11/3/2017

Renal Pharmacokinetics
Teresa V. Lewis, PharmD, BCPS
Assistant Professor of Pharmacy Practice
University of Oklahoma College of Pharmacy
Adjunct Assistant Professor of Pediatrics
University of Oklahoma College of Medicine
Kahoot 1

Objectives
1. Describe the effects of kidney dysfunction on the
pharmacokinetics and pharmacodynamics
2. List the limitations of renal function estimation equations
for predicting true GFR
3. Know and apply the Cockcroft-Gault formula for
estimating creatinine clearance (Clcr) in adult males and
females
4. Utilize given renal function estimation equations to
estimate the level of renal function for a given adult or
pediatric patient
5. Identify when renal dosage adjustment is necessary when
given patient details and drug parameters
2

Objectives
6. Calculate the dosage adjustment factor (Q) of a given
drug that is used in a patient who has renal
dysfunction
7. Appropriately individualize drug therapy for a given
patient when provided the pharmacokinetic
parameters of the drug (e.g. kel, fraction of drug
excreted by the kidneys, etc)
8. Provide recommendations for drug dosage
adjustments that are appropriate for the given adult or
pediatric patients level of renal impairment when
provided information from a drug monograph
3

1
 11/3/2017

Outline
Background
Clinical aspects of renal dosage adjustments
Renal function estimation equations
Pediatric specific renal function estimation equations
Dose modifications (Individualizing therapy)

Why We Need To Know A Patients Renal

Function
~90% of all drugs are eliminated by the kidney

Pharmacokinetics (PK) and Kidney

Dysfunction
Bioavailability of some drugs may be increased or decreased
Volume of distribution may be increased for many drugs. This
may be due to:
o Decreased protein binding
o Increased tissue binding
o Alterations in body composition (e.g. fluid overload)
Decreased renal metabolic activity
Decrease in the renal clearance of drugs
Renal failure can also cause alterations in non-renal elimination
of some drugs

2
 11/3/2017

Pharmacodynamics and Kidney

Dysfunction
Alterations in drug response may occur
Increased risk for adverse drug reactions
Risk for accumulation of toxic metabolites

Glomerular Filtration Rate (GFR)

Amount of blood that passes through the glomeruli each minute

Best indicator of kidney function
GFR should be used to evaluate renal function for classifying
chronic kidney disease (CKD) and for renal dosage adjustments
Normal GFR values vary by age, gender, and body size
o Kidney size is proportional to body size
o Kidney function is proportional to kidney size
o Expressed as mL/minute/1.73m2

Glomerularcirculationandfunction.In:Avner ED,HarmonWE,Niaudet P,YoshikawaN,eds.PediatricNephrology6th ed.Berlin:Springer,2009:3164

Specialpharmacokineticandpharmacodynamic considerationsinchildren.In:BurtonME,ShawLM,Schentag JJ,EvansWE,eds.AppliedPharmacokinetics& 8
Pharmacodynamics:principlesoftherapeuticdrugmonitoring4th ed.Baltimore,MD:LippincottWilliams&Wilkins,2006:187212.

Normal GFR Values By Age

160
GFR (mL/min/1.73 m2)

140
120
100
80
60
40
20
0

Hogg RJ. Pediatrics 2003; 111(6):1416-21. 9

Frequently asked questions about GFR estimates. National Kidney Foundation.

3
 11/3/2017

Reason For Lower Kidney Function In

Neonates
1. Lower renal blood flow

2. Immature glomeruli

3. Immature renal tubule function

Renaltubulardevelopment.In:Avner ED,HarmonWE,Niaudet P,YoshikawaN,eds.PediatricNephrology6th ed.Berlin:Springer,2009:3164.

Glomerularcirculationandfunction.In:Avner ED,HarmonWE,Niaudet P,YoshikawaN,eds.PediatricNephrology6th ed.Berlin:Springer,2009:3164 10
Optimizingpediatricdosing:adevelopmentalpharmacologicapproach.Pharmacotherapy 2009;26(6):68090. DOI:10.1592/phco.29.6.680

Lower Kidney Function Due to Aging

(Elderly)
1. Declining renal blood flow

2. Increased number of sclerotic glomeruli &

decreased number of functioning glomeruli

3. Compromised renal tubule function from

lifelong oxidative stress

Aymanns C,KellerF,Maus S,Harmtann B,Czock D.ReviewonPharmacokineticsandPharmacodynamicsandtheAgingKidney.CJASN.2010;5(2):31427 11

Turnheim K.Whendrugtherapygetsold:pharmacokineticsandpharmacodynamicsintheelderly.ExperimentalGerontology 2003;38:84353.

