04 vancomycin pharmacokinetics20060830 - dr ted...

Vancomycin Pharmacokinetics

Myrna Y. Munar, Pharm.D., BCPSAssociate Professor of Pharmacy

Goals

Review the PK properties of vancomycinCompare and contrast methods of dosage regimen design for vancomycinApply the PK model to develop and adjust individualized dosing regimens for patients

Objectives

Through the preparation for and participation in this lecture, a successful student should be able to:

Identify the appropriate PK model and equations commonly used to dose vancomycinDescribe the PK highlights of vancomycin, and identify the normal population PK parametersIdentify absorption characteristics of vancomycinList the distribution characteristics and protein binding of vancomycin

ObjectivesDiscuss when peak and trough serum vancomycin concentrations should be obtainedDescribe the elimination and excretion of vancomycinIdentify the normal population PK parameters and the suggested dosage recommendations for vancomycinDetermine appropriate target vancomycin concentrations for a given patientDiscuss adverse effects of vancomycin and relate to serum concentrations Identify those disease states known to influence the PK of vancomycin

Objectives

Discuss the effect of various diseases or physiologic states on the disposition of vancomycinEvaluate the advantages and limitations of dosing nomograms for vancomycinCompare and contrast the use of a one- vs two-compartment model to dose vancomycin

ObjectivesGiven a patient history and therapeutic goal, develop a loading dose and maintenance dose regimen for vancomycin using dosing nomograms and an appropriate PK modelGiven a patient history, therapeutic goal and serum concentration data, calculate k and VD and use to adjust the patient’s maintenance dose regimenIdentify indications for monitoring serum vancomycin concentrationsDevelop a PK monitoring plan for a given patient receiving vancomycin

IntroductionObtained from Streptomyces orientalisMOA:

Glycopeptide antibiotic with bactericidal activity by blocking cell wall synthesis at a site different from penicillinsSecondary damage to cytoplasmic membrane

Bactericidal against most gram + organisms (except Enterococci)

Slow-killing activitySynergism with gentamicin against gram positive organisms

----< 0.1Clostridum difficile

0.78 - > 101.250.5 – 5.0Clostridia spp

0.29 – 500.630.31 – 5.0Strep bovis

5 - > 1003.10.8 - > 100Strep faecalis

0.3 0 - > 500.780.1 – 1.56Strep viridans

--0.50.25 – 1.0Staph pneumonia

2.5 – 203.11.56 – 6.25Staph epidermidis

1.25 – 5.0

1.25 – 5.0

2.0

1.5

1.0 – 5.0

0.3 – 12.0

Staphylococcus aureusMethicillinsusceptibleMethicillin resistant

MBC (mcg/ml)MIC Median (mcg/ml)

MIC Range(mcg/ml)

Bacteria

Concern for Resistance

Promote appropriate useGlycopeptide-resistant enterococci(GRE)

Aka vancomycin-resistant enterococci(VRE)Multiply resistant organism

High-level resistance; vanco MIC > 64Organisms resistant to vancomycin may have no alternative therapy

Vancomycin OHSU Formulary Restriction

Approved uses at OHSUDocumented infection caused by gram-positive organisms not susceptible to other agents (i.e. penicillins, cephalosporins, and clindamycin)Documented infection caused by susceptible organism in patients with a documented, life-threatening allergy to beta-lactam antimicrobials ( i.e. penicillins and cephalosporins)Oral treatment of antibiotic-associated colitis which is severe and potentially life-threatening or has failed to respond to 3 days of oral metronidazole or oral bacitracin

Vancomycin OHSU Formulary Restriction

Approved uses at OHSU continuedThree days or less of empiric therapy when there is reasonable suspicion of oxacillin resistant S. aureus, S. epidermidis (coagulase-negative staph), or ampicillin-resistant enterococcusSurgical prophylaxis in patients with documented cefazolin allergy; or documented, severe penicillin allergies and no recent history of tolerating a cephalosporin

http://ozone.ohsu.edu/HealthSystems/pharmacy/vancgdl.htmLists approved and non-approved uses at OHSU

PK Highlights

Primarily excreted unchanged by glomerular filtrationTwo-compartment drug dosed with a one-compartment modelEvolving approach to PK dosing

