PK/PD: TOWARDS DEFINITIVE CRITERIA

PK/PD in clinical Practice:new level of PK/PD

Francesco Scaglione Department of Pharmacology, Toxicology and Chemotherapy, University of Milan, Milan, Italy

PK/PD results and evolution

2000

Persistend effect

Time/Conc. dependent activity

}Improvement of dose and intervals

}Outcome

resistance

?

Several objectives of PK/PD

Phase 2-3 clinical trial

resistanceImprovement of therapy

PK/PD evolution

Custom-made therapy

2000

Effect overEffect over the time;the time;

Peculiar EffectsPeculiar Effects

Effect overEffect over the time;the time;

Peculiar EffectsPeculiar Effects

AADDMMEE

AADDMMEE

In VitroIn Vitroand in vivoand in vivo

activityactivity

In VitroIn Vitroand in vivoand in vivo

activityactivity

Pharmacology : what for physician?

0

2

4

6

810

12

1416

18

20

0 1 2 3 4 5 6 7 8 9 10 11 12time h

conc

entr

atio

n (µ

g/m

l)

Considerations when choosing an antibacterial agent

Pathogen MIC

Drug

Absorption Distribution Metabolism Excretion Optimal

dosing regimen

Concentration at infection

site

Outcome

Clinical efficacy Bacterial eradication Compliance with

dosing regimen Tolerability Rate of resolution Prevention of

resistance

PD Time- vs concentration-

dependent killing Bactericidal vs bacteriostatic

activity Tissue penetration Persistence of antibacterial effect

PK

Microbiology Mechanism of

action Antibacterial

spectrum

Time (hours)0

MIC

Peak/MIC

AUC/MIC

Time >MIC

PAE

PK/PD parameters affecting efficacyConcentration

Improving the probability of positive outcomes

IMPROVING THE ODDS

HOST

BUG

DRUG

PK/PD parameters determining efficacy AbsorptionAbsorption Serum levelsSerum levels Distribution and penetration to site of Distribution and penetration to site of

infectioninfection Intracellular penetrationIntracellular penetration Relationship of PK parameters to MICRelationship of PK parameters to MIC

Infections are treated with the same dosing regimen irrespective of the absolute susceptibility of the microrganisms as well as the PK of the actual patient

In clinical practice

Aminoglycoside dosing characteristics for 78 patients with pneumonia caused by gram-

negative bacteria

VariableBefore IPM (n = 78)

After IPM (n = 60)

Aminoglycoside dose (mg)a 105 (90-140)

230 (175-320)

Cmax (µg/ml)a 5.3 (3.9-6.3) 6.7 (5.2-7.6)

Cmin (µg/ml)a 0.6 (0.3-1.1) 0.8 (0.5-1.1)

a Values are medians (interquartile ranges).

Adapted from Angela D. M. Kashuba; AAC 1999

Aminoglycoside pharmacokinetic and pharmacodynamic variables for 78 patients with pneumonia caused by

gram-negative bacteria

VariableMedian (interquartile

range)

Aminoglycoside CL (ml/min/1.73 m2)

Aminoglycoside half-life (h)

AUC0-24 (µg · h/ml)

First Cmax/MIC

Second Cmax/MIC

71.5 (50.4-91.3)

3.5 (2.6-5.0)

52.2 (34.5-77.5)

3.6 (1.4-6.2)

3.7 (1.9-6.9)

Adapted from Angela D. M. Kashuba; AAC 1999

Peak level of tobramycin 3mg/kg in ten patients in ICU

0.0

2.5

5.0

7.5

10.0

mg

/L

Trauma

FACTORS INVOLVED IN INFLAMMATION

Complement

Necrosis

Bacteria

PMNMN

Lymphocytes

TNF- IL - 1IL - 6

PAFPGELTCTXA

Protease

oxygen Radicals

endothelialDamage

Increase of capillary

permeability

Oedema

VARIATIONS OF INTERSTITIAL FLUID DURING INFECTIONS

bloodINTERSTITIAL

FLUID

Cells

THEORETICAL CONCENTRATION OF AN ANTIBIOTIC

Time

Serum

Interstitial fluid

Con

cent

ratio

n Large volume compartment

0 1 2 3 4 5 6 70

10

20

30

40

50

days

L

Vd of Tobramicin in 13 patients admitted in ICU

0 1 2 3 4 5 6 70.0

2.5

5.0

7.5

10.0

days

mg

/L

Serum peak of Tobramicin in 13 patients admitted in ICU

‘‘Time above MIC’Time above MIC’

