Title: Effect of Kidney Disease on Drug Metabolism and Transport
1Effect of Kidney Disease on Drug Metabolism and
Transport
- Vincent Pichette MD, PhD, FRCP(c), FACP
- Associate Professor of Medicine and Pharmacology
- Université de Montréal
- Montréal, Québec, Canada
2Prevalence of CKD in US (JAMA 2982047, 2007)
3Prevalence of CKD in US (JAMA 2982047, 2007)
4Repercussions of CRF on pharmacokinetics of drugs
- Despite the adjustment of dosage in function of
glomerular filtration, there is an accumulation
of several drugs that could only be explained by
a decrease in their nonrenal clearance.
5Repercussions of CRF on metabolic clearance of
drugs
Clin Pharmacol Ther. 2003. 73(5) 475-7.
6Repercussions of CRF on metabolic clearance of
drugs
Clin Pharmacol Ther. 2003. 73(5) 427-34.
7Repercussions of CRF on nonrenal clearance of
drugs (Clin Pharmacol Ther, in press)
8Method (5/6 nephrectomy)
9Repercussions of CRF on liver cytochrome P450
(JASN 12326, 2001)
a p lt 0.001
10Alterations in liver metabolic enzymes in CRF
rats (Clin Pharmacol Ther, in press)
11Alterations in intestinal metabolic enzymes in
CRF rats (Clin Pharmacol Ther, in press)
12Alterations in liver transporters in CRF rats
(Clin Pharmacol Ther, in press)
13Alterations in intestinal transporters in CRF
rats (Clin Pharmacol Ther, in press)
14Effect of CRF on hepatic UDP-glucuronyltransferase
s (DMD 34621, 2006)
15Mechanism of drug enzymes and transporters
down-regulation in CRF
- Circulating factors in uremia
16Down-regulation of liver P450 role of uremic
mediators(BJP, 1371039,2002)
17Down-regulation of liver P450 role of uremic
mediators(BJP, 1441067, 2005)
18Effect of CRF on hepatic N-acetyltransferases
(JASN, in press)
19Liver drug transporters in CRF (DMD, 36124, 2008)
20Intestinal drug transporters in CRF (JPET
320978, 2007)
21Which circulating factor ?
- Several uremic toxins accumulate in CRF
- CRF is a state of chronic inflammation
cytokines - CRF is associated with numerous metabolic
disturbances - Secondary hyperparathyroidism elevated
parathyroid hormone (PTH)
22Does PTH depletion by paratyroidectomy in CRF
rats prevents the downregulation of P450 3A by
uremic serum ?
J Am Soc Nephrol. 173041, 2006
23Decrease drug liver uptake in CRF
DMD 321239, 2004
24Effects of hemodialysis
25Down-regulation of liver P450 role of uremic
mediators(BJP, 1441067, 2005)
26Down-regulation of liver P450 role of uremic
mediators(BJP, 1441067, 2005)
27Down-regulation of liver P450 role of uremic
mediators (BJP, 1441067, 2005)
28Down-regulation of liver P450 role of uremic
mediators (BJP, 1441067, 2005)
29Effects of hemodialysis (JASN 172363-2367, 2006)
30Effects of hemodialysis (submitted)
31(No Transcript)
32Conclusions
- CRF interferes with the elimination of many drugs
because of the reduction in GFR and tubular
secretion and dose adjustment is made according
to GFR - Reduced drug metabolism and transport should also
be taken into account
33Acknowledgements
- Francois Leblond
- Karine Desbiens
- Judith Naud
- Josée Michaud
- Pierre Dubé
- Emilie Simard
- Caroline Boisvert
- Jessica Harding
- Mélina Dani
- Thomas D Nolin
- Edith Sim
- Canadian Institute of Health Research
- Le Fond de la Recherche en Santé du Québec
34Impact of Renal Replacement Therapy (RRT) on Drug
Clearance
William E. Smoyer, M.D. Vice President and
Director Clinical and Translational
Research Nationwide Childrens Hospital Ohio
State University
35Introduction
- Dramatic Increase in the Use of Renal Replacement
Therapies (RRT) over the Last 10 Years - Intermittent Therapies (Hemodialysis)
- Continuous Therapies (CRRT)
- Marked Increase in the Variety of RRTs
- CVVH (Convective solute clearance)
- CVVHD (Diffusive solute clearance)
- CVVHDF (Convective diffusive solute clearance)
- SLED (Slow low efficiency dialysis)
- EDD (Extended daily dialysis)
36Introduction
- Each RRT Therapy Requires New Drug Dosing
Knowledge to Optimize Pharmacotherapy - Few Data Available on Effective Drug Dosing using
newer forms of RRT - Growing challenge with respect to pharmacotherapy
- Maximize drug efficacy
- Minimize drug toxicity
37Trends in RRT - 1
- Growth in Continuous RRT (CRRT)
- In 1999, 72 of American Nephrologists reported
using CRRT - High Permeability Membranes Used
- Altered drug removal characteristics
- CRRT Drug Removal ? HD Drug Removal !
