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PK-PD of ANTIBIOTICS

N A F R I A L D IDepartment of Pharmacology

Faculty of Medicine, University of Indonesia

Jakarta Antimicrobial UpdateApril 12, 2013

INTRODUCTION

Successful antibiotic (AB) treatment depends on:

• Intrinsic sensitivity of bacteria to AB• Sufficient AB concentration at the site of

infection for a sufficient duration.• But must remain below toxic level

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INTRODUCTION

• In vitro activity is only a guide as to whether an AB is likely to be effective for an infection.

• Pharmacokinetics describes the time course of drug concentration in plasma or other body fluid

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INTRODUCTION

– MIC is the parameter of Intrinsic sensitivity – However:

• In vitro efficacy does not always indicates clinicalefficacy

• MIC is very variable from pathogen to pathogen• Drug concentration is timely variable• Some infection occur outsite blood circulation

• To be therapeutically effective, the minimal drug concentration at the infected site should be at least equal to MIC

• In most instances it is advisable to achieve multiples of this concentration.

INTRODUCTION

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Pharmacokinetic Parameters

• Three most important PK parameters:– Cmax (peak serum concentration) – Cmin (trough level)

– AUC (Area Under the serum concentration time Curve).

• PK parameters quantify the serum level time course, but they do not describe the killing activity of an antibiotic.

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PK-PD

• Integrating the PK parameters with the MIC gives three PK-PD parameters which quantify the activity of an antibiotic.

• PK-PD parameters:– Peak / MIC – T > MIC– AUC24h / MIC.

PK-PD

PK-PD is aimed to design appropriate dosage regimen:

– To obtain a successful therapy– Avoiding toxicity– Preventing emergent of resistance

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PK-PD Parameters

• Based on the exisrtence of persistent effectsAM pattern can be classified into 3 groups:1. Concentration dependent with moderate to

prolonged persistent effects2. Time-dependent killing with minimal to

moderate persistent effects3. Time-dependent killing with prolonged

persistent effects

Patterns of Antimicrobial Activity

• Telithromycin: Higher dose à higher killing activity• Azithromycin and Clarithromycin: no good correlation between

dose and killing activity

Time vs Concentration Dependent Killing

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– PK parameters• Cmax/MIC: 8-10• AUC24h/MIC : 25-125

– Goal of treatment: • maximize concentrations• optimize amount of drug

– Single dose may be better and safer• Aminoglycosides, Flouroquinolones, Ketolides, metronidazole, Ampho B.

1. Concentration Dependent Killing

• Tobramycin and Ciprofloxacin: Higher dose à higher killing activity• Ticarcillin: same response rate with drug level 4, 16, and 64

timesMIC

• Relationship between Cmax/MIC ratio and the rate of clinical response

• N = 236 patients, Gram-negative bacterial infections

• Aminoglycosides (gentamicin, tobramycin, amikacin)

• Response rate attained submaximal respons with Peak/MIC ratio > 8.

Moor et al. 1984 J. Infect. Dis.

2 4 6 8 10 12

60

80

100

Maximum Cmax/MIC ratio

Res

pons

e ra

te (%

)

Cmax /MIC ratio need to attain 8-10

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Ceftazidim: Time dependent killing

ØPK parameter: T > MIC (Time above MIC) ØEffective T > MIC : 40-50% (mostly for Gr +)ØGoal of treatment: maximize duration of exposureØSlow infusion is betterØIf using T > MIC, a value of 70% may be needed

(mostly Gram -)§ Beta lactam, macrolides, clindamycin, flucytosine, linezolid

2. Time-dependent Killing(with prolong persistent effects )

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Percentage bacteriologic cure for ß-lactam agents against Streptococcus pneumoniae (black circle) and Haemophilus influenzae (white circle) in children with acute otitis media

Craig WA, Andes W.. Pediatr Infect Dis J 1996;15:255-9.

Time above MIC vs Bacteriologic cure

3. Time-dependent Killing(with minimal to moderate persistent effects)

Ø PK parameter: AUC24h/MICØ Goal of treatment: optimize amount of

drugØ Effective AUC24h/MIC: 25-125§ Azithromycin, vancomycin, tetracyclines, fluconazole

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• AUC24h/MIC of Fluoroquinolones

Gram positive : AUC/MIC needed: 25-125

Gram negative : AUC/MIC needed: 100-250

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How to Perform PK-PD

• Unlike the sensitivity test, the data of Cmaxand AUC is not routinely performed in patient setting.

