Download Scaglione

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
Persistend effect
}
Time/Conc. dependent
activity
2000
?
Improvement Outcome
of dose and
resistance
intervals
}
Several objectives of PK/PD
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
Considerations when choosing
an antibacterial agent
Microbiology


Mechanism of
action
Concentration
at infection
site
Antibacterial
spectrum
Outcome
Drug
Pathogen
MIC
PK

Absorption

Distribution

Metabolism

Excretion

Optimal
dosing
regimen

Clinical efficacy

Bacterial eradication

Compliance with
dosing regimen
Time- vs concentrationdependent killing

Tolerability

Rate of resolution

Bactericidal vs bacteriostatic
activity

Prevention of
resistance

Tissue penetration

Persistence of antibacterial effect
PD

PK/PD parameters affecting
efficacy
Concentration
Peak/MIC
AUC/MIC
Time >MIC
MIC
PAE
0
Time (hours)
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

In clinical practice
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
Aminoglycoside dosing characteristics for 78 patients
with pneumonia caused by gram-negative bacteria
Variable
Aminoglycoside dose
(mg)a
Cmax (µg/ml)a
Cmin (µg/ml)a
a
Before IPM
(n = 78)
After IPM
(n = 60)
105 (90-140)
230 (175-320)
5.3 (3.9-6.3)
6.7 (5.2-7.6)
0.6 (0.3-1.1)
0.8 (0.5-1.1)
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
Variable
Median (interquartile range)
Aminoglycoside CL (ml/min/1.73
m2)
71.5 (50.4-91.3)
Aminoglycoside half-life (h)
AUC0-24 (µg · h/ml)
3.5 (2.6-5.0)
52.2 (34.5-77.5)
First Cmax/MIC
3.6 (1.4-6.2)
Second Cmax/MIC
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
10.0
mg/L
7.5
5.0
2.5
0.0
FACTORS INVOLVED IN INFLAMMATION
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
Vd of Tobramicin in 13 patients
admitted in ICU
50
40
L
30
20
10
0
0
1
2
3
4
days
5
6
7
mg/L
Serum peak of Tobramicin in
13 patients admitted in ICU
10.0
7.5
5.0
2.5
0.0
0
1
2
3
4
days
5
6
7
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
Microbiology
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 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 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
outcome
Length
failure
hospitalization
- days*
PK/PD
11 (7-16)
39/223
analysed
(17.5%)
PK/PD
Not
analysed
16 (9-23 )
*From the diagnosis of infection
147/457
(31.9 %)
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