Transcript PK/PD results and evolution

8th ISAP Symposium
Can PK/PD be used
in everyday clinical practice?
Francesco Scaglione
Department of Pharmacology, Toxicology
and Chemotherapy,
University of Milan, Milan, Italy
PK/PD
results and evolution
Persistend effect
}
Time/Conc. dependent
activity
2000
?
Improvement Outcome
of dose and
resistance
intervals
}
Several objectives
resistance
Phase 2-3
clinical trial
Improvement of
therapy
PK/PD
evolution
2000
Custom-made therapy
In Vitro
and in vivo
activity
A
D
M
E
Effect over
the time;
Peculiar Effects
concentration (µg/ml)
Pharmacology : what for physician?
20
18
16
14
12
10
8
6
4
2
0
0
1
2
3
4
5 6 7
time h
8
9 10 11 12
Optimizing antimicrobial therapy
DRUG
PK
Concentration
at infection
site
Pathogen
MIC
Bacterial
kill
Pharmacodynamics = relationship between
concentration and effect
PHARMACODYNAMICS
PEAK/ MIC
c
AUC/MIC
MIC
T>MIC
t
Improving the probability of
positive outcomes
IMPROVING THE ODDS
HOST
BUG
DRUG
PK/PD parameters determining
efficacy
Absorption
 Serum levels
 Distribution and penetration to site of
infection
 Intracellular penetration
 Relationship of PK parameters to MIC

Peak level of tobramycin 3mg/kg
in ten patients in ICU
10.0
mg/L
7.5
5.0
2.5
0.0
FACTORS INVOLVED IN INLAMMATION
TNF- a
IL - 1
IL - 6
Trauma
Necrosis
Bacteria
PMN
MN
Lymphocytes
PAF
PGE
LTC
TXA
endothelial
Damage
Increase of
capillary
permeability
Protease
Complement
oxygen
Radicals
Oedema
VARIATIONS OF INTERSTITIAL FLUID DURING
INFECTIONS
blood
INTERSTITIAL
FLUID
Cells
THEORETICAL CONCENTRATION OF AN ANTIBIOTIC
Concentration
Serum
Interstitial
fluid
Large volume
compartment
Time
Concentration
Time Over MIC
Peak/MIC
M IC2
M IC1
‘Time above MIC’
Time
Ideal approach to adjust the dose
Initial dosing regimen(chosen by patient’s
physician)
Blood sampling( two or more postdistributional sample)
Pharmacokinetic analysis (peak,AUC,CL)
Adjust dose or/and intervals (PK/PD)
Redetermine concentrations
Adjust again ?
First problem
PK approach to adjust the dose is
poor applicable for routinely use
(at moment)
N°samples
 Personnel
 Costs
second problem
PK/PD breakpoints
betalactams
(ceftriaxone)
aminoglicosides
quinolones
glicopeptides
macrolides
tetraciclines
Program to customize the therapy
in 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 infusion
And T>MIC : 5.6 hours from start
infusion
mg/L
Concentrations of ceftazidime
and cefotaxime in serum
65
60
55
50
45
40
35
30
25
20
15
10
5
0
C 0.5 h
C 5.6 h
Peak levels of amikacin
mg/L
40
30
20
10
0
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 10 mg/kg OD to 15 mg/kg OD
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 Stenotrophomonas spp 4
Staphylococcus aureus 42
Legionella species
2
Enterobacter species
Citrobacter species
2
33
Klebsiella species
15
Acinetobacter
1
Escherichia coli
14
Proteus species
1
Haemophilus influenzae 11
Serratia marcescens
7
Streptococcus pneumoniae 4
Aminoglicosides
Dose adjusted according to creatinine
clearance
Creatinine clearance
mL/min
40
30
25
20
17
15
12
10
% of initial dose at
24h dosing interval:
92%
86
81
75
70
67
61
56
Ceftazidime-Cefotaxime-Levofloxacin
Dose adjusted according to creatinine
clearance
>50 mL/min: normal dose
20-50 mL/min: 1/2-3/4 normal dose
<20 mL/min: 1/4-1/2 normal dose
Ciprofloxacin
Dose adjusted according to creatinine
clearance
> 20 mL/min: normal dose
<20 mL/min: 1/2 normal dose
outcome
Length
failure mortality
hospitalization
- days*
PK/PD
11 (7-16)
39/223
11
analysed
(17.5%) (4.9%)
PK/PD
Not
analysed
16 (9-23 )
*From the diagnosis of infection
147/457
46
(31.9 %) (10.1%)
hospitalization days
correlation between time to adjust
the dose and hospitalisation days
20
15
10
5
0
0
25
50
75
100
125
150
hours to adjust doses
175
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
Conclusions IV
homework
When you came back at home, please
tray to convince Top Managers as well as
Physicians (mainly surgeons), that the
PK/PD approach is clinically and
economical advantageous