# Presentation: 553558

## Effect 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

## Prevalence of CKD in US (JAMA 298:2047, 2007)

## Prevalence of CKD in US (JAMA 298:2047, 2007)

## Repercussions 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.** **

## Repercussions of CRF on metabolic clearance of drugs

- Clin Pharmacol Ther. 2003. 73(5) : 475-7.

## Repercussions of CRF on metabolic clearance of drugs

- Clin Pharmacol Ther. 2003. 73(5) : 427-34.

## Repercussions of CRF on nonrenal clearance of drugs (Clin Pharmacol Ther, in press)

## Method (5/6 nephrectomy)

## Repercussions of CRF on liver cytochrome P450 (JASN 12:326, 2001)

**Repercussions of CRF on liver cytochrome P450 ****(JASN 12:326, 2001)**

- a p < 0.001

## Alterations in liver metabolic enzymes in CRF rats (Clin Pharmacol Ther, in press)

## Alterations in intestinal metabolic enzymes in CRF rats (Clin Pharmacol Ther, in press)

## Alterations in liver transporters in CRF rats (Clin Pharmacol Ther, in press)

## Alterations in intestinal transporters in CRF rats (Clin Pharmacol Ther, in press)

## Effect of CRF on hepatic UDP-glucuronyltransferases (DMD 34:621, 2006)

## Mechanism of drug enzymes and transporters down-regulation in CRF

- Circulating factors in uremia

## Down-regulation of liver P450: role of uremic mediators(BJP, 137:1039,2002)

## Down-regulation of liver P450: role of uremic mediators(BJP, 144:1067, 2005)

## Effect of CRF on hepatic N-acetyltransferases (JASN, in press)

## Liver drug transporters in CRF (DMD, 36:124, 2008)

## Intestinal drug transporters in CRF (JPET 320:978, 2007)

## Which 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)

## Does PTH depletion by paratyroidectomy in CRF rats prevents the downregulation of P450 3A by uremic serum ?

*J Am Soc Nephrol*. 17:3041, 2006

## Decrease drug liver uptake in CRF

- DMD 32:1239, 2004

## Effects of hemodialysis

## Down-regulation of liver P450: role of uremic mediators(BJP, 144:1067, 2005)

## Down-regulation of liver P450: role of uremic mediators(BJP, 144:1067, 2005)

## Down-regulation of liver P450: role of uremic mediators (BJP, 144:1067, 2005)

## Down-regulation of liver P450: role of uremic mediators (BJP, 144:1067, 2005)

## Effects of hemodialysis (JASN 17:2363-2367, 2006)

**Effects of hemodialysis**** ****(JASN 17:2363-2367, 2006)**

## Effects of hemodialysis (submitted)

## Conclusions

- 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

## Acknowledgements

- 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

## Impact of Renal Replacement Therapy (RRT) on Drug Clearance  

- William E. Smoyer, M.D.
- Vice President and Director
- Clinical and Translational Research
- Nationwide Children’s Hospital
- Ohio State University

## Introduction

- 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)

## Introduction

- 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

## Trends 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

## Trends 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 1;356(9223):26-30.
- Some sepsis CRRT regimens recommend 6L/hr (96 mL/min)
- Almost no mention of drug removal in these sepsis CRRT regimens

## Trends 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

## Trends 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

## Trends 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

## Current 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 _< 20% of drugs_
- SLED/EDD dosing studies conducted for _< 1% of drugs_
- CRRT has markedly different effects on drug clearance vs. IHD or PD
- How are clinicians to dose drugs in these patients?

## Current 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?

## Issues 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 1991;50:688-94)
- Imipenem (Mueller BA, et al. AJKD 1993;21:172-9)
- 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?

## Issues Related to “Treated with Dialysis” - 1

_**1990’s**_
- 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_...