• It needs serial measures of drug concentration• Thus, PK-PD is normally performed in animal

model• The magnitude of PK/PD parameters required

for efficacy is relatively similar in different animal species and human being

Strategies to Increase % Time>MIC (Example of Doripenem)

vGive a higher dose

v Increase duration of infusionØProlonged infusion

• Same dose and dosing interval, but prolong the duration of infusion

ØContinuous infusion• Loading dose, followed by total daily dose over 24

hours infusion

Nicolau DP. Pharmacodynamic optimization of beta-lactams in the patient care setting. Crit Care. 2008;12 Suppl 4:S2. Epub 2008 May 21.

vDoripenem is the only approved carbapenem for 1-hour and 4-hour extended infusion1

vHighest Cummulative Fraction Response (CFR) against P. aeruginosa in comparison with imipenem and meropenem2

vSuperior stability vs. other carbapenems for extended infusion3,4,5

CFR : Cumulative Fraction of Response

1. DORIBAX Prescribing Information (Malaysia) 2008.2. Roberts JA, Kwa A, Montakantikul P, Gomersall C, Kutie JL, Nicolau DP. Pharmacodynamic profiling of intravenous antibiotics against prevalent Gram-negative organisms across the

globe: the PASSPORT Program—Asia Pacific Region. International Journal of Antimicrobial Agents 37 (2011) 225–229.3. DORIBAX (doripenem for injection) [European Public Assessment Report]. Janssen-Cilag International NV., Beerse, Belgium.4. Meronem® I.V. (meropenem for injection) [Summary of Product Characteristics]. AstraZeneca UK Ltd., Luton, UK.5. Primaxin® I.V. (imipenem and cilastatin for injection) [Summary of Product Characteristics]. Merck Sharp & Dohme Ltd., Hoddesdon, UK.

Strategies to Increase % Time>MIC (Example of Doripenem)

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DORIBAX IS THE ONLY APPROVED CARBAPENEM FOR 1-HOUR INFUSION AND 4-HOUR EXTENDED INFUSION4-Hour Infusion Allows Targeting of Higher MICs

Without Increasing the Dose

*Optional infusion time for NP/VAP patients who are at risk for infections with less susceptible pathogens.

DORIBAX Prescribing Information (Malaysia) 2008.

500 mg IV administered over 1 h500 mg IV administered over 4 h*

25

20

15

10

5

00 1 2 3 4 5 6 7 8

Time (hours)

Concentration (µg/mL)

DORIBAX Prescribing Information (Malaysia) 2008.

Improved Doripenem Targeting of Higher MICs with 4-hour Infusion

100%

0

20

40

60

80

100

MIC, µg/mL

Target Attainment,

%

0.06 0.12 0.25 0.5 1 2 4 8 16

Doripenem 500 mg q8h, 1-h infusion

Doripenem 500 mg q8h, 4-h infusion

35%

78%

95%

CUMULATIVE FRACTION OF RESPONSE (CFR)

PASSPORT: Probability of target attainment of Antibacterial agents Studied for Susceptibility and Pharmacodynamic Optimization in Regional Trials

Roberts JA, Kwa A, Montakantikul P, Gomersall C, KutieJL, Nicolau DP. Pharmacodynamic profiling of intravenous antibiotics against prevalent Gram-negative organisms across the globe: the PASSPORT Program—Asia Pacific Region. International Journal of Antimicrobial Agents 37 (2011) 225–229.

vCFR is the possibility that the antibiotic regimen will reach its pharmacodynamic index against the entire population of organismsvThe PASSPORT analysis showed that doripenem has

the highest CFR against P. aeruginosa in comparison with imipenem and meropenemvAgainst P. aeruginosa, doripenem 1 gm and 2 gm

extended infusion achieved > 90% CFR

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Doripenem has the highest CFR against P. Aeruginosa

Roberts JA, Kwa A, Montakantikul P, Gomersall C, Kutie JL, Nicolau DP. Pharmacodynamic profiling of intravenous antibiotics against prevalent Gram-negative organisms across the globe: the PASSPORT Program—Asia Pacific Region. International Journal of Antimicrobial Agents 37 (2011) 225–229.

Doripenem achieved 79 –93 % CFRImipenem achieved 60–79 % CFR Meropenem achieved 73 –85 %CFR

DoripenemImipenem Meropenem

74.6

79

60.4

68.6

76.9

68.4

78.7

86.7

83.7

9087.7

92.6

73

76.2

78.377.8

81.8 81.8

85.1

Cum

ulat

ive

Frac

tion

of R

espo

nse

(%)

1. DORIBAX (doripenem for injection) [European Public Assessment Report]. Janssen-Cilag International NV., Beerse, Belgium.2. Meronem® I.V. (meropenem for injection) [Summary of Product Characteristics]. AstraZeneca UK Ltd., Luton, UK.3. Primaxin® I.V. (imipenem and cilastatin for injection) [Summary of Product Characteristics]. Merck Sharp & Dohme Ltd., Hoddesdon, UK.

DORIPENEM Provides a Favourable Stability Following Reconstitution

Stability Time, h

Diluent Room Temperature

2-80C(Refrigerator)

DORIPENEM Normal Saline 12 72*

Imipenem Normal Saline 3 24

Meropenem Normal Saline 8 48

Doripenem 5% Dextrose 4 24*

Imipenem 5% Dextrose 3 24

Meropenem 5% Dextrose 3 14

* Once removed from the refrigerator, infusions should be completed within the room temperature stability time,provided the time does not exceed refrigeration stability time.

Keel RA, Sutherland CA, Crandon JL, Nicolau DP. Stability of doripenem, imipenem and meropenem at elevated room temperatures. Int J AntimicrobAgents. 2011 Feb;37(2):184-5. Epub 2010 Aug 10.

DORIPENEM Has Superior Stability at Elevated Room Temperatures

Temperature

300C 350C 400C

DORIPENEM 16 h 12 h 8 h

Imipenem 6 h 4 h 3 h

Meropenem 12 h 8 h 