alternative body 
200  weight metrics such as ideal body weight (IBW) or adjusted body weight (ABW) when 
201  calculating  CLcr is likely  to provide a more accurate estimate of renal function than total 
202  body weight.13 
203   
                                              
8 Levey AS, LA Stevens, CH Schmid, YL Zhang, AF Castro 3rd, Feldman HI, JW Kusek, P Eggers, F Van Lente, T 
Greene, J Coresh, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration), 2009, A New Equation to 
Estimate Glomerular Filtration Rate, Ann Intern Med, 150(9):604-12. 
 
9 Levey AS, J Coresh, T Greene, LA Stevens, YL Zhang, S Hendriksen, JW Kusek, F Van Lente, Chronic Kidney 
Disease Epidemiology Collaboration, 2006, Using Standardized Serum Creatinine Values in the Modification of 
Diet in Renal Disease Study Equation for Estimating Glomerular Filtration Rate, Ann Intern Med, 145(4):247-54. 
 
10 Dubois D, EF Dubois, 1916, A Formula to Estimate the Approximate Surface Area if Height and Weight Be 
Known, Arch Intern Med, 17:863-871. 
 
11 Mosteller RD, 1987, Simplified Calculation of Body Surface Area, N Engl J Med, 317:1098. 
 
12 Cockcroft, DW and MH Gault, 1976, Prediction of Creatinine Clearance from Serum Creatinine, Nephron, 
16(1):31-41. 
 
13 Pai, MP, 2010, Estimating the Glomerular Filtration Rate in Obese Adult Patients for Drug Dosing, Advances in 
Chronic Kidney Disease, 17(5):e53-e62. 
 
 
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204  Because of the widespread availability  and incorporation  of eGFR into current clinical  practice, 
205  use of eGFR to determine renal function in pharmacokinetic studies is recommended.14,15  
206  However, given the strengths and limitations  of each method, use of measured GFR (using an 
207  exogenous marker), measured CLcr, or any contemporary, widely accepted, and clinically 
208  applicable estimating  equation for the population  being studied is considered reasonable to assess 
209  renal function in PK studies.   
210   
211  In pediatric  patients,  renal function  can also be either measured  or estimated.   There are 
212  multiple  equations  for estimation,  and, as with adults,  any widely  accepted contemporary 
213  equation  for use in pediatric  patients is acceptable.  In pediatric  patients  below  two years of 
214  age, maturation,  gestational  age and other factors need to be taken into  account.  Therefore, 
215  early communication  with the Agency is recommended.   For our draft recommendations  on 
216  assessing  renal function  in pediatric  patients,  refer to the FDA draft guidance  for industry 
217  entitled  General Clinical Pharmacology Considerations for Pediatric Studies for Drugs and 
218  Biological Products (December 2014).16 
219   
220  B.  Full Pharmacokinetic Study Design 
221   
222  A full PK study design is recommended for drugs that are described in Section III.A.   
223     
224  1.  Study Participants  
225   
226  To adequately characterize the impact of impaired renal function on the PK of a drug, the renal 
227  function of study participants should range from normal function to severe impairment.   The 
228  classification  of renal function described in Table 1 can be used to enroll participants into the 
229  dedicated renal impairment  study.  It can also help derive dosing recommendations.   
230   
231   
232   
233   
234   
235   
                                              
14 Hudson, JQ and TD Nolin, 2018, Pragmatic Use of Kidney Function Estimates for Drug Dosing:  The Tide is 
Turning, Advances in Chronic Kidney Disease, 25(1):14-20. 
 
15 Matzke, GR, GR Aronoff, AJ Atkinson Jr, WM Bennett, BS Decker, KU Eckardt, T Golper, DW Grabe, B 
Kasiske, F Keller, JT Kielstein, R Mehta, BA Mueller, DA Pasko, F Schaefer, DA Sica, LA Inker, JG Umans, P 
Murray, 2011, Drug Dosing Consideration in Patients With Acute and Chronic Kidney Disease:  A Clinical Update 
From Kidney Disease: Improving Global Outcomes (KDIGO), Kidney International, 80(11):1122-1127. 
 