## Issues 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

## Issues 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*. 2002;346:305-10 )
- Decreased mortality with QD vs. QOD HD
- Clark WR. et al. *J Am Soc Nephrol.* 1997;8(5):804-12._[ ](http://www.ncbi.nlm.nih.gov/entrez/utils/fref.fcgi?PrId=3051&itool=AbstractPlus-def&uid=9176851&db=pubmed&url=http://jasn.asnjournals.org/cgi/pmidlookup?view=long&pmid=9176851)_
- 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

## Issues Related to “Treated with Dialysis” - 4

- Treatment of Acute Kidney Injury (AKI)
- _>_50% 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

## Patient 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

## Suggested FDA Guidance Changes

- Hemodialysis (HD)
- All studies be conducted using a standardized “dose” of hemodialysis using a kT/Vurea of _>_1.2
- 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

## Suggested 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

## Summary

- 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

## Evaluation 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.

## Overview

- Approach to renal insufficiency clinical studies
- Sitagliptin
- Severe renal insufficiency and ESRD
- Renal insufficiency and metabolism
- Limitations

## Approach

- 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

## Other considerations

- Dose
- Hypothesis
- Single dose vs. multiple dose
- Concurrent vs. historical controls
- Timing
- Geographic location
- Pharmacodynamics

## Sitagliptin 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 | >80 mL/min/1.73 m2 |
| Mild | 50 to 80 mL/min/1.73 m2 |
| Moderate | 30 to 50 mL/min/1.73 m2 |
| Severe | <30 mL/min/1.73 m2 |
| ESRD/hemodialysis | Requiring hemodialysis |

## Special 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 1⁄2 hour intervals during dialysis

## Mean 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 (N=6)

- Mean sitagliptin plasma concentrations increased with increasing degrees of renal insufficiency

## Sitagliptin 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)

## Clearance Versus Creatinine Clearance Following Administrationof Single Oral Doses of Sitagliptin 50 mg to Patients With Varying Degreesof Renal Insufficiency and Healthy Subjects

- Clearance 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

## Mean Sitagliptin Plasma Concentrations Following Single Oral 50 mg Dosesof Sitagliptin to End Stage Renal Disease Patients UndergoingHemodialysis at 4 or 48 Hours Postdose

- Mean Sitagliptin Plasma Concentrations Following Single Oral 50 mg Dosesof Sitagliptin to End Stage Renal Disease Patients UndergoingHemodialysis 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

## Additional 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

## Conclusions

- Mild renal insufficiency does not have a clinically meaningful effect on sitagliptin pharmacokinetics
- No dose adjustment is required for individuals with a creatinine clearance _>_50 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 _>_30 mL/min/1.73 m2 but <50 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 < 30 mL/min/1.73 m2) or ESRD should receive 1/4th of the usual clinical dose of sitagliptin

## Severe Renal Insufficiency vs. ESRD:Mean Sitagliptin Plasma Concentrations Following Single Oral 50 mg Dosesof Sitagliptin to End Stage Renal Disease Patients UndergoingHemodialysis or Patients with Severe Renal Insufficiency

- Severe Renal Insufficiency vs. ESRD:Mean Sitagliptin Plasma Concentrations Following Single Oral 50 mg Dosesof Sitagliptin to End Stage Renal Disease Patients UndergoingHemodialysis or Patients with Severe Renal Insufficiency

- The sitagliptin plasma concentration profile was similar between patients with severe renal insufficiency and ESRD Patients undergoing dialysis

## Severe Renal Insufficiency vs. ESRD:Drug 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 <30 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

## Severe Renal Insufficiency vs. ESRD:Mean Drug A Plasma Concentrations Following Single Oral Dosesto End Stage Renal Disease Patients Undergoing Hemodialysis, Patients with Severe Renal Insufficiency, or Historical Controls

- Severe Renal Insufficiency vs. ESRD:Mean 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

## Renal Insufficiency and Metabolism:Drug 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 <30 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

## Individual Drug B AUC0-inf and Cmax Following Single Dose in Severe Renal Insufficiency Patients and Healthy Subjects

**Individual Drug B AUC****0-inf ****and Cmax Following Single Dose in Severe Renal Insufficiency Patients and Healthy Subjects**

## Individual Drug B AUC0-inf and Cmax Following Single Dose in Severe Renal Insufficiency Patients and Healthy Subjects(Current Study and Historical Data†) 

**Individual Drug B AUC****0-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

## Limitations

- Interpretation
- Timing
- Limited numbers
- Recruitment, particularly of severe renal insufficiency patients
- Assessment of safety and tolerability
- Single dose vs. multiple dose
- Special populations