Effect of Kidney Disease Effect of Kidney Disease on Drug Metabolism and on Drug Metabolism and

Transport Transport

Vincent Pichette MD, PhD, FRCP(c), Vincent Pichette MD, PhD, FRCP(c), FACPFACP

Associate Professor of Medicine and Associate Professor of Medicine and PharmacologyPharmacology

Université de Montréal Université de Montréal

Montréal, Québec, CanadaMontréal, Québec, Canada

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

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

Repercussions of CRF on Repercussions of CRF on pharmacokinetics of drugspharmacokinetics of drugs

Despite the adjustment of dosage in Despite the adjustment of dosage in function of glomerular filtration, function of glomerular filtration, there is an accumulation of several there is an accumulation of several drugs that could only be explained drugs that could only be explained by a decrease in their nonrenal by a decrease in their nonrenal clearance.clearance.

Repercussions of CRF on Repercussions of CRF on metabolic clearance of drugsmetabolic clearance of drugs

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

Repercussions of CRF on Repercussions of CRF on metabolic clearance of drugsmetabolic clearance of drugs

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

Repercussions of CRF on Repercussions of CRF on nonrenal clearance of drugs nonrenal clearance of drugs ((Clin Clin

Pharmacol Ther, in pressPharmacol Ther, in press))

Method (5/6 Method (5/6 nephrectomy)nephrectomy)

Repercussions of CRF on Repercussions of CRF on liver cytochrome P450 liver cytochrome P450

(JASN 12:326, 2001)(JASN 12:326, 2001)

a p < 0.001

Control CRF

Weigth (g) 310 10 308 23

Creatinine (umol/L) 57 3 154 12a

Urea (mmol/L) 5.6 0.7 26. 3.9a

Clearance (mL/min) 0.88 0.5 0.33 0.03a

Alterations in liver Alterations in liver metabolic enzymes in CRF metabolic enzymes in CRF

ratsrats (Clin Pharmacol Ther, in press)(Clin Pharmacol Ther, in press)

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

Alterations in liver Alterations in liver transporters in CRF rats transporters in CRF rats (Clin (Clin

Pharmacol Ther, in press)Pharmacol Ther, in press)

Alterations in intestinal Alterations in intestinal transporters in CRF ratstransporters in CRF rats

(Clin Pharmacol Ther, in press)(Clin Pharmacol Ther, in press)

Effect of CRF on hepatic Effect of CRF on hepatic UDP-glucuronyltransferases UDP-glucuronyltransferases

(DMD 34:621, 2006)(DMD 34:621, 2006)

Mechanism of drug Mechanism of drug enzymes and transporters enzymes and transporters

down-regulation in CRFdown-regulation in CRF Circulating factors in uremiaCirculating factors in uremia

Down-regulation of liver Down-regulation of liver P450: role of uremic P450: role of uremic

mediatorsmediators(BJP, 137:1039,2002)(BJP, 137:1039,2002)

0

20

40

60

80

100

120

2C6 2C11 2D 3A1 3A2

CYP450 isoforms

Sta

ndar

dize

d de

nsito

met

ry u

nits

* * **

2C6

2C11

2D

3A1

3A2

CRFCPF

0

20

40

60

80

100

120

2C6 2C11 2D 3A1 3A2

CYP450 isoforms

Sta

ndar

dize

d de

nsito

met

ry u

nits

* * **

2C6

2C11

2D

3A1

3A2

CRFCPF

Down-regulation of liver Down-regulation of liver P450: role of uremic P450: role of uremic

mediatorsmediators(BJP, 144:1067, 2005)(BJP, 144:1067, 2005)

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

press)press)Is there a serum factor that could be responsible

for these changes?

0

50

100

150

NAT2 mRNA expression NAT2 protein expression

% C

TL

val

ue

CTL

CRF

**

*, p < 0.05

Is there a serum factor that could be responsible for these changes?

0

50

100

150

NAT2 mRNA expression NAT2 protein expression

% C

TL

val

ue

CTL

CRF

**

*, p < 0.05

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

Intestinal drug Intestinal drug transporters in CRF transporters in CRF (JPET (JPET

320:978, 2007)320:978, 2007)

Which circulating factor ?Which circulating factor ? Several uremic toxins accumulate in Several uremic toxins accumulate in

CRFCRF CRF is a state of chronic CRF is a state of chronic

inflammation : cytokinesinflammation : cytokines CRF is associated with numerous CRF is associated with numerous

metabolic disturbancesmetabolic disturbances Secondary hyperparathyroidism: Secondary hyperparathyroidism:

elevated parathyroid hormone (PTH)elevated parathyroid hormone (PTH)

Does PTH depletion by Does PTH depletion by paratyroidectomy in CRF rats prevents paratyroidectomy in CRF rats prevents

the downregulation of P450 3A by the downregulation of P450 3A by uremic serum ?uremic serum ?

J Am Soc Nephrol. 17:3041, 2006

Decrease drug liver Decrease drug liver uptake in CRFuptake in CRF

DMD 32:1239, 2004

Effects of hemodialysisEffects of hemodialysis

Down-regulation of liver Down-regulation of liver P450: role of uremic P450: role of uremic

mediatorsmediators(BJP, 144:1067, 2005)(BJP, 144:1067, 2005)

Down-regulation of liver Down-regulation of liver P450: role of uremic P450: role of uremic

mediatorsmediators(BJP, 144:1067, 2005)(BJP, 144:1067, 2005)

Down-regulation of liver Down-regulation of liver P450: role of uremic P450: role of uremic

mediators mediators (BJP, 144:1067, 2005)(BJP, 144:1067, 2005)

Down-regulation of liver Down-regulation of liver P450: role of uremic P450: role of uremic

mediators mediators (BJP, 144:1067, 2005)(BJP, 144:1067, 2005)