AbsorptionOral: F < 0.05May be significantly absorbed

Patients who are functionally anephricPatients who have GI bleeds/ulcerations

Concentrations up to 30 mcg/ml have been reported

IV: F = 1.0; IM: very painfulIntraperitoneal: F = 0.5 – 0.6 with a 6 hour dwell timeIntrathecal/Intraventricular : CNS infections require intrathecal instillation

Dose = 5 – 20 mg q 24 h

Get your clicker ready

Please make your selectionChoose the FALSE statementA) Vancomycin cannot be given orally because of poor

oral bioavailability, F < 0.05B) Vancomycin is active against Clostridium difficile,

therefore it can be given orally to treat antibiotic-associated colitis aka pseudomembranous colitis

C) According to OHSU guidelines, vancomycin can be given for oral treatment of antibiotic-associated colitis which is severe and potentially life-threatening or has failed to respond to 3 days of oral metronidazole or oral bacitracin

D) Vancomycin is not the first line agent for antibiotic-associated colitis because of changing or increasing resistance patterns

Distribution

Distributes into pleural, pericardial, ascitic, bile, and synovial fluidsCrosses placentaExcreted in breast milkCSF concentrations in n=9 children with bacterial meningitis were 14 – 28% of serum concentrations

Two-Compartment Model

Alpha (distribution) phase = 0.5 – 1 hrsBeta (elimination) phase = 3 – 9 hrs

Average terminal phase t1/2 = 7hrsTerminal t1/2 & CL correlated with CrCl

Vancomycin Infusion Guidelines

150120> 1500

12090>1250 - 1500

12060<1000 - 1250

Time to draw Cpeak(min after start of infusion)

Infusion Duration (min)

Dose (mg)

All trough values should be drawn immediately prior to next dose (within30 min of next dose).All serum levels should be drawn from an IV site other than the IV siteutilized for infusion of the drug.

Peak Concentrations (Cpeak)

When to draw peak concentrations:To assure that distribution is complete, peaks should be drawn at 5 alpha-half-lives after administration (2.5 – 5 hours )

However, most obtain peaks as follows:Normal renal function: draw 1 hour after a 1 hour infusionImpaired renal function (CrCl < 50 ml/min): draw 2 hours after a 1 hour infusion

PK- Distribution

alpha

beta

0 2 4 6 8 10

true PK

extrap PK

measured PK

Time (hrs)

Seru

m C

once

ntra

tion

Drawing peaks in the distributive phase will lead to errors in calculating:

A) Volume of distributionB) ClearanceC) Elimination rate constant (k)D) Half-life (t1/2)E) C and D

Distribution

VD,ss = 0.8 L/kg (range: 0.5 – 0.9 L/kg)Vc = 0.2 = 0.6 L/kgProtein binding

50 – 60% in healthy volunteers30 – 40% in infected patients0 – 31% (mean = 18.5%) in end-stage renal disease (ESRD)

Elimination

Route: primarily excreted (80 – 90%) unchanged by glomerular filtrationMay have some tubular secretion or reabsorptionSome evidence of non-renal clearance

CLNR = 6 ml/min in normal renal functionCLNR = 4 – 6 ml/min in ESRD

Renal Functionk

(hr-1

)

CrCl ml/min

y=mx + bk=0.00083 hr-1 (CrCl ml/min) + 0.0044Matzke

Half-life (t1/2) & Clearance (CL)

T1/2 = 7 hours in normal renal functionT1/2 = 5 – 7 days in anephricsVancomycin CL (ml/min/kg)

= 0.695 (CrCl in ml/min/kg) + 0.05

Anephric CL = 5 – 7 ml/min

Vancomycin Serum Concentrations

Generally accepted guidelinesPeaks 25 – 40 mcg/ml = mg/LTroughs 5 -15 mcg/ml = mg/L

Depends on type, severity of infectionTrough 20 mcg/ml targeted in certain clinical situations

Rationale based on average MIC for Staph aureusof 5 mg/L; therefore, a peak of 6 – 8 x MIC (30 –40 mg/L) and a trough 1 – 2 x MIC (5 – 15 mg/L) would be effective


Please make your selection

A) Vancomycin exhibits concentration-dependent bactericidal activity

B) Vancomycin exhibits time-dependent bactericidal activity

C) NeitherD) Both

PD Properties of AntimicrobialsPattern of Activity Antibiotics Goal of Therapy PK/PD

Parameter

Type IConcentration-dependent killing andProlonged persistent effects

AGDaptomycinFQKetolides

Maximize concentrations 24h-AUC/MICPeak/MIC

Type IITime-dependent killing and Minimal persistent effects

CarbapenemsCephalosporinErythromycinLinezolidPenicillins

Maximize duration of exposure T>MIC

Type IIITime-dependent killing andModerate to prolonged persistent effects.

