Pharmacokinetics in the Critically Ill

Pharmacokinetics in the critically ill

Department of

Intensive Care MedicineRoyal Brisbane Hospital University of Queensland

Professor Jeffrey Lipman

Pharmacokinetics in the critically ill

Department of

Intensive Care MedicineRoyal Brisbane Hospital University of Queensland

Professor Jeffrey LipmanUnless you understand this

DRUGS DON’T WORK

Intensive Care Med 2013; 39: 2070-2082

December 2013

Important conceptRecommended dosages are obtained from

healthy volunteers and possibly (ward) “sick” patients

Clinical pharmacology:drug development

Antibiotic regimens are derived from non-critically ill volunteers. Their haemodynamic system is normal, as is their liver and kidney blood flow. They have not leaky capillaries nor have they drips and pipes in every orifice.

SEPSIS

Increased Cardiac Output

Leaky Capillaries &/or altered protein binding

End Organ Dysfunction (e.g. renal or hepatic)

Increased CL Increased Vd Decreased CL

Low Plasma Concentrations

High Plasma Concentrations

Normal Organ Function

Normal Plasma Concentrations

Unchanged Vd

Roberts and Lipman Critical Care Medicine 2009; 37:840-851

LOW EXPOSURE TO ANTIBIOTICS ENABLES

DEVELOPMENT OF RESISTANCE

Critical Care Medicine August 2008;36:2433-40

Cmax Peak ConcentrationCmin Trough Concentrationt1/2 Half-life

V (or VD) Volume of distribution

AUC Area under curveCl Clearance

Protein binding

Antibiotic related IMPORTANTIMPORTANTpharmacokinetic parameters

Volume of Distribution

Gous et al Anaesth Intens Care 1995

Gous et al Anaesth Intens Care 1995

AMIKACIN DATA Marik P. Anaesth Intens Care 1993

….we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations.

35mg/kg loading 35mg/kg/day

Col

istin

CM

SSTANDARD DOSE INSUFFICIENT

Plachouras et al Antimicrob Agents Chemother 2009;53:3420-6

Antibiotics that stay in extravascular and extracellular space ie that don’t penetrate “solid” organs, (hydrophilic tendencies) namely AMINOGLYCOSIDES

GLYCOPEPTIDES

β-LACTAMS (to a lesser extent)

COLISTIN

VOLUME OF DISTRIBUTIONALTERATIONS IN ICU

DOSE ADJUSTMENT – MESSAGE 1

LOADING DOSE

INCREASED VOLUME OF DISTRIBUTION MEANS LOADING DOSE

TO “FILL UP ALL SPACES”

Critical Care Medicine March 2009Revised from Clinical Pharmacokinetics 2006

Increased CL


Increased CL


1

100

0 4 8 12

Time (hr)

Co

nc

en

tra

tio

n (

mg

/L) (A)

1

100

0 4 8 12

Time (hr)

Co

nc

en

tra

tio

n (

mg

/L)

(B)

1st dose Day 3-6

1. Cefpirome levels lower2. No difference between D1 vs later dose

CEFEPIME (O) vs CEFPIROME ()�

0

50

100

150

200

250

0 50 100 150 200 250 300Creatinine Clearance (mL/min)

Dru

g C

lea

ran

ce (m

L/m

in)

Cefepime CefpiromeLipman et al Anesth Analg 2003

Creatinine clearance

0

50

100

150

200

250

0 50 100 150 200 250 300Creatinine Clearance (mL/min)

Dru

g C

lea

ran

ce (m

L/m

in)

Cefepime Cefpirome

Creatinine clearance

Augmented Renal ClearanceCr Cl>130ml/min

Lipman et al Anesth Analg 2003

AUGMENTED RENAL CLEARANCE – who gets it?

Those manifesting ARC were younger (P <0.001), male (P = 0.012), with lower acute physiology and chronic health evaluation (APACHE) II (P= 0.008) and modified sequential organ failure assessment (SOFA) scores (P = 0.013), and higher cardiac indices (P = 0.013). In multivariate analysis, age ≤50 years, trauma, and a modified SOFA score ≤4, were identified as significant risk factors.


UDY et al Critical Care Medicine March 2014: 42 : 520-527

Measurements and Main Results: …. Overall, 65.1% manifested augmented renal clearance on at least one occasion during the first seven study days; themajority (74%) of whom did so on more than or equal to 50% of their creatinine clearance measures.

65.1%


AUGMENTED RENAL CLEARANCE – how long does it last?


Conclusions: Augmented renal clearance appears to be a common finding in this patient group, with sustained elevation of creatinine clearance throughout the first week in ICU.


IN SUMMARY

Younger patients who have an inflammatory response (any) with “normal” renal function

Particularly those that need fluid loading and or inotropic support to defend a blood pressure


AUGMENTED RENAL CLEARANCE

CHEST 2012; 142(1):30–39

Trough conc/MIC ratio vs Creat Cl

Udy et al Chest 2012;142:30-39

ARC pictorial explanation

Udy et al Clin Pharmacokinet 2010; 49:1-16

IF YOU DON’T LOOK PROPERLYYOU WON’T SEE IT.