- No Current FDA Guidance for Drug Manufacturers to
Evaluate Drug Removal during CRRT - No Current FDA Guidance for RRT Device
Manufacturers to Evaluate Drug Removal
Characteristics
38Trends in RRT - 2
- High Volume CRRT
- U of M pediatric CRRT patients receive 2 L/1.73
m2/hr dialysate flow (Cr Cl 33 mL/min/1.73 m2) - U of M adult CRRT patients receive 2 L/hr
dialysate flow - 35mL/kg/hr associated with better outcomes in
adults - Ronco C et al Lancet 2000 Jul
1356(9223)26-30. - Some sepsis CRRT regimens recommend 6L/hr (96
mL/min) - Almost no mention of drug removal in these sepsis
CRRT regimens
39Trends in RRT - 3
- High Permeability Membranes
- Larger drugs now removed
- e.g. Vancomycin (MW 1450 Daltons)
- Non-Renal Indications
- Inborn Errors of Metabolism
- Hyperammonemia / Metabolic acidosis
- Refractory Fluid Overload
- Congestive Heart Failure
- Intoxications
- Hyperosmolarity
- Prophylactic Contrast Dye Removal
40Trends in RRT - 4
- Increased Pediatric Usage of RRT
- Improved RRT equipment now available
- Better volumetric control
- Some pediatric-specific tubing filters
- Improved techniques for use in small children
- Pediatric/Neonatal RRT differs from Adult RRT
- Large extracorporeal circuit volume (vs. adults)
- CRRT circuit often requires priming
- 5 Albumin / Blood
41Trends in RRT - 5
- Hybrid RRT (primarily in adults)
- SLED Slow Low Efficiency Dialysis
- EDD Extended Daily Dialysis
- Use a standard dialysis machine and run all day
- Drug removal much different than with standard
intermittent hemodialysis
42Current Dilemma
- RRT Technology has surpassed FDA Guidance for
Drug Dosing - Common use of newer RRT has created huge
knowledge deficits of how to dose drugs
appropriately in patients undergoing newer types
of RRT - CRRT drug dosing studies conducted for lt 20 of
drugs - SLED/EDD dosing studies conducted for lt 1 of
drugs - CRRT has markedly different effects on drug
clearance vs. IHD or PD - How are clinicians to dose drugs in these
patients?
43Current FDA Guidance for Industry
- Pharmacokinetics in Patients with Impaired Renal
Function Study Design, Data Analysis, and
Impact on Dosing and Labeling (May 1998) - For drugs likely to be given to ESRD patients
treated with dialysis - PK performed (both dialysis/nondialysis
conditions) to determine extent to which dialysis
contributes to elimination of drug and active
metabolites - Primary questions
- Should dose be adjusted due to HD?
- If so, to what extent?
44Issues Related to ESRD
- Many patients receive RRT without ESRD
- Acute Kidney Injury (AKI)
- Drug PK inherently different than during ESRD
Volume overload common in AKI - Large non-renal Cl differences in AKI vs. ESRD
- Vancomycin (Macias WL, et al. CPT
199150688-94) - Imipenem (Mueller BA, et al. AJKD 199321172-9)
- Key Unanswered Questions
- Is studying clearance in ESRD enough any more?
- Since RRT now widely used in AKI, should it also
be tested in this setting?
45Issues Related to Treated with Dialysis - 1
- 1990s
- Low flux
- Dialysis dose not quantified
- Smaller surface area
- CAPD
- Membranes not biocompatible
- 2008
- High flux
- Kt/V target 1.2
- Larger surface area
- CCPD
- Membranes biocompatible
All dialysis changes since 1990s in ? drug
Cl. Previously-established doses no longer
applicable
46Issues Related to Treated with Dialysis - 2
- What are the current trends in RRT?
- Then ESRD outpatient treatment thrice weekly
- Now Nocturnal nightly home hemodialysis (HD)
- Now Nocturnal every other nightly home HD
- Even standard intermittent HD now uses
- Very different dialysate flows
- Very different dialyzers
- Resultant drug clearance rates largely unknown
- Guidelines for drug dosing with contemporary
forms of RRT not available
47Issues Related to Treated with Dialysis - 3
- Treatment of Acute Kidney Injury (AKI)
- Pre-1998 HD in ICU three times weekly
- Today CRRT or daily IHD
- Schiffl et al. (N Engl J Med. 2002346305-10 )
- Decreased mortality with QD vs. QOD HD
- Clark WR. et al. J Am Soc Nephrol.