AzithromycinClindamycinOxazolidinonesTetracyclinesVancomycin

Maximize amount of drug 24h-AUC/MIC

Pharmacodynamics

PK/PD predictors of outcome

Time > MICGoal: exceed MIC for entire dosing interval AUIC

AUIC; AUC24/MIC> 125 (? > 400) proposed to correlate w/ bacterial eradication and prevent resistance development

Schentag JJ. Crit Care Med 2001;29(4):N100-7.

Pharmacodynamics

Unlike aminoglycosides, vancomycin does not exhibit peak-associated (concentration-dependent) killingVancomycin exhibits time-dependent bacterial killing usually best achieved at troughs 3 – 5 x MICTroughs are monitoredPeaks are important primarily from a toxicity standpoint

Ototoxicity

Incidence: < 2%; damage to 8th cranial nerveDeafness, vertigo, dizziness, tinnitusMay be reversible or permanentReported with peak vancomycin concentration > 80 mg/L or rapid infusionsCommonly associated with vancomycin given with erythromycin or aminoglycosidesAssociated with earlier, less pure vancomycin

Ototoxicity

Patients at risk:renal impairmentreceiving high IV doses for prolonged periods of timereceiving other ototoxic drugs

Nephrotoxicity

Associated with earlier, less pure vancomycinVery low, rare reports with newer formulationsRarely, acute interstitial nephritis has been reportedNephrotoxicity associated with combined therapy with furosemide, aminoglycosides, or amphotericin B has been reported

True or False

Way back when Dr. Munar was going to pharmacy school, vancomycin was referred to as Missisippi mud.

Nephrotoxicity

Patients at risk:NeutropeniaPeritonitisElderlyLiver diseaseMale patients

Red Neck Syndrome

Histamine-like reaction with rapid administration of vancomycin (>500 mg over 30 minutes)Recommend administration rates of < 15 mg/min (eg 1 g over 1 hour)Central development of erythema and rash at base of neck, flushing, pruritis, hypotension, chills, tachycardia, and headache; rarely cardiac arrest and seizures

Red Neck SyndromeUsual onset a few minutes after start of infusion, but may not occur until after infusion has endedUsually resolves spontaneously over several hours after d/c infusionReaction may necessitate use of anti-histamines, corticosteroids, or IV fluidsLengthening time of infusion to 2 hours or pretreatment w/antihistamine may decrease future reactions

Other

NeutropeniaRashPhlebitis

Factors Affecting PK of Vancomycin

Obesity

Evidence suggests VD and CL in obese patients correlates best with ACTUAL vs IBW (Blouin)Use an adjusted body weight in morbidly obese patients

Pediatrics

131 – 16350 – 8115 – 30CL (ml/min/1.73m2)

0.538 –0.818

0.377 –0.964

0.49 –0.736

VD,ss (L/kg)

ChildrenInfantsNeonates

Rodvold, 1997

Burn Patients

VD,ss = 0.59 + 0.17 L/kgCL = 142.8 + 34.5 ml/min

Ref: Pleasants

Dosage Regimen Design

Patient Database

Demographic data: age, weight, height, genderVital signsDisease states presentRenal functionConcurrent drug therapyOrganism and site of infectionPertinent labs

Therapeutic Objective

Decide on target serum concentrationsIdentify monitoring parameters for efficacy and toxicity (BUN, SCr, I/O, WBC w/diff, C & S, x-rays, temperature)

Usual Range of Doses

Adults (normal renal fxn)500 – 1000 mg q 6-12 hAbout 25 mg/kg/day

Eg 500 mg q 6 h or 1 g q 12 h

Anephrics7.5 mg/kg q 7 -10 days

Usually 1 g every weekException: pt undergoing high-flux hemodialysis

Use these guidelines for comparative purposes after performing calculations

Monitoring: Is it Justified?

