pkpd for beginners

7/28/2019 PKPD for Beginners

1/31

PK/PD for the beginner

Winnie Lee

Pharmacy Department, SGH


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


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.


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.


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.


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


7/31

PK/PD Parameters

0

1

2

3

4

5

0 2 4 6 8 10 12 14

Time (h)

Concentration

AUC


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


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


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)


11/31

Why Apply PK/PD Principles?

ImprovedRates of Cure

Faster

Sterilization

Enhanced

Rate of

Response

DecreasedResistance


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


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.


14/31


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.


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.


17/31

EFFECT OF PK ON AST

Bioavailability


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


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


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


21/31

EFFECT OF PK ON AST

Distribution


22/31

Distribution (Vd)

Central i.e. blood &highly perfused organs

(heart, kidneys)

Peripheral Tissue

Muscle

Bone CSF

Eye

Tissue

penetration

Proteinbinding


23/31

Drug must get to where it is needed in

order for it to exert its action.


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


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.


26/31

EFFECT OF PD ON AST

Cidal vs Static activity


27/31

Lay Definitions

Static prevents microorganism growth

Cidal kills microorganisms

Are these really 2 pure

distinct categories?


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.


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.


30/31

Impact on AST

Cidal drugs beta-lactams, carbapenems, caspofungin

Static drugs macrolides, tigecycline, linezolid, fluconazole


31/31

Thank you!

pkpd for beginners

Documents