19978(5)804-12. - IHD requirements for AKI patients requires daily
HD - Dosing in QD vs. QOD IHD inherently different
- Data in AKI not noted in 1998 FDA Guidance
48Issues Related to Treated with Dialysis - 4
- Treatment of Acute Kidney Injury (AKI)
- gt50 of inpatient RRT is not HD!
- Continuous RRT (CRRT)
- Slow Low Efficiency Dialysis (SLED)
- Extended Daily Dialysis (EDD)
- Drug dosing different for each of these forms of
RRT - CRRT now most common form of RRT in both
pediatric and adult ICU patients - Very little data on drug dosing in CRRT
- Currently no FDA guidance for dosing in CRRT
49Patient Safety in CRRT
- Critically ill adult and pediatric patients
currently vulnerable - Despite common use no CRRT dosing studies now
required for labeling - No incentive for Pharmaceutical Mfrs to perform
PK studies
50Suggested FDA Guidance Changes
- Hemodialysis (HD)
- All studies be conducted using a standardized
dose of hemodialysis using a kT/Vurea of gt1.2 - Dialyzers of a prescribed surface area and
ultrafiltration coefficient be used in all PK
studies - Pediatric PK studies should be performed and
used to develop pediatric drug dosing information
51Suggested FDA Guidance Changes
- CRRT
- Dosing guidance should be developed for drugs
likely to be used in ICU setting - Dose of delivered CRRT for PK studies should be
set at 35 mL/kg/hr (or 2000 mL/hr/1.73 m2) - PK studies should be performed with most commonly
used hemodiafilters - Pediatric PK studies should be performed and
used to develop pediatric drug dosing information
52Summary
- Dramatic increase in use and types of RRT
- Resulted in huge knowledge deficits in
appropriate use of many drugs - FDA Guidance for labeling now lags available RRT
technology and current medical practice - Drug efficacy concerns
- Drug safety concerns
53Evaluation of Pharmaceutics in Patients with
Impaired Renal Function
- Clinical Pharmacology Advisory Committee (CPAC)
- March 19, 2008
- John A. Wagner, M.D., Ph.D.
- Merck Co., Inc.
54Overview
- Approach to renal insufficiency clinical studies
- Sitagliptin
- Severe renal insufficiency and ESRD
- Renal insufficiency and metabolism
- Limitations
55Approach
- Full vs Limited
- Full typically mild, moderate, severe, and ESRD
on hemodialysis and healthy concurrent control
subjects - Limited typically severe or ESRD on
hemodialysis and healthy concurrent control
subjects - Adaptive
56Other considerations
- Dose
- Hypothesis
- Single dose vs. multiple dose
- Concurrent vs. historical controls
- Timing
- Geographic location
- Pharmacodynamics
57Sitagliptin Renal Insufficiency Study
- Design Open label, single dose
- Subjects 24 patients with renal insufficiency
(6 mild, 6 moderate, 6 severe, and 6 end-stage
renal disease (ESRD) on hemodialysis) as defined
below, and 6 healthy concurrent control subjects -
- Dose 50-mg
- Analyte Sitagliptin
- Samples Plasma up to 96 hr postdose urine
through 48 hr postdose
Degree of Renal Insufficiency 24-Hour Creatinine Clearance
Normal gt80 mL/min/1.73 m2
Mild 50 to 80 mL/min/1.73 m2
Moderate 30 to 50 mL/min/1.73 m2
Severe lt30 mL/min/1.73 m2
ESRD/hemodialysis Requiring hemodialysis
58Special design considerations for ESRD
- Period 1 6 patients with ESRD requiring
hemodialysis received a single 50-mg oral dose of
sitagliptin followed by 96 hours of plasma
sampling for sitagliptin levels 48 hours prior to
their normally scheduled hemodialysis session - Period 2 the same 6 patients enrolled in period
1 received a second 50-mg oral sitagliptin dose 4
hours prior to their normally scheduled
hemodialysis session followed by 72 hours of
plasma sampling for sitagliptin levels - The subsequent hemodialysis session initiated
immediately following the 4-hour blood draw - Dialysate and plasma samples were collected at ½
hour intervals during dialysis
59Mean Sitagliptin Plasma Concentrations Following
Administration of Single Oral Doses of 50-mg of
Sitagliptin to Patients With Varying Degrees of
Renal Insufficiency and Healthy Subjects (N6)
- Mean sitagliptin plasma concentrations increased
with increasing degrees of renal insufficiency
60Sitagliptin Plasma AUC (Dose-Adjusted to 50 mg)
Versus Creatinine Clearance Following
Administration of Single Oral Doses of
Sitagliptin to Patients With Varying Degrees of
Renal Insufficiency and Healthy Control Subjects
- The dotted lines indicate 0.5 and 2.0-fold the
geometric mean dose adjusted (to 50-mg) AUC0-? of
the healthy control subjects - Based on the continuous analysis, sitagliptin