EfficacyLack of clear correlation between levels and clinical outcomeConsiderations

MIC for pathogensPK/PD properties assoc. w/ efficacy (e.g., time above MIC, AUIC, AUC/MIC)

SafetyRisk of toxicity based predominantly on animal models/case reportsCorrelation with serum concentrations not clearMay augment oto-, nephrotoxicity of AG

Monitoring

Practice varies

Recommend trough every 5-7 days, unless change in PK parameters dictates more frequently

May consider peak concentrations in certain circumstances (next slide)

Increasing data for monitoring AUC/AUIC

Considerations for checking peak/ trough or more frequent monitoring

Critically ill ptsSite of infection (endocarditis, osteomyelitis…)Poor therapeutic responseSuspected unusual PKConcurrent oto- or nephrotoxic agentsUnusually high MIC valuesSevere renal impairment

Approach

Begin patients on usual dosesObtain steady-state serum concentrationsAdjust doseNomograms are available for patients with impaired renal function

Path to follow for starting dose

Determine CrCl

For this exercise, use Cockroft & GaultWe will discuss the various methods for calculating glomerular filtration rate (GFR) or creatinine clearance (CrCl) in the renal PK topics

Cockroft & Gault

M: IBW (kg) = 50 kg + 2.3 (Ht. Inches > 5’)F: IBW (kg) = 45.4 kg + 2.3 (Ht. Inches > 5’)Features:

For patients Scr < 4.5 mg/dl; within 30% of IBW; age > 18 yearsRequires steady-state Scr values

Ref: Nephron 1976;16:31-41

( )( ) )females.(IBW

Scragemin)/ml(CrCl 850

72140

⋅−

=

Renal Functionk

(hr-1

)

CrCl ml/min

y=mx + bk=0.00083 hr-1 (CrCl ml/min) + 0.0044Matzke

Population PK Equations

Determine k (Matzke)

k (hr-1) = 0.00083(CrCl) + 0.0044

CrCl in ml/min

Determine t1/2 (hrs) = 0.693/k

Determine Vd (L) = 0.8 L/kgRange 0.5-0.9 L/kgUse actual body weightUse adjusted body weight if morbidly obese

Optimum Dosing Interval (tau)

tCC

ktau

desired

desired +⎥⎥⎦

⎤

⎢⎢⎣

⎡−=

max,

min,ln1

Tau = dosing interval

Small t = infusion time

small t = t = infusion timetau = dosing interval

Short IV Infusions

( ) ( )

( ))(

max,min,

max,

)(1max1min

1max

111/

1/1/

tTaukssss

kTaukt

ss

tTauk

ktkt

D

eCCe

eCL

tdoseC

eCC

eCL

tdoseORekV

tdoseC

−−

−−

−−

−−

=

⎟⎠⎞

⎜⎝⎛−

⎟⎠⎞

⎜⎝⎛ −=

=

−−=

Cmax1

Cmin1

Tau-t

Recall,dose/t = rate of drug infusion1 – e-kt = fraction of SS achieved by time t OR fraction of drug lost during time te-k(Tau-t) = fraction of drug remaining at end of dosing interval= time tau minus tRac = accumulation factor, allows you to fast forward to steady-state (SS)

( )

( ))(

max,min,

max,

)(1max1min

1max

111

*/

1*

/

tTaukssss

kTaukt

Dss

tTauk

kt

D

eCC

ee

kVtdoseC

eCC

ekVtdoseC

−−

−−

−−

−

=

⎟⎠⎞

⎜⎝⎛−⎟⎟

⎠

⎞⎜⎜⎝

⎛−=

=

−=

Rac

Short IV Infusions

rate in over rate out

( )

⎟⎟⎠

⎞⎜⎜⎝

⎛−−

=

⎟⎠⎞

⎜⎝⎛−⎟⎟

⎠

⎞⎜⎜⎝

⎛−=

−

−

−−

kt

kTau

desiredD

kTaukt

D

eeCkVtdose

ee

kVtdoseC

11**/

111

*/

max,

max

Optimum Dose

Solve for dose/t

Double check

Use optimal dosing regimen suggested to determine expected

Cmin and Cmax


Short IV Infusions

( ))(

max,min,

max, 111/

tTaukssss

kTaukt

Dss

eCC

ee

kVtdoseC

−−

−−

=

⎟⎠⎞

⎜⎝⎛−⎟⎟

⎠

⎞⎜⎜⎝

⎛−=

Tau-t

Path to follow for working from known concentrations

Mechanics of Obtaining Serum Concentrations

DoseInfused IV

DoseInfused IV

DoseInfused IV

Trough Before Dose

Peak After Distribution

At SS, assume trough

Log

C p

Time

Delta time! = tau minus t

Example

MI was prescribed vancomycin 1 g over 1 hour every 24 hours (0800). Vancomycin concentrations were obtained around the 4th dose, given at 0800. The concentrations are as follows:Time 0800; Vancomycin 12 mcg/mlTime 1000; Vancomycin 30 mcg/ml