Causes of Chronic Kidney Disease (CKD)

and End Stage Renal Disease(ESRD)

Diabetes:Leading Hypertension:2nd Glomerulardisease:

cause leadingcause 3rd leadingcause

Cystic Tubulointerstitial
diseases diseases

12

4
 11/3/2017

National Kidney Foundation-Kidney Disease

Outcomes Quality Initiative (KDOQI) 2002
CKD Classification
Glomerular FiltrationRate
Stage Description (GFR)
ml/min/1.73m2
1 Kidney damagewithnormalorGFR > 90
2 KidneydamagewithmildinGFR 6089
3 Moderate inGFR 3059
4 SevereinGFR 1529
5 Kidneyfailure <15(ordialysis)
13
National Kidney Foundation. Am J Kidney Dis 39:S1-S266, 2002 (suppl 1)

Green=low risk
Yellow=moderate risk
Orange=high risk
Red=very high risk

14
Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int Suppl. 2013; 3(1):1-150

Outline
Background
Clinical aspects of renal dosage adjustments
Renal function estimation equations
Pediatric specific renal function estimation equations
Dose modifications (Individualizing therapy)

15

5
 11/3/2017

Stepwise Approach to Dose

Individualization
1. Obtain patient history and clinical information
2. Estimate GFR
3. Review patients medications
4. Individualize drug therapy
5. Monitor for efficacy and toxicity
6. Adjust drug regimen based on response or changes in patient
status

Battistella M,MatzkeGR.DrugTherapyIndividualizationforPatientswithChronicKidneyDisease.In:DiPiro JT,TalbertRL,YeeGC,

MatzkeGR,WellsBG,PoseyL.eds.Pharmacotherapy:APathophysiologicApproach,10eNewYork,NY:McGrawHill;. 16
http://accesspharmacy.mhmedical.com/content.aspx?bookid=1861&sectionid=146061579.AccessedNovember01,2017.

Serum Creatinine (Scr)

Freely filtered
Actively secreted
Scr lags behind glomerular filtration rate (GFR) by 1-2 days
due to:
1. Slow accumulation
2. Increased tubular secretion
3. Increased extra-renal clearance

17

Limitations of Creatinine Based Renal

Function Estimation Equations
Creatinine can be absorbed
from exogenous sources
such as meat
Estimation of creatinine
clearance (Clcr) is
dependent upon muscle
mass as defined by lean
body weight which is difficult
to define.

18

6
 11/3/2017

Limitations of Creatinine Based Renal

Function Estimation Equations
Populations that have reduced muscle
mass as a fraction of total body weight
may generate less creatinine
Ideal body weight is used but lean body
mass is highly variable between
individuals (obese, body builders, elderly,
amputees, patients who are bed ridden,
etc)

19

Limitations of Creatinine Based Renal

Function Estimation Equations
Creatinine production may not be constant in malnourished
individuals, those with hepatic disease, or critically ill patients
Non-renal elimination of creatinine by gut metabolism can
contribute to inaccurate assessment of GFR in patients with end
stage renal disease (ESRD)

20

Limitations of Creatinine Based Renal

Function Estimation Equations
The rise in Scr is not detectable until significant loss of
functioning nephrons occurs
Clinical laboratories report a wide range of normal values for
Scr (e.g. Scr range for a 6 year-old child: 0.16-0.66 mg/dL)
Precision of laboratory instruments for measuring creatinine can
affect estimation of renal function (measurement of creatinine in
serum and urine must be accurate)

21

7
 11/3/2017

Outline
Background
Clinical aspects of renal dosage adjustments
Renal function estimation equations
Pediatric specific renal function estimation equations
Dose modifications (Individualizing therapy)

22

GFR vs ClCr
The terms Clcr and GFR are frequently used interchangeably
Clcr is expressed as mL/min
GFR is adjusted for body surface area (BSA) and is expressed as
mL/min/1.73m2
If the drug information resource lists dosing in terms of Clcr (mL/min) but
you calculated GFR (mL/min/1.73 m2):
o For most patients it is not necessary to unadjust for BSA
o For very large or very small adults, it may be necessary to unadjust for BSA

23

24 Hour Urine: (For Adults & Children)

CLcr in mL/min

.
GFR in mL/min/1.73m2

Ucr = Urine creatinine
(mg/dL)
Body surface area Mosteller formula V = Urine volume (mL)
Scr = serum creatinine

(mg/dL)
T = Sampling period
(min)
A = Body surface area
(m2)

Taketomo CK,etal.PediatricDrugInformationHandbook15th Ed. 24

PublicHealthNutrition 1999;2:58791.

