pkpd for beginners (4)

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PK/PD for the beginner

Winnie Lee

Pharmacy Department, SGH

Content

What is PD/PD?

Time-dependent

Concentration-dependent

Effect of PK on antibiotic susceptibility

Bioavailability

Distribution

Effect of PD on antibiotic susceptibilityCidal vs static

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In order for an antimicrobial to be

effective it must first reach the active

site of an organism in a sufficientquantity and remain there for an

adequate length of time to interruptnormal life functions of the organism.

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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.


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Adapted from: Craig WA. Pharmacokinetic/Pharmacodynamic Parameters: Rationale forAntibacterial Dosing of Mice and Men. CID, Jan 1998; 26:1-12.

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PHARMACOKINETICS PARAMETERS

Absorption

Not applicable to intravenous drugs

DistributionWhere 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

PK/PD Parameters

0

1

2

3

4

5

0 2 4 6 8 10 12 14

Time (h)

Concentration

AUC

Concentration-Dependent Bactericidal Activity

The rate and/or extent of

bactericidal activityincrease with increasingantimicrobialconcentrations.

The goal of a dosingregimen is to optimize thepeak:MIC. (Peak:MIC of10 to 20 is desired)


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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 thetime concentrations remainabove the MIC (t>MIC).

Pharmacodynamic (PD)parameters predictive of outcome

Parametercorrelating withefficacy Cmax:MIC AUC:MIC T>MIC

Examples Aminoglycosides

Fluoroquinolones

Azithromycin

Fluoroquinolones

Ketolides

Carbapenems

Cephalosporins

MacrolidesPenicillins

Organism kill Concentration-

dependent

Concentration-

dependent

Time-dependent

Therapeuticgoal

Maximiseexposure

Maximiseexposure

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)

Why Apply PK/PD Principles?

ImprovedRates of Cure

FasterSterilization

Enhanced

Rate ofResponse

DecreasedResistance

Optimising outcomes requires more than

just selecting the right drug

Optimising outcomes requires more than

just selecting the right drug

Infection

Host defences

BacteriaHost

Drug

Right drug

+

Right dose

McKinnon, Davis. Eur J Clin MicrobiolInfect Dis 2004;23:271288


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EUCAST Approach

PK/PD Breakpoints (Clinical, non-species)

Definition of susceptibleA microorganism is defined as susceptible by a level

of antimicrobial activity associated with a highlikelihood of therapeutic success

Setting breakpoints involves clinical resultsfrom various types of study, wildtype MIC

distributions 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.

Deriving breakpoints from PDT

Ceftazidime

Ref: Mouton JW et al. The role of PK/PD in setting c linical breakpoints: the EUCAST approach.

Clin Microb Infect 2012; 18: E37-E45.

Probability of Target Attainment

Ceftazidime

Ref: Mouton JW et al. The role of PK/PD in setting c linical breakpoints: the EUCAST approach.

Clin Microb Infect 2012; 18: E37-E45.


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EFFECT OF PK ON AST

Bioavailability

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

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

Penicillin

F = 60% to 73%

Affected by gastric pH

as natural penicillins aresusceptible to

hydrolysis

Pen-G IV: S < 2; R > 8

Pen V PO: S < 0.06; R >

2


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EFFECT OF PK ON AST

Distribution

Distribution (Vd)

Central i.e. blood &

highly perfused organs(heart, kidneys)

Peripheral

Tissue

Muscle

Bone

CSF

Eye

Tissue

penetration

Proteinbinding

Drug must get to where it is needed in

order for it to exert its action.

Streptococcus

Meningitis

1. Cefepime

S < 0.5; R > 2

2. Ceftriaxone

S < 0.5; R > 2

3. Penicill in

S < 0.06; R > 0.12

Non-meningitis

1. Cefepime

S < 1; R > 4

2. Ceftriaxone

S < 1; R > 4

3. Penicill in

S < 2; R > 8


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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. ClinMicro Rev 2010; p858-883.

EFFECT OF PD ON AST

Cidal vs Static activity

Lay Definitions

Static prevents microorganism growth

Cidal kills microorganisms

Are these really 2 pure

distinct categories?

Microbiological Definitions

Minimum bactericidal concentration (MBC)lowest concentration of an antibacterial agent that

either totally prevents growth or results in a >99.9%decrease in the initial inoculum (i.e., a 3-log10reduction in colony-forming units [cfu]/mL) onsubculture.

Time-kill curves

Serum bactericidal titerSBT is the greatest serum dilution that usually kills

99.9% of the initial bacterial inoculum after incubationfor 1824 h.


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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.

Impact on AST

Cidal drugs beta-lactams, carbapenems, caspofungin

Static drugs macrolides, tigecycline, linezolid, fluconazole

Thank you!

pkpd for beginners (4)

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