16 When final, this guidance will represent the FDAs current thinking on this topic. 
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236  Table 1. Classifications of Renal Functiona,b for Dedicated Renal Impairment Studies 
Description  Range of Values for Renal Function (mL/min) 
Control (normal renal function)   90 
 
Mild impairment  60-89 
 
Moderate impairment  30-59 
Severe impairment  15-29 
Kidney failurec  <15 or dialysis  patients on non-dialysis  days 
237   
238  a eGFR: estimate of GFR based on an estimation equation and expressed in mL/min.  To convert mL/min/1.73 m2 to 
239  mL/min multiply by the individuals BSA calculated using an appropriate formula and divide by 1.73. 
240   
241  b CLcr: estimated creatinine clearance based on the C-G equation. 
242   
243  c Kidney failure: This classification is strictly for the purposes of conducting a dedicated renal impairment study and 
244  should not be used for the purposes of classifying kidney disease. 
245   
246  To characterize the impact of impaired  renal function on the PK of drugs that are expected to 
247  have a wide therapeutic range, study subjects can be stratified based on renal function 60 
248  mL/min  (normal renal function or mild renal impairment),  15-59 mL/min (moderate to severe 
249  renal impairment),  and <15 mL/min or dialysis  patients on non-dialysis  days. 
250   
251  Subjects with impaired renal function should be hemodynamically  stable.  Further, subjects with 
252  impaired renal function should be similar  to the reference group with respect to factors known to 
253  affect the drugs PK.  Subjects taking medications  that are likely  to impact drug metabolism  or 
254  excretion should be excluded from renal impairment  studies. 
255   
256  Ideally, the control group in this study should be representative of the typical patient population 
257  for the drug under study, considering the patients renal function and other factors known to 
258  affect the drugs PK.   
259   
260  2.  Sample Size 
261   
262  The number of subjects enrolled in each renal function group should be sufficient to ensure 
263  precise estimation of the relevant pharmacokinetic  parameters.  Justification  should be provided 
264  for the sample size selected.  For example, one approach could be to prospectively target a 95 
265  percent confidence interval within 60 percent and 140 percent of the geometric mean estimate of 
266  relevant pharmacokinetic parameters for the drug in each renal function group with at least 80 
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267  percent power.17 
268   
269  3.  Drug Administration 
270   
271  A single-dose study is usually sufficient to accurately describe the PK of the drug and its active 
272  metabolites,  especially when the drug and active metabolites exhibit dose-proportional  and time-
273  independent PK at the concentrations anticipated in the patients to be studied.  In rare cases, e.g. 
274  when the drug shows dose- or time-dependent PK, a multiple-dose  study should be conducted. 
275   
276  In most single-dose studies, the same dose can be administered to all patients regardless of renal 
277  function, because the peak concentration of a drug is not substantially  affected by renal function.  
278  In multiple-dose  studies, lower doses or less frequent administration  can be considered in 
279  patients with impaired renal function to prevent the accumulation of the drug and its metabolites.  
280  The dosage regimen can be adjusted based on the best available pre-study estimates of the PK of 
281  the drug and its active metabolites in patients with impaired renal function.  In multiple-dose 
282  studies, the dosing should be continued long enough to achieve steady-state drug levels.  A 
283  loading  dose strategy can be considered to shorten the time to reach steady-state drug levels, 
284  particularly  if the elimination  half-life is greatly prolonged  in patients with impaired renal 
285  function. 
286   
287  4.  Sample Collection and Analysis 
288   
289  Plasma or whole blood as well as urine samples should be collected and analyzed for the parent 
290  drug and any metabolites of interest.  The frequency and duration of plasma sampling  and urine 
291  collection  should be sufficient to accurately estimate the relevant pharmacokinetic parameters for 
292  the parent drug and its active metabolites (see section V). 
293   
294  Plasma protein binding  is often altered in patients with impaired renal function.  For systemically 
295  active drugs and metabolites,  the unbound concentrations generally determine the rate and extent 
296  of delivery to the sites of action.  Measurement of unbound drug concentrations is recommended 
297  for each plasma sample only if the binding  is concentration-dependent or is affected by 
298  metabolites or other time-varying  factors.  Otherwise, the unbound fraction should be determined 
299  using a limited  number of samples or even a single sample from each patient.  For drugs and 
300  metabolites with a low extent of plasma protein binding  (e.g., less than 80 percent), changes in 
301  PK resulting from alterations in protein binding  due to impaired renal function are generally 
302  expected to be small relative to those in patients with normal renal function.  In such cases, a 
303  description and analysis of the PK of the drug or metabolite in terms of total concentrations is 
304  sufficient. 
                                              
17 Wang Y, PR Jadhav, M Lala, J Gobburu, 2012, Clarification on Precision Criteria to Derive Sample Size When 
Designing Pediatric Pharmacokinetic Studies, J Clin Pharmacol, 52(10):1601-1606. 
 
