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 susceptibility

Cidal vs static

In order for an antimicrobial to be

effective it must first reach the active site of an organism in a sufficient quantity and remain there for an adequate length of time to interrupt normal 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 including pharmacologic action.

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

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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
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PK/PD Parameters

5 Concentration 4

3
2 1 0 0 2 4 6 8 Time (h) 10 12 14

AUC

Concentration-Dependent Bactericidal Activity

The rate and/or extent of bactericidal activity increase with increasing antimicrobial concentrations. The goal of a dosing regimen is to optimize the peak:MIC. (Peak:MIC of 10 to 20 is desired)

1.0E+07 1.0E+05

1.0E+03 1.0E+01 0 5
Control 0.5xMIC 4xMIC

10
0.125xMIC 1xMIC 8xMIC

15
0.25xMIC 2xMIC 16xMIC

20

Concentration-Independent Bactericidal Activity

The rate and extent of killing do not increase with increasing antibiotic concentrations. Bactericidal activity is increased by increasing the length of exposure. The goal of dosing regimens is to optimize the time concentrations remain above the MIC (t>MIC).

1.0E+07

1.0E+05

1.0E+03

1.0E+01 0 10
Control 4xMIC

20
0.5xMIC 8xMIC

30
MIC 16xMIC

40
2xMIC 32xMIC

50

Pharmacodynamic (PD) parameters predictive of outcome

Parameter correlating with efficacy Examples Cmax:MIC AUC:MIC Aminoglycosides Azithromycin Fluoroquinolones Fluoroquinolones Ketolides Concentrationdependent Maximise exposure Concentrationdependent Maximise exposure T>MIC Carbapenems Cephalosporins Macrolides Penicillins Time-dependent

Organism kill

Therapeutic goal

Optimise duration 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?

Improved Rates of Cure

Decreased Resistance

Faster Sterilization

Enhanced Rate of Response

Optimising outcomes requires more than just selecting the right drug
Drug Right drug + Right dose

Infection

Bacteria
Host defences

Host

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

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 high likelihood of therapeutic success

Setting breakpoints involves clinical results from 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 clinical 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 clinical breakpoints: the EUCAST approach. Clin Microb Infect 2012; 18: E37-E45.

Bioavailability

EFFECT OF PK ON AST

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 are susceptible to hydrolysis Pen-G IV: S < 2; R > 8 Pen V PO: S < 0.06; R > 2

Distribution

EFFECT OF PK ON AST

Distribution (Vd)
Central i.e. blood & highly perfused organs (heart, kidneys) Peripheral
Tissue Muscle Bone CSF Eye
Protein binding

Tissue penetration

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. 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

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.

Cidal vs Static activity

EFFECT OF PD ON AST

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-log10 reduction in colony-forming units [cfu]/mL) on subculture.

Time-kill curves Serum bactericidal titer

SBT is the greatest serum dilution that usually kills 99.9% of the initial bacterial inoculum after incubation for 1824 h.

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!