AUC, Cmax and C24hr increased with decreasing
creatinine clearance (CrCl)
61Clearance Versus Creatinine Clearance Following
Administrationof Single Oral Doses of
Sitagliptin 50 mg to Patients With Varying
Degreesof Renal Insufficiency and Healthy
Subjects
- Sitagliptin renal clearance is proportional to
creatinine clearance
62Mean Sitagliptin Plasma Concentrations Following
Single Oral 50 mg Dosesof Sitagliptin to End
Stage Renal Disease Patients UndergoingHemodialys
is at 4 or 48 Hours Postdose
- Hemodialysis removes sitagliptin by only a modest
extent - Timing of hemodialysis in ESRD patients had
modest effects on the sitagliptin plasma
concentration profile - Sitagliptin can be administered without respect
to the timing of hemodialysis in patients with
ESRD
63Additional observations
- The dialysis clearance for the hemodialysis
initiated at 4 hours postdose was 241 mL/min - The fraction of the dose excreted unchanged in
dialysis (i.e., removed into the dialysate) over
the dialysis session was approximately 13.5 and
3.5 for hemodialysis at 4 hours and 48 hours
postdose, respectively - In vitro plasma protein binding of sitagliptin
was not meaningfully altered in uremic plasma
from patients with renal insufficiency as
compared to plasma from healthy concurrent
controls
64Conclusions
- Mild renal insufficiency does not have a
clinically meaningful effect on sitagliptin
pharmacokinetics - No dose adjustment is required for individuals
with a creatinine clearance gt50 mL/min/1.73 m2 - Patients with moderate renal insufficiency have
an approximately 2-fold higher plasma drug
exposure as compared to subjects with normal
renal function - Patients with moderate renal insufficiency (i.e.,
creatinine clearance gt30 mL/min/1.73 m2 but lt50
mL/min/1.73 m2) should receive 1/2 of the usual
clinical dose of sitagliptin - Patients with severe renal insufficiency and end
stage renal disease (ESRD) requiring hemodialysis
have an approximately 4-fold higher plasma drug
exposure as compared to subjects with normal
renal function - Patients with severe renal insufficiency (i.e.,
creatinine clearance lt 30 mL/min/1.73 m2) or ESRD
should receive 1/4th of the usual clinical dose
of sitagliptin
65Severe Renal Insufficiency vs. ESRDMean
Sitagliptin Plasma Concentrations Following
Single Oral 50 mg Dosesof Sitagliptin to End
Stage Renal Disease Patients UndergoingHemodialys
is or Patients with Severe Renal Insufficiency
- The sitagliptin plasma concentration profile was
similar between patients with severe renal
insufficiency and ESRD Patients undergoing
dialysis
66Severe Renal Insufficiency vs. ESRDDrug A
Severe Renal Insufficiency and ESRD Study
- Design Open label, single dose
- Subjects 16 female and male subjects (18-70
years) - 6 patients with severe renal Insufficiency
(creatinine CL lt30 ml/min/1.73 m2) - 6 patients with ESRD on hemodialysis
-
- Dose Single dose
- Analytes Drug A concentrations
- Samples Plasma up to 168 hr postdose
-
67Severe Renal Insufficiency vs. ESRDMean Drug A
Plasma Concentrations Following Single Oral
Dosesto End Stage Renal Disease Patients
Undergoing Hemodialysis, Patients with Severe
Renal Insufficiency, or Historical Controls
- Drug A plasma concentration profiles were similar
between patients with severe renal insufficiency
and ESRD Patients undergoing dialysis - Drug A is not dialyzed to a significant degree
(dialysis blood clearance 0.3 mL/min) - Drug A plasma concentration rises during
dialysis, suggesting a hemoconcentration effect
Drug A
68Renal Insufficiency and MetabolismDrug B Severe
Renal Insufficiency Study
- Design Open label, single dose
- Subjects 16 female and male subjects (18-70
years) - 8 patients with severe renal Insufficiency
(creatinine CL lt30 ml/min/1.73 m2) - 8 healthy matched control subjects race,
gender, age (?5 years), BMI (?3.5 unit) -
- Dose Single
- Analyte Drug B
- Samples Plasma up to 360 hr postdose
-
69Individual Drug B AUC0-inf and Cmax Following
Single Dose in Severe Renal Insufficiency
Patients and Healthy Subjects
70Individual Drug B AUC0-inf and Cmax Following
Single Dose in Severe Renal Insufficiency
Patients and Healthy Subjects(Current Study and
Historical Data)
Pooled single dose data from 6 phase I studies,
dose normalized
71Limitations
- Interpretation
- Timing
- Limited numbers
- Recruitment, particularly of severe renal
insufficiency patients - Assessment of safety and tolerability
- Single dose vs. multiple dose
- Special populations