View
230
Download
0
Category
Preview:
Citation preview
7/28/2019 PKPD for Beginners
1/31
PK/PD for the beginner
Winnie Lee
Pharmacy Department, SGH
7/28/2019 PKPD for Beginners
2/31
Content
What is PD/PD?
Time-dependent
Concentration-dependent
Effect of PK on antibiotic susceptibility
Bioavailability
Distribution
Effect of PD on antibiotic susceptibility
Cidal vs static
7/28/2019 PKPD for Beginners
3/31
9/19/2013 3
In o rder for an ant im icrobial to be
effect ive i t mus t f i rstreachthe act ive
si te of an organism in a su ff ic ient
quant i ty andremainthere for anadequate leng th o f t ime tointerrupt
normal life functions of the organism.
7/28/2019 PKPD for Beginners
4/31
9/19/2013 4
PHARMACOKINETICS:
Describes the way that the body handles a drug.
PHARMACODYNAMICS:
Describes the characteristics of the interaction
between a drug and its active site includingpharmacologic action.
7/28/2019 PKPD for Beginners
5/31
9/19/2013 5
Adapted from: Craig WA. Pharmacokinetic/Pharmacodynamic Parameters: Rationale for
Antibacterial Dosing of Mice and Men. CID, Jan 1998; 26:1-12.
7/28/2019 PKPD for Beginners
6/31
9/19/2013 6
PHARMACOKINETICS PARAMETERS
Absorption
Not applicable to intravenous drugs
Distribution
Where the drug goes to in the body
Apparent volume of distribution (Vd)
Metabolism
E.g. active metabolites (macrolides)
Elimination Renal clearance
Hepatic / biliary clearance
Miscellaneous e.g. oxidation
7/28/2019 PKPD for Beginners
7/31
PK/PD Parameters
0
1
2
3
4
5
0 2 4 6 8 10 12 14
Time (h)
Concentration
AUC
7/28/2019 PKPD for Beginners
8/31
Concentration-Dependent Bactericidal Activity
The rate and/or extent ofbactericidal activityincrease with increasing
antimicrobialconcentrations.
The goal of a dosingregimen is to optimize thepeak:MIC. (Peak:MIC of10 to 20 is desired)
1.0E+01
1.0E+03
1.0E+05
1.0E+07
0 5 10 15 20
Control 0.125xMIC 0.25xMIC
0.5xMIC 1xMIC 2xMIC
4xMIC 8xMIC 16xMIC
7/28/2019 PKPD for Beginners
9/31
Concentration-Independent Bactericidal Activity
The rate and extent ofkilling do notincrease withincreasing antibioticconcentrations.
Bactericidal activity isincreased by increasing thelength of exposure.
The goal of dosingregimens is to optimize the
time concentrations remainabove the MIC (t>MIC).
1.0E+01
1.0E+03
1.0E+05
1.0E+07
0 10 20 30 40 50
C ontrol 0.5xMIC MIC 2xMIC
4xMIC 8xMIC 16xMIC 32xMIC
7/28/2019 PKPD for Beginners
10/31
Pharmacodynamic (PD)
parameters predictive of outcome
Parametercorrelating withefficacy Cmax:MIC AUC:MIC T>MIC
Examples Aminoglycosides
Fluoroquinolones
Azithromycin
Fluoroquinolones
Ketolides
Carbapenems
Cephalosporins
Macrolides
Penicillins
Organism kill Concentration-
dependent
Concentration-
dependent
Time-dependent
Therapeuticgoal
Maximise
exposure
Maximise
exposure
Optimiseduration
of exposure
Drusano, Craig. J Chemother 1997;9:3844;
Drusano, et al. Clin Microbiol Infect 1998;4(Suppl. 2):S27S41;
Vesga, et al. 37th ICAAC (1997)
7/28/2019 PKPD for Beginners
11/31
Why Apply PK/PD Principles?
ImprovedRates of Cure
Faster
Sterilization
Enhanced
Rate of
Response
DecreasedResistance
7/28/2019 PKPD for Beginners
12/31
Optimising outcomes requires more than
just selecting the right drug
Infection
Hostdefences
BacteriaHost
Drug
Right drug
+
Right dose
McKinnon, Davis. Eur J Clin Microbiol Infect Dis 2004;23:271288
7/28/2019 PKPD for Beginners
13/31
EUCAST Approach
PK/PD Breakpoints (Clinical, non-species)
Definition of susceptible
A microorganism is defined as susceptible by a level
of antimicrobial activity associated with a highlikelihoodof therapeutic success
Setting breakpoints involves clinical resultsfrom various types of study, wildtype MICdistributions for relevant species of organisms,antimicrobial dosing and PK/PD of antibiotic
Ref: Mouton JW et al. The role of PK/PD in setting clinical breakpoints: the EUCAST
approach. Clin Microb Infect 2012; 18: E37-E45.