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305   
306  C.  Reduced Pharmacokinetic Study Design 
307   
308  For drugs that are predominantly  eliminated  via nonrenal routes and likely  to be used in patients 
309  with impaired renal function,  a reduced study design can be used to determine the need for dose 
310  adjustment.  The intent of a reduced study design is to represent a worst-case scenario, i.e., one 
311  that shows the greatest impact impaired renal function could have on the PK of the drug.  Prior 
312  submissions  to the Agency and literature reports suggest that for such a study, subjects with 
313  severe renal impairment  (see Table 1) can be considered to represent the worst-case scenario.18  
314  If a reduced pharmacokinetic  study shows a clinically  relevant effect on the PK of the drug in 
315  subjects with severe renal impairment,  the sponsor should characterize the effect of impaired 
316  renal function on the drugs PK in subjects with the remaining levels of impaired renal function 
317  (see Table 1).  If no difference in PK is observed between patients at the extremes of renal 
318  function, then no further study is recommended.  Other study design considerations described in 
319  sections IV.B also apply to this setting.  
320   
321  D.  Characterizing the Impact of Renal Function in Phase 2 and Phase 3 Trials 
322   
323  If there is adequate representation of patients with varying degrees of renal function (see section 
324  III), as well as sufficient data to describe the impact of impaired renal function on the PK of the 
325  drug, population  pharmacokinetic  (popPK) analyses of data from phase 2 and/or phase 3 clinical 
326  trials could be sufficient to characterize the impact of renal function on drug exposure for the 
327  population  that was represented in the trials.  If patients with severe renal impairment  were not 
328  enrolled in sufficient numbers, a reduced design renal impairment  study could be needed to 
329  provide appropriate dosing recommendations  in labeling for the impaired renal function 
330  population  not represented in clinical  trials.  When possible, renal function should be assessed as 
331  independent predictor of  exposure-response relationships.   
332   
333  To allow for successful use of a popPK approach or exposure-response analysis, the study design 
334  should retain some of the critical components of the dedicated renal impairment  studies 
335  described in the previous section on full study designs (section IV.B).  The following  are 
336  important considerations: 
337   
338    Sufficient numbers of patients over a range of renal function  
339   
340    Accurate records of dosing and sample collection  times 
341   
                                              
18 Zhang L, Xu N, Xiao S, Arya V, Zhao P, , Lesko LJ, Huang SM, 2012, Regulatory Perspectives on Designing 
Pharmacokinetic Studies and Optimizing Labeling Recommendations for Patients with Chronic Kidney Disease, J 
Clin Pharmacol, 52(1 Suppl): 70S-90S. 
 
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342    Adequate numbers of samples per patient 
343   
344    Unbound drug concentrations when appropriate 
345   
346    Active metabolite levels, where applicable,  in addition  to levels of the parent drug 
347   
348    Use of the same measure of estimated renal function, especially when data are pooled 
349  across studies  
350   
351    Exposure-response analyses, when available,  should account for impaired  renal function 
352  as an independent predictor of response 
353   
354  For additional  information  on the application  of popPK approaches, refer to the FDA draft 
355  guidance for industry entitled Population Pharmacokinetics (July 2019).19 
356   
357  E.  Effect of Dialytic Therapies on the PK of a Drug 
358   
359  The primary questions to be addressed by studying the effect of dialytic  therapies on the PK of a 
360  drug are:  (1) whether the drug dosage should be adjusted because of dialysis;  (2) if so, by how 
361  much; (3) and the timing  of drug administration  relative to dialysis.  The results of the study also 
362  provide insight regarding the value of dialysis  for the treatment of a drug overdose. 
363   
364  1.  Intermittent Dialytic Therapies 
365   
366  This section mainly focuses on intermittent hemodialysis  (IHD) as it is the most common 
367  dialysis  method used in ESRD patients in the United States.  However, some of the general study 
368  design principles  described below for IHD can be applied to other modalities.    
369   
370  It is critical for the IHD study to include both on- and off-dialysis  periods.  Each subject can 
371  receive a single dose on two occasions, once with the dose administered prior to a dialysis 
372  session, with dialysis  typically  commencing just before the anticipated T  following 
max
373  administration  of the drug.  On the second occasion, the drug should be administered in such a 
374  way that it reflects the exposures expected during an off-dialysis  day (e.g., not in close proximity 
375  to the end of a dialysis session).   
376   
377  Because most dialysis centers in the United States currently use high-flux  dialyzers during IHD, 
378  pharmacokinetic  studies should be conducted in patients being treated with high-flux  IHD.  It is 
379  important to record the blood flow (Q ), dialysate flow (Q ), and the make and model of the 
B D
380  dialyzer used in the study to interpret study results and extrapolate to other dialysis  conditions. 
                                              