INCREASE FREQUENCY

INCREASED CLEARANCES MEANS LOW TROUGHS

FOR AB’s THAT NEED t>MIC NEED TO INCREASE FREQUENCY

Critically ill patients have lowered protein concentrations and thus altered protein binding, unpredictable volumes of distribution, and vastly altered clearances compared to non-critically ill patients.

Protein binding

More than 40% of all patients had a baseline serum albumin concentration of 25 g/l or less

AT BASELINE

2006;333:1044

1

10

100

1000

0 200 400 600 800 1000 1200 1400 1600

Time (min)

Pla

sma

ceftr

iaxo

ne c

once

ntra

tion

(mg/

L)

Joynt et al J Antimicrob Chemother 2001

TOTAL UNBOUND/FREE

CEFTRIAXONE

ERTAPENEM 1GM/DAY (?..!)

Level ‘therapeutic’ target = 100% f T>MIC

DOSE INCR 1GM BD

DOSE INCR 1GM TDS

DOSE INCR 1GM TDSAS EXTENDED INFUSION

DOSE INCR 1GM TDSAS EXTENDED INFUSION

and only then did we get adequate levels!

More than 40% of all patients had a baseline serum albumin concentration of 25 g/l or less

AT BASELINE

2006;333:1044


INCREASE FREQUENCY

BEWARE HIGHLY PROTEIN BOUNDANTIBIOTICS

USUALLY MEANS QUICKER ELLIMINATION (in ICU)

Reviewed in Clinical Pharmacokinetics January 2011

Reviewed in Clinical Pharmacokinetics January 2013

Sepsis changes PK

Extracorporeal circuits

Altered CL and Increased Vd cf AKI

? Plasma concentrations

Kidney Filter

Ultrafiltrate Dialysate

FLOW

FLOW

Semi-permeable Membrane

(C)RRT(Continuous) Renal

Replacement Therapy

Ultrafiltrate

FLOW

Semi-permeable Membrane

CRRT Effects on Electrolytes and Water ..…

and Drugs.

+/- Dialysate

UrCr

K Ca PO4

UrCrCr

CrCr

UrUr

K Ca PO4

H2OH2O

FLOW

BEST WE HAVE

Choi et al Crit Care Med 2009;37:2268-82


COME DO A PhD WITH US

EXTRACORPOREAL CIRCUITS

??

Sepsis changes PK




If dosing does not account for these changes – sub-optimal therapy!

Sub-optimal patient outcomes

TDM DEFINITION

Therapeutic Drug Monitoring (TDM)

refers to analysis and subsequent interpretation of drug concentrations in biological fluids

PLACE

TDM should be used to

maximise efficacy

minimize toxicity

To personalise dosing for high probability of therapeutic success, prevent development of resistance, provide low probability of toxicity

AMINOGLYCOSIDES AND GLYCOPEPTIDES

Assays developed for side-effect profiles

Large market to prevent toxicity

Rapid turnaround, easy to use immunoassays


maximise efficacy

minimize toxicity

BETA-LACTAMS

Safe drugs

Large therapeutic range


maximise efficacyminimize toxicity

J Chromatogr B 2010;878:2039-2043

Roberts JA et al. Int J Antimicrob Agents 2010;36:332-39

Roberts JA, Hope WW, Lipman J. Int J Antimicrob Agents 2010;35:419-20

Roberts JA et al. Int J Antimicrob Agents 2010;36:332-39

A total of 236 patients were subject to TDM over an 11-month period. The mean ± standard deviation age was 53.5 ± 18.3 years. Dose adjustment was required in 175 (74.2%) of the patients, with 119 of these patients (50.4%) requiring dose increases after the first TDM.

Dose adjustment was required in 175 (74.2%)

For various reasons therapeutic drug monitoring (TDM) of most antibiotics is difficult but not impossible. We have set up a TDM service for all our beta-lactam use and have (not surprisingly ) shown that in more than half of our ICU patients we are dose adjusting once receiving back a drug level!

MESSAGE 5

MAIN DIFFERENCES IN ICU

Increased volume of distribution

Increased cardiac output

Increased hepatic and renal blood flows

Low serum proteins, hence protein binding

Increased clearances

Renal replacement techniques unique to ICUs

Sepsis changes PK




If dosing does not account for these changes – sub-optimal therapy!

Sub-optimal patient outcomes


LOADING DOSE

INCREASED VOLUME OF DISTRIBUTION MEANS LOADING DOSE

TO “FILL UP ALL SPACES”


INCREASE FREQUENCY

INCREASED CLEARANCES MEANS LOW TROUGHS

FOR AB’s THAT NEED t>MIC NEED TO INCREASE FREQUENCY


INCREASE FREQUENCY

BEWARE HIGHLY PROTEIN BOUNDANTIBIOTICS

USUALLY MEANS QUICKER ELLIMINATION (in ICU)


EXTRACORPOREAL CIRCUITS

??

For various reasons therapeutic drug monitoring (TDM) of most antibiotics is difficult but not impossible. We have set up a TDM service for all our beta-lactam use and have (not surprisingly ) shown that in more than half of our ICU patients we are dose adjusting once receiving back a drug level!

MESSAGE 5

THE END !

[email protected]

www.som.uq.edu.au/btccrc

Health & Medicine

Pharmacokinetics in the Critically Ill