7/28/2019 PKPD for Beginners
14/31
7/28/2019 PKPD for Beginners
15/31
Deriving breakpoints from PDT
Ceftazidime
Ref: Mouton JW et al. The role of PK/PD in setting clinical breakpoints: the EUCAST approach.Clin Microb Infect 2012; 18: E37-E45.
7/28/2019 PKPD for Beginners
16/31
Probability of Target Attainment
Ceftazidime
Ref: Mouton JW et al. The role of PK/PD in setting clinical breakpoints: the EUCAST approach.Clin Microb Infect 2012; 18: E37-E45.
7/28/2019 PKPD for Beginners
17/31
EFFECT OF PK ON AST
Bioavailability
7/28/2019 PKPD for Beginners
18/31
Bioavailability (F)
Measurement of the rate & extent to which a
drug reaches the systemic circulation
(Absorption)
Intravenous 100%
Oral 55% to >90%
Highly variable due to multiple factors e.g.
GI transit time
Drug-drug and drug-food interaction
7/28/2019 PKPD for Beginners
19/31
Cefuroxime axetil
F = 36% (fasting) to 52%
(post-meal)1
Acetoxyethyl-ester prodrug
EUCAST2 for S. pneumoniae
For IV, S: < 0.5 mcg/ml; R:
>1 mcg/ml
For PO, S: < 0.25mcg/ml; I:> 0.5 mcg/ml
Ref:
1. Finn, A., A. Straughn, M. Meyer, and J. Chubb. 1987. Effect of dose and food on
the bioavailability of cefuroxime axetil. Biopharm. Drug Dispos. 8:519-526.
2. EUCAST Ver 2.0
7/28/2019 PKPD for Beginners
20/31
Penicillin
F = 60% to 73%
Affected by gastric pH
as natural penicillins are
susceptible tohydrolysis
Pen-G IV: S < 2; R > 8
Pen V PO: S < 0.06; R >2
7/28/2019 PKPD for Beginners
21/31
EFFECT OF PK ON AST
Distribution
7/28/2019 PKPD for Beginners
22/31
Distribution (Vd)
Central i.e. blood &highly perfused organs
(heart, kidneys)
Peripheral Tissue
Muscle
Bone CSF
Eye
Tissue
penetration
Proteinbinding
7/28/2019 PKPD for Beginners
23/31
Drug must get to where it is needed in
order for it to exert its action.
7/28/2019 PKPD for Beginners
24/31
Streptococcus
Meningitis
1. Cefepime
S < 0.5; R > 2
2. Ceftriaxone
S < 0.5; R > 2
3. Penicillin
S < 0.06; R > 0.12
Non-meningitis
1. Cefepime
S < 1; R > 4
2. Ceftriaxone
S < 1; R > 4
3. Penicillin
S < 2; R > 8
7/28/2019 PKPD for Beginners
25/31
Ref: Nau R, Sorgel F, Eiffert H. Penetration of drugs through the blood-cerebrospinal fluid / blood-brain barrier for treatment of central nervous
system infections. Clin Micro Rev 2010; p858-883.
7/28/2019 PKPD for Beginners
26/31
EFFECT OF PD ON AST
Cidal vs Static activity
7/28/2019 PKPD for Beginners
27/31
Lay Definitions
Static prevents microorganism growth
Cidal kills microorganisms
Are these really 2 pure
distinct categories?
7/28/2019 PKPD for Beginners
28/31
Microbiological Definitions
Minimum bactericidal concentration (MBC)
lowest concentration of an antibacterial agent thateither totally prevents growth or results in a >99.9%decrease in the initial inoculum (i.e., a 3-log10
reduction in colony-forming units [cfu]/mL) onsubculture.
Time-kill curves
Serum bactericidal titer SBT is the greatest serum dilution that usually kills
99.9% of the initial bacterial inoculum after incubationfor 1824 h.
7/28/2019 PKPD for Beginners
29/31
Clinical Utility
Lack of strong correlation between clinical
efficacy and microbiologic definition
One abx class that is generally bactericidal can
be bacteriostatic if used at low concentrations
or against particular microbes
? Usefulness of performing MBC routinely.
7/28/2019 PKPD for Beginners
30/31
Impact on AST
Cidal drugs beta-lactams, carbapenems, caspofungin
Static drugs macrolides, tigecycline, linezolid, fluconazole
7/28/2019 PKPD for Beginners
31/31
Thank you!
Recommended