19 When final, this guidance will represent the FDAs current thinking on this topic. 
 
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381   
382  2.  Continuous Dialytic Therapies 
383   
384  For critical care medications likely  to be used in patients on continuous  renal replacement 
385  therapy (CRRT), the findings  from IHD studies might not be sufficient to derive dosing 
386  recommendations for patients using this modality.   Therefore, it is important to evaluate the 
387  impact of CRRT on the PK of the drug to derive appropriate dosing recommendations.  Given 
388  the practical challenges (e.g. the patients hemodynamic  stability  and the difficulty  in obtaining 
389  blood samples) when conducting  such a study, planning  optimal sampling  times is critical for the 
390  collection  of relevant pharmacokinetic  information  in this setting.  In addition,  the methods for 
391  CRRT vary widely across institutions.   As far as it is practicable, it is important to design and 
392  conduct these studies so that the results are generalizable across CRRT settings.  A single-dose 
393  study is acceptable and can be the most feasible approach.  If a multiple-dose  assessment is 
394  possible,  it can characterize the effect of CRRT as a patients condition  changes.  One approach 
395  that could allow collection  of information  that informs dosage is to use a fixed blood flow rate 
396  (Q ) with one or two commonly prescribed effluent flow rates (Q ).20  Sponsors are strongly 
B E
397  encouraged to seek FDAs input early in the process of designing  such studies. 
398   
399  3.  Sample Collection and Data Analysis 
400   
401  To accurately estimate the clearance in ESRD patients undergoing  IHD during the non-dialysis 
402  (or between dialysis)  period, dosing and sampling times should be planned to capture the full 
403  pharmacokinetic  profile of the drug and, where applicable,  its active metabolites. 
404   
405  To determine the clearance during dialysis,  blood samples should be collected pre-dialysis  and at 
406  appropriate intervals during the dialysis  period.  The entire dialysate should be collected, its 
407  volume recorded, and a sample retained to determine drug concentrations.   
408   
409  Concentrations of the drug and any active metabolites should be measured in the blood entering 
410  the dialyzer as well as dialysate samples.  The total amount of drug removed in the dialysate 
411  should be determined.  The dialysis  clearance (CL ) can be calculated from the equation below, 
D
412  where t  marks the start time, and t  is the time of termination  of the hemodialysis  session: 
0 1
413   
414   
AAAAAAAAAAAA RRRRRRAARRRRRRRRRR
415    CCCCDD =
AAAACCtt0tt1
                                              
20 Nolin TD, GR Aronoff, WH Fissell, L Jain, R Madabushi, K Reynolds, L Zhang, SM Huang, R Mehrotra, MF 
Flessner, JK Leypoldt, JW Witcher, I Zineh, P Archdeacon, P Roy-Chaudhury, SL Goldstein, 2015, 
Pharmacokinetics Assessment in Patients Receiving Continuous RRT: Perspectives from Kidney Health Initiative, 
Clin J Am Soc Nephrol, 10(1):159164. 
 