Effects of hemodialysisEffects of hemodialysis

(JASN 17:2363-2367, 2006)(JASN 17:2363-2367, 2006)

Effects of hemodialysis Effects of hemodialysis (submitted)(submitted)

ConclusionsConclusions

CRF interferes with the elimination of CRF interferes with the elimination of many drugs because of the reduction many drugs because of the reduction in GFR and tubular secretion and dose in GFR and tubular secretion and dose adjustment is made according to GFRadjustment is made according to GFR

Reduced drug metabolism and Reduced drug metabolism and transport should also be taken into transport should also be taken into accountaccount

AcknowledgementsAcknowledgements

Francois LeblondFrancois Leblond Karine DesbiensKarine Desbiens Judith NaudJudith Naud Josée MichaudJosée Michaud Pierre DubéPierre Dubé Emilie SimardEmilie Simard Caroline BoisvertCaroline Boisvert Jessica HardingJessica Harding Mélina DaniMélina Dani Thomas D NolinThomas D Nolin Edith SimEdith Sim

• Canadian Institute of Health Research• Le Fond de la Recherche en Santé du Québec

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

IntroductionIntroduction 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)

IntroductionIntroduction

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 - 1Trends 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 - 2Trends 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 - 3Trends 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 - 4Trends 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 - 5Trends 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: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 IndustryCurrent 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”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 Issues Related to “Treated with Dialysis” - 1“Treated with Dialysis” - 11990’s

Low flux

Dialysis dose not quantified

Smaller surface area

CAPD

Membranes not biocompatible

2008High 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 Issues Related to “Treated with Dialysis” - 2“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 Issues Related to “Treated with Dialysis” - 3“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. 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 Issues Related to “Treated with Dialysis” - 4“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 CRRTPatient 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 ChangesSuggested FDA Guidance Changes Hemodialysis (HD)

1. All studies be conducted using a standardized “dose” of hemodialysis using a kT/Vurea of >1.2

2. Dialyzers of a prescribed surface area and ultrafiltration coefficient be used in all PK studies

3. Pediatric PK studies should be performed and used to develop pediatric drug dosing information

Suggested FDA Guidance ChangesSuggested FDA Guidance Changes CRRT

1. Dosing guidance should be developed for drugs likely to be used in ICU setting

2. Dose of delivered CRRT for PK studies should be set at 35 mL/kg/hr (or 2000 mL/hr/1.73 m2)

3. PK studies should be performed with most commonly used hemodiafilters

4. Pediatric PK studies should be performed and used to develop pediatric drug dosing information

SummarySummary 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 ½ hour intervals during dialysis

Time (hr)0 12 24 36 48 60 72 84 96

Sita

glip

tin P

lasm

a C

once

ntra

tion

(nM

)

0

200

400

600

800

1000

Healthy Control Subjects Mild Renal Insufficiency Moderate Renal Insufficiency Severe Renal Insufficiency End Stage Renal Disease (48-hr Dialysis)

0 12 24 36 48 60 72 84 961

10

100

1000

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)

Dos

e-A

djus

ted

(to 5

0 m

g) A

UC

(uM

.hr)

0

4

8

12

16

20

24

28

Creatinine Clearance (mL/min)10 30 50 70 90 110 130 150 170 190 210 230

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

Re

na

l Cle

ara

nce

(m

L/m

in)

0

100

200

300

400

500

600

700

800

900

C reatin ine C learance (m L/m in)0 50 100 150 200 250 300

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

Time (hr)0 6 12 18 24 30 36 42 48 54 60 66 72

Sita

glip

tin P

lasm

a C

on

cen

tra

tion

(n

M)

0

100

200

300

400

500

600

700

Dialysis at 4-hr Postdose PredialyzerPostdialyzerDialysis at 48-hr Postdose

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 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

Time (hr)0 12 24 36 48 60 72 84 96

Sit

agli

ptin

Pla

sma

Con

cent

rati

on (

nM)

0

200

400

600

800

Severe renal insufficiencyESRD (Dialysis at 48 hours postdose)

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 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

Mean (N=6) MK-0767 Plasma Concentrations Following Administration of a Single 5-mg Dose of MK-0767 to Patients with Severe Renal Insufficiency and to

End-Stage Renal Disease Patients on Hemodialysis (Protocol 015) Compared to Historical Data in Healthy YoungI and ElderlyII Subjects

Time (hr)

0 24 48 72 96 120 144 168

Mea

n P

lasm

a M

K-0

767

Con

cent

ratio

n (n

g/m

L)

0

100

200

300

400

500

IPooled 5 and 10 mg (scaled to 5 mg using nominal dose) data from Prot. 001, and 5 mg data from Prot. 010.IIPooled 10 mg data from elderly subjects (Prot. 003) scaled to 5 mg using nominal dose.

Young Men (PN001)IESRD - hemodialysis

CrCl < 30 mL/min/1.73 m2

Healthy Elderly (PN003)II

Young Men and Women (PN010)I

Dru

g

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

0

200

400

600

800

RenallyImpaired

Matched Healthy Controls

0

10

20

30

40

50

60

70

80

RenallyImpaired

AUC0-inf (nM-hr) Cmax (nM)

HealthyHistorical

HealthyHistorical

Matched Healthy Controls

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

0

200

400

600

800

RenallyImpaired

Matched Healthy Controls

0

10

20

30

40

50

60

70

80

RenallyImpaired

AUC0-inf (nM-hr) Cmax (nM)

HealthyHistorical

HealthyHistorical

Matched Healthy Controls

Individual 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

Limitations

Interpretation Timing Limited numbers Recruitment, particularly of severe

renal insufficiency patients Assessment of safety and

tolerability Single dose vs. multiple dose Special populations