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Kidney Disease: Improving Global Outcomeswww.kdigo.org

Drug Prescribing in Kidney Disease:Initiative for Improved Dosing

Effects of impaired kidney function ondrug pharmacokinetics and

pharmacodynamics

Section Leaders:William Bennett and Domenic Sica

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Passage of a Drug Dose Through the Body

(Pharmacokinetics)

Oralabsorption

EliminationTissue receptor:

action

Parenteral drugadministration

Systemiccirculation

Bound to proteins Free

(Bioavailability is theproportion of an oral dosereaching systemic system)

Liver

First-pass effect

Parent drug

Active/inactive metabolites Pharmacodynamics

Kidneys

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Effects of Age and Renal Dysfunction onPharmacokinetics and Pharmacodynamics

All processes affected by both variables incomplex ways

Drug elimination primarily affected by

GFR(age +/- CKD)

Formulae for GFR estimation not validated fordrug dosing purposes

Biologic readouts better than kinetic surrogatesie. blood levels vs. BP, INR, etc. Drug interactions multiple and personal

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Pharmacokinetic Parameters

Affected by Age/GFRParameter (abbreviation) Clinical ApplicationBioavailability (F) Determines the amount of drug

reaching the systemic circulationand therefore the amount at thesite of action

Volume of Distribution (VD) Determines the size of a loadingdoseClearance (Cl) Determines the maintenance doseHalf-life (T1/2) Determines the amount of time

needed to reach steady stateserum concentrations or eliminatethe drug (four times the T1/2)

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Effect of Renal Dysfunctionon Drug Usage

Accumulation of drugs normally excreted

Accumulation of active metabolites

Change in drug distribution - protein binding

Decrease in renal drug metabolism

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Goals of Therapy

Maintain efficacy

Avoid accumulation and toxicity

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Prescribing for a Patientwith Renal Dysfunction

Ascertain level of renal function (estimatedGFR/C Cr)

Establish integrity of liver metabolism

Establish loading dose Maintenance dose - dose reduction vs. interval

extension Check for drug interactions Decide whether blood level monitoring is indicated

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Estimated GFR MDRDFormula

eGFR (mL/min/1.73 m 2) = 175 [SerumCreatinine (umol/L) x 0.0113] -1.154 x age(years) -0.203

If female, multiply the result by 0.742 If African American, multiply the result by 1.21 Not valid for eGFR > 60 Not valid for very fat, very thin, paraplegics,

elderly

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Cockroft-Gault Equation

140-age x (lean body weight) x 0.85 (if female)72 x serum creatinine

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References Regarding GFREstimation for Drug Dosing

Wango et al., Comparison of MDRD andCG equations for antimicrobial doseadjustments. Ann Pharmacother 2006,

40:1248. Stevens et al., Comparison of drug dosing

recommendations based on measuredGFR and estimating equations. Am JKidney Dis 2009, 54:33.

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The Loading Dose

Loading dose = desired Cp SS x VD x patients weight

Cp SS = plasma concentration of the drug desired at steadystate

VD = volume of distribution

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Methods of Drug Dose Adjustment in Patients with

CKD

Constant DoseVarying Interval

Constant IntervalVarying Dose

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Examples of RenallyExcreted Metabolites in CKD

ActiveDiazepam

Desmethyldiazepam

ToxicMeperidine

Normeperidine

Additive

Procainamide NAPA

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0.1

0.6

1.1

1.6

2.1

2.6

3.1

3.6

2 6 2 8 3 0 3 2 3 3 3 4 3 5 3 7 7 1 7 9 9 4 1 0 5

1 2 3

Time (hours)

u g / m l

N-Acetyl Procainamide (NAPA) Procainamide

Pre-Dialysis

Post-Dialysis

Pre-Dialysis

Post-Dialysis

Pre-Dialysis

Post-Dialysis

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Specific Drugs withRenal Dysfunction

Narcotics

Antibiotics/Antivirals LMW Heparins

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1

10

100

1000

0 4 8 12 16 20 24

Time (hours)

P l a s m a c o

n c e n t r a t i o n ( n m o l / l )

Morphine 3-glucuronideMorphine 6-glucuronideMorphine

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Antibiotics to be Adjusted* Cephalosporins Imipenems:

Syndromes of neurotoxicity described Penicillins: Neurotoxicity/seizures

Acyclovir/Ganciclovir: Leukopenia,neurotoxicity, renal dysfunction

Minimal Adjustments:Fluoroquinolones, sulfonamides

* GFR < 20% normal

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Low Molecular WeightHeparin (LMWH) in CKD)

Lim et al. Annals of Int Med 2006 LMWH excreted by kidneys

eGFR < 30 mL/min lengthens t 1/2 andincreases anticoagulant anti-X a

Increased risk of major bleeding not

easily reversed Need for downward dose adjustment

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Rules of Thumb for ChangingMaintenance Drug Dosage

Available options: Decrease the dose, keeping the interval constant Increase the dose interval, keeping the dose constant

Decide the appropriate dosage regimen for the patientas if renal function were normal

Determine the fraction of drug and active metabolite thatis excreted unchanged by the kidneys

Calculate the dosage adjustment factor. This factor is theratio of the half-life of the drug in the patient to the half-life of the drug in the normal person

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Rules of Thumb for ChangingMaintenance Drug Dosage (contd) Use the dosage adjustment factor in one of the

following ways after considering which is mostappropriate for the individual drug: Divide the dose you determined for normal renal function

by the dosage adjustment factor and continue with the

same dosage interval Continue with the same dose but multiply the dosage

interval you determined for normal renal function by thedosage adjustment factor

A regimen of combined dose reduction and dose intervalprolongation may maintain a more uniform serumconcentration

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Drug Level MonitoringDrug toxicity is serious and occurs at

levels close to therapeutic

Therapeutic and biologic end pointsare not easily defined

To exclude non-compliance or markedinterindividual differences

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Problems with Current Data Kinetic studies performed in few

stable CKD patients withoutcomorbidities, acute illness Liver and non-renal metabolism

varies (age, genetics, illness, otherdrugs)

No cookbook to make rationalindividual patient decisions;Requires Wisdom

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Conclusions Prescribing in CKD is an art not science at

this point

No substitute for knowing the drugpharmacology and the individual patient

Individualize. Go Low/Go Slow is a goodgeneral rule

Review med lists including OTC

supplements at each visit Watch for nephrotoxins

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Breakout Group 1:

Discussion Questions/Objectives

Effects of impaired kidney function on drug PK and PD

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Breakout Group 1:

Clinical Recommendations


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Breakout Group 1: Research &

Regulatory Recommendations


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