8
 11/3/2017

Adult Renal Function

Estimation Equations

25

Cockcroft-Gault (C-G)

0.85

Ideal body weight (IBW)

50 2.3 60
45.5 2.3 60

Memorizetheseequations
26

C-G: Which Weight To Use

Use ideal body weight (IBW)
Exception: Use actual body weight (ABW) if the patients
actual body weight is lower/smaller than IBW

27

9
 11/3/2017

C-G: Special Population Correction

Factor and Adjustments
Obesity: IBW vs adjustment (IBW + 0.4(ABW-IBW)) Neither
approach have been validated
Elderly: Some clinicians round Scr values up to 0.8 or 1.0
mg/dL. Current data does not support using correction factors
for elderly patients
For patients with questionable renal function, a timed urine
collection may be the best approach, especially in the frail
elderly

28

Question: Do all the patients below have the same level

of renal function?

2 year-old female; Ht=32 in, Wt=25 lbs, Serum creatinine (Scr)

1.5 mg/dL
25 year-old female; Ht=65 in, Wt=150 lbs, Scr 1.5 mg/dL
25 year-old male; Ht=65 in, Wt=150 lbs, Scr 1.5 mg/dL
82 year-old female; Ht=65 in, Wt=150 lbs, Scr 1.5 mg/dL

29

Use The C-G Equation to Estimate Clcr

In 25 Year-Old Example Patients
25 year-old female 25 year-old male
Ht = 65 in Ht = 65 in
Wt=150 lbs Wt=150 lbs
Scr 1.5 mg/dL Scr 1.5 mg/dL

30

10
 11/3/2017

Use The C-G Equation to Estimate Clcr

In The Elderly Patient Example
82 year-old female
Ht = 65 in
Wt=150 lbs
Scr 1.5 mg/dL

31

MDRD (4 Variable Equation)

. .
175 1.212
. .
175 1.212 0.742

eGFR expressed in mL/min/1.73m2

Age in years
Scr=serum creatinine in mg/dl
AA=African American
Note: the MDRD equation only accurately estimates renal function in
patients with GFR < 60 ml/min/1.73m2

32

Use The MDRD-4 Variable Equation to Estimate

GFR In 25 Year-Old Non-African American
Example Patients
25 year-old female 25 year-old male
Ht = 65 in Ht = 65 in
Wt=150 lbs Wt=150 lbs
Scr 1.5 mg/dL Scr 1.5 mg/dL

33

11
 11/3/2017

Use The MDRD-4 Variable Equation to Estimate

GFR In 25 Year-Old African American Example
Patients
25 year-old female 25 year-old male
Ht = 65 in Ht = 65 in
Wt=150 lbs Wt=150 lbs
Scr 1.5 mg/dL Scr 1.5 mg/dL

34

Use The MDRD-4 Variable Equation to Estimate

GFR The Elderly Patient Example
82 year-old African 82 year-old Non-African
American female American female
Ht = 65 in Ht = 65 in
Wt=150 lbs Wt=150 lbs
Scr 1.5 mg/dL Scr 1.5 mg/dL

35

Outline
Background
Clinical aspects of renal dosage adjustments
Renal function estimation equations
Pediatric specific renal function estimation equations
Dose modifications (Individualizing therapy)

36

12
 11/3/2017

Schwartz Equation
GFR = ml/min/1.73m2
K = constant of proportionality
Low birth weight < 1 yr = 0.33
Full-term < 1 yr = 0.45
2-12 year-old = 0.55
13-21 yearold female = 0.55
13-21 year-old male = 0.70
L = length in cm
Scr = serum creatinine (mg/dL)

SchwartzGJ,etal.Pediatrics 1976;58:25963.
37
Taketomo CK,etal.PediatricDrugInformationHandbook15th Ed

Chronic Kidney Disease in Children

(CKiD) Bedside Equation
GFR = ml/min/1.73m2
L = length in cm
Scr = serum creatinine (mg/dL)

Note:UseoftheCKiD Bedsideequationhasnotbeenvalidatedininfants

38
JAmSoc Nephrol 2009;20(3):629637.

Estimate GFR For The 2 Year-Old Female Patient

Example

Schwartz Equation Bedside Schwartz Equation

Ht=32 in Ht=32 in
Wt=25 lbs Wt=25 lbs
Scr 1.5 mg/dL Scr 1.5 mg/dL

39

13
 11/3/2017

How Would You Adjust The Dose of Meropenem For Each

Of The Patients To Treat an Intra-abdominal Infection?