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416  Blood samples before and at the end of dialysis  should also be used to measure drug binding  to 
417  plasma proteins.  The fraction of the administered dose that is recovered in the dialysate should 
418  be calculated to assess the need for administering  supplemental  drug doses to hemodialysis 
419  patients. 
420   
421  The analysis should also consider the potential  for a rebound due to redistribution  of drug from 
422  peripheral tissues after dialysis and characterize its implications  for drug dosing. 
423   
424  F.  Considerations for Pharmacodynamic  Assessments 
425   
426  Whenever appropriate and feasible, pharmacodynamic  assessments should be included  in studies 
427  of impaired renal function.  Such assessments will be important in situations where changes in 
428  renal function result in pharmacodynamic changes that are independent of pharmacokinetic 
429  changes (e.g., oral anticoagulants).  In such situations,  the pharmacokinetic and 
430  pharmacodynamic  data could be critical to derive appropriate dosage adjustments for patients 
431  with impaired renal function.  The selection of the pharmacodynamic endpoints  should be 
432  discussed with the appropriate FDA review staff. 
433   
434   
435  V.  DATA ANALYSIS 
436   
437  A.  Estimating Pharmacokinetic Parameters 
438   
439  Plasma concentration data and urinary excretion data should be analyzed to estimate PK 
440  parameters of the drug and its active metabolites.  The pharmacokinetic  parameters of interest 
441  include the area under the plasma concentration-time  curve (AUC), peak concentration (C ), 
max
442  fraction unbound  (f ), apparent clearance (CL/F), renal clearance (CL ), apparent nonrenal 
u R
443  clearance (CL /F), apparent volume of distribution  (V/F), and effective and terminal half-life 
NR
444  (t ), where applicable.  The pharmacokinetic parameters of active metabolites can include the 
1/2
445  AUC, C , CL , and t .  Non-compartmental and/or compartmental modeling  approaches to 
max R 1/2
446  parameter estimation can be employed. 
447   
448  B.  Modeling the Relationship Between Renal Function and Pharmacokinetic 
449  Parameters 
450   
451  The FDA recommends a regression approach in which estimated renal function and the 
452  pharmacokinetic  parameters are treated as continuous  variables.  This method is usually 
453  preferred to an analysis in which estimated renal function is treated as a categorical variable 
454  corresponding  to the normal, mild,  moderate, and severe renal impairment groups.  In either 
455  case, the potential  for confounding  due to differences in baseline covariates that can affect a 
456  drugs PK (e.g., age, gender, race, and weight) should be evaluated. 
457   
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458  The sponsor should calculate and report estimates of the parameters of the chosen model as well 
459  as measures of their precision (e.g., standard errors or confidence intervals).   
460   
461  C.  Developing Dosage Recommendations in Patients with Renal Impairment 
462   
463  Dosage recommendations in patients with impaired renal function should be determined based 
464  on the overall understanding  of the relationship  between renal function,  drug exposure, and the 
465  exposure-response relationships  (efficacy and safety).  For drugs with a wide therapeutic range, 
466  changes in the drugs PK based on renal function might not always result in a dosage adjustment 
467  for patients with impaired renal function.  When there is a need for a different dosage 
468  recommendation  in patients with impaired renal function compared to those with normal renal 
469  function, these dosage recommendations  should be based on exposure-matching  to a reference 
470  group with an acceptable benefit-risk profile for the drug.  The reference group does not have to 
471  be limited  to patients with normal renal function.21   
472   
473  There are a number of approaches to dosage selection for patients with impaired renal function.  
474  For example, pharmacokinetic  simulations  that project systemic exposures that fall within the 5th 
475  and 95th percentiles of those achieved in the reference group can be used.  Another approach is to 
476  establish no-effect boundaries, which represent an interval within which a change in systemic 
477  exposure is deemed not significant  enough to warrant clinical  action (see also section V.B.1 in 
478  the FDA final guidance for industry Clinical Drug Interaction Studies  Cytochrome P450 
479  Enzyme- and Transporter-Mediated Drug Interactions (January 2020)).  
480   
481  The sponsor should use the data from modeling  and simulation  to determine the level of renal 
482  function below which a different dosage is recommended.  It is not necessary to rely on pre-
483  specified categories of impaired renal function as shown in Table 1.   
484   
485  In some situations,  dosage recommendations in patients with impaired renal function can 
486  significantly  differ between different estimating equations of renal function.  In such situations,  it 
487  is important to understand the reasons underlying  the discrepant results and dosage 
488  recommendations in the labeling  should address which measure or estimating equation to use.  
489   
490   
491  VI.  LABELING RECOMMENDATIONS 
492   
493  The Prescribing Information should include a summary of essential information  about the effect 
494  of renal function on the PK and PD (if known) of the drug to inform the safe and effective use of 
495  the drug in patients with impaired renal function by the health care provider: 
                                              
21 This topic was discussed at an Advisory Committee Meeting convened on May 7, 2019. Please see Footnote Error! B
ookmark  not defined. for further information. 
 
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496   
497    Renal elimination  of the drug and relevant metabolites 
498    
499    Pharmacokinetic or pharmacodynamic changes relative to renal function and 
500  hemodialysis 
501   
502    Clinical  implications  of these pharmacokinetic  or pharmacodynamic changes 
503   
504    Any recommended risk mitigation  strategies in patients with renal impairment  (e.g., 
505  different dosage recommendations,  or monitoring  recommendations) 
506   
507  For specific recommendations on how to incorporate use information  in subjects with impaired 
508  renal function in labeling,  refer to 21 CFR 201.57 and the following  FDA final guidances for 
509  industry: 
510   
511    Labeling for Human Prescription Drug and Biological Products  Implementing the 
512  PLR Content and Format Requirements (February 2013). 
513   
514    Dosage and Administration Section of Labeling for Human Prescription Drug and 
515  Biological Products  Content and Format (March 2010). 
516   
517    Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling 
518  for Human Prescription Drug and Biological Products  Content and Format (October 
519  2011). 
520   
521    Adverse Reactions Section of Labeling for Human Prescription Drug and Biological 
522  Products  Content and Format (January 2006). 
523   
524    Clinical Pharmacology Section of Labeling for Human Prescription Drug and 
525  Biological Products  Content and Format (December 2016)  
526   
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