Mechanics of Obtaining Serum Concentrations

DoseInfused IV

DoseInfused IV

DoseInfused IV

Trough Before Dose 0800

Peak After Distribution 1000

At SS, assume trough 0800 next day

Log

C p

Time

Delta time!

In order to calculate k, we assume that delta t is:

A) The difference between 0800 and 1000, which is 2 hours

B) The difference between 1000 and 0800 the following day, which is 22 hours

C) I can’t tell from the graph

Elimination Rate Constant (k)

tCC

k

ort

CCk

Δ

⎟⎟⎠

⎞⎜⎜⎝

⎛

=

Δ−

=−

2

1

12

ln

lnln This equation will give you a negative value.-k = negative number,therefore + k = positive number

Example

MI was prescribed vancomycin 1 g over 1 hour every 24 hours (0800). Vancomycin concentrations were obtained around the 4th dose, given at 0800. The concentrations are as follows:Time 0800; Vancomycin 12 mcg/mlTime 1000; Vancomycin 30 mcg/ml

Calculate k & t1/2

A) k = 0.46; t1/2 = 1.5 hrsB) k = 0.042; t1/2 approx. 17 hrsC) I can’t tell.

PK- Distribution

alpha

beta

0 2 4 6 8 10

true PK

extrap PK

measured PK

Time (hrs)

Seru

m C

once

ntra

tion

Determine patient Cmax & Cmin

ktt

ktt

eCC

oreCC

−

−

=

=

max

max

If Cmax & Cmin acceptable, continue dosing.If not, determine new regimen.

Volume of Distribution (VD)

( )kt

kt

D eCCe

ktdoseV −

−

−−

⋅=minmax

1/


Optimum Dosing Interval (tau)

tCC

ktau

desired

desired +⎥⎥⎦

⎤

⎢⎢⎣

⎡−=

max,

min,ln1

Tau = dosing interval


( )

⎟⎟⎠

⎞⎜⎜⎝

⎛−−

=

⎟⎠⎞

⎜⎝⎛−⎟⎟

⎠

⎞⎜⎜⎝

⎛−=

−

−

−−

kt

kTau

desiredD

kTaukt

D

eeCkVtdose

ee

kVtdoseC

11**/

111

*/

max,

max

Optimum Dose

Solve for dose/t


Short IV Infusions

( ) ( )

( ))(

max,min,

max,

)(1max1min

1max

111/

1/1/

tTaukssss

kTaukt

ss

tTauk

ktkt

D

eCCe

eCL

tdoseC

eCC

eCL

tdoseORekV

tdoseC

−−

−−

−−

−−

=

⎟⎠⎞

⎜⎝⎛−

⎟⎠⎞

⎜⎝⎛ −=

=

−−=

Cmax1

Cmin1

Tau-t

Recall,dose/t = rate of drug infusion1 – e-kt = fraction of SS achieved by time t OR fraction of drug lost during time te-k(Tau-t) = fraction of drug remaining at end of dosing interval= time tau minus tRac = accumulation factor, allows you to fast forward to steady-state (SS)

( )

( ))(

max,min,

max,

)(1max1min

1max

111

*/

1*

/

tTaukssss

kTaukt

Dss

tTauk

kt

D

eCC

ee

kVtdoseC

eCC

ekVtdoseC

−−

−−

−−

−

=

⎟⎠⎞

⎜⎝⎛−⎟⎟

⎠

⎞⎜⎜⎝

⎛−=

=

−=

Rac

Short IV Infusions

rate in over rate out


Short IV Infusions

( ))(

max,min,

max, 111/

tTaukssss

kTaukt

ss

eCCe

eCL

tdoseC

−−

−−

=

⎟⎠⎞

⎜⎝⎛−

⎟⎠⎞

⎜⎝⎛ −=

Tau-t

04 vancomycin pharmacokinetics20060830 - dr ted...

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