2 year-old female
25 year-old female
25 year-old male
82 year-old female

Note: Typical Meropenem dose for this indication:

Child: 20 mg/kg/dose IV every 8 hours
Adults: 1 gram IV every 8 hours

LexiComp 40

Converting from GFR to ClCr

Calculate renal function using the MDRD-4 Variable equation

for a 73 year-old Caucasian female, Ht=58 in, Wt=90 lbs,
Scr=1.39mg/dL. Express your answer in terms of Clcr (mL/min)

MDRD 4 Variable Estimation

. .
175 1.212
. .
175 1.212 0.742

41

Patient Example: Application To A Drug

(Bactrim)

42

14
 11/3/2017

Outline
Background
Clinical aspects of renal dosage adjustments
Renal function estimation equations
Pediatric specific renal function estimation equations
Dose modifications (Individualizing therapy)

43

Ways To Adjust Doses In Patients With

Renal Dysfunction
1. Change dose without changing dosing interval
2. Change the dosing interval without changing dose
3. Change the dose and dosing interval

44

Concentration Time Curve With Different

Dosing Adjustments
Altered dose
Altered dose interval
Altered dose and interval

45
FromDr WoosLecture

15
 11/3/2017

Things To Consider When Determining

Dosage Modifications
Is there a clearly defined pharmacodynamic endpoint?
o Is the clinical effect associated with achieving a target drug
concentration? (e.g. aminoglycosides, vancomycin, etc)
o Is toxicity is associated with high drug concentrations? (e.g.
aminoglycosides)

46

Use Of This Approach Is Based On The

Following Assumptions
1. Drug elimination is by linear, 1st order, 1 compartment model
2. GFR and tubular function decrease in a parallel fashion
3. Other PK parameters (absorption, distribution, metabolism)
remain constant
4. Metabolites are not pharmacologically active or do not
accumulate in renal disease
5. Drug pharmacodynamics are not affected by renal disease

47

Calculating The Adjustment Factor

1 1

1 1

Q is the adjustment factor

fe is the fraction of drug excreted unchanged in the urine
KF is the patients kidney function relative to normal kidney
function. (Normal kidney function is generally considered to be
120 mL/min)

48

16
 11/3/2017

Altering The Dosing Interval

R is the dosing interval in reduced renal function

N is the normal dosing interval
Q is the adjustment factor

49

Calculating A New Dose

DR is the dose (mg) reduced renal function

DN is the normal dose (mg)
R is the dosing interval in reduced renal function
N is the normal dosing interval
Q is the adjustment factor

50

Calculate the adjustment factor (Q) for

Drug A in a 60 year-old male (Wt: 70kg)
Drug A Normal Dose=1000mg every q 8hrs
Fractional excretion (fe) of Drug A = 0.9
The patients Clcr=30 mL/min

51

17
 11/3/2017

Calculate the new dose for Drug A in the

same 60 year-old male (Wt: 70kg)
Drug A Normal Dose=1000mg every q 8hrs
Fractional excretion (fe) of Drug A = 0.9
The patients Clcr=30 mL/min

52

Calculate the new dosing interval for Drug A

in the same 60 year-old male (Wt: 70kg)
Drug A Normal Dose=1000mg every q 8hrs
Fractional excretion (fe) of Drug A = 0.9
The patients Clcr=30 mL/min

53

Calculate a new dose for Drug A using a dosing interval of

q12hrs in the same 60 year-old male (Wt: 70kg)

Drug A Normal Dose=1000mg every q 8hrs

Fractional excretion (fe) of Drug A = 0.9
The patients Clcr=30 mL/min

54

18
 11/3/2017

Calculate dosage adjustment factor Q

Vancomycin Dose: 500 mg q6hrs; V=33L; Cp0 = 15 mg/L
Normal subject: 1 1
fe=0.95
kel=0.116 hr-1 (t1/2 = 6 hr)
Patients renal function is 1/10 of Application of PK principles (see Dr
normal renal function Woos renal clearance ppt slide #35)
Q=Kelckd/Kelnorm
Q=

Estimate a new dosing regimen

Vancomycin Dose: 500 mg q6hrs; V=33L; Cp0 = 15 mg/L

Normal subject:
fe=0.95
kel=0.116 hr-1 (t1/2=6 hr)
Patients renal function is 1/10
of normal renal function

56

Calculate dosage adjustment factor Q

Kanamycin: 250 mg q6hrs; V=13.3L
Normal subject: 1 1
kel=0.3 hr-1 (t1/2=2.3 hr)
kelckd=0.034 hr-1 (t=20hrs) Application of PK principles (see Dr
Patients renal function is 1/10 of Woos renal clearance lecture slide
normal renal function #38)
Q=Kelckd/Kelnorm
Q=

57

19
 11/3/2017

Estimate a new dosing regimen

Kanamycin: 250 mg q6hrs; F=1, V=13.3L
Normal subject:
kel=0.3 hr-1 (t1/2=2.3 hr)
kelckd=0.034 hr-1 (t=20hrs)
Patients renal function is 1/10
of normal renal function

58

Useful References

Lexi-Comp Online
Micromedex
Drug Information HandbookLexi-Comp
Aronoff GR, Berns JS, Brier ME, et al. Drug
Prescribing in Renal Failure. 4th ed.
Philadelphia, PA: American College of
Physicians; 1999.

59

Questions?

60

20