Co

nce

ntr

atio

nC

on

cen

trat

ion

M ICM IC11

TimeTime

M ICM IC22

Time Over MICPeak/MIC

Ideal approach to adjust the doseInitial dosing regimen(chosen by patient’s physician)

Blood sampling( two or more post-distributional sample)

Pharmacokinetic analysis (peak,AUC,CL)

Adjust dose or/and intervals (PK/PD)

Redetermine concentrations

Adjust again ?

First problemPK approach to adjust the dose is poor applicable for routinely use (at moment)

N°samples Personnel CostsMicrobiology

second problemPK/PD breakpoints

betalactams (ceftriaxone)

aminoglicosides

quinolones

glicopeptides

macrolides

tetraciclines

Program to customize the therapyin our hospital

Isolation of the pathogen and MIC

Design therapy traditionally(by patient’s physician)

Pharmacokinetic

Adjust dose or interval using PK/PD

Redetermine concentrations

PK/PD values adopted

•Aminoglicosides Peak/MIC 8•Quinolones peak/MIC 10 •Betalactams peak/MIC 4

and T>MIC 70%

same value for monotherapy or combination

Sampling time

•Aminoglicosides Peak : 0.5 h from end 30 min infusion•Quinolones peak : 0.5 h from end 60 min infusion•Betalactams peak :0.5 h from end 30 min infusionAnd T>MIC : 5.6 hours from start infusion

Concentrations of ceftazidime and cefotaxime in serum

05

101520253035404550556065

mg

/L

C 0.5 h C 5.6 h

Peak levels of amikacin

0

10

20

30

40

mg

/L

PK/PD dose adjustment

Levofloxacin 500 mg to 750 OD or BID

Ciprofloxacin 500mg to 750 BID

Cefotaxime-Ceftazidime 2g q 8 to 2g q6

Amikacin 15 mg/kg OD to 20 mg/kg OD*

* Patients are daily monitored for safety

preliminary results

October 2000 – April 2001

Patients included 680

Evaluated for PK/PD 223 (32.8%)

Dose or interval adjusted 84 (37.7%)

Adjustment failed in 6 (5 cipro -1 amikacin)

diagnosis

Nosocomial pneumonia 105

Sepsis 44

upper UTI 57

Necrotizing Fascitis 8

Others 9

Organisms isolated

Pseudomonas aeruginosa 87

Staphylococcus aureus 42

Enterobacter species 33

Klebsiella species 15

Escherichia coli 14

Haemophilus influenzae 11

Serratia marcescens 7

Streptococcus pneumoniae 4

Stenotrophomonas spp 4

Legionella species 2

Citrobacter species 2

Acinetobacter 1

Proteus species 1

outcome

Length Length hospitalizationhospitalization

- days- days**

failurefailure

PK/PD PK/PD analysedanalysed

11 (7-16)11 (7-16) 39/223 39/223 (17.5%)(17.5%)

PK/PDPK/PD

Not Not analysedanalysed

16 (9-23 )16 (9-23 ) 147/457147/457

(31.9 %)(31.9 %)

*From the diagnosis of infection

0 25 50 75 100 125 150 1750

5

10

15

20

hours to adjust doses

ho

spit

aliz

atio

n d

ays

correlation between time to adjust the dose and hospitalisation days

Conclusions I

The PK/PD approach may:

improve the outcome

shorten the time to clinical improvement

Reduce the length of hospitalisation

Conclusions II

The initial higher costs for analysis and personnel are compensate for the reduction of the hospitalisation, with a financial gain

Conclusions III

Can PK/PD be used

in everyday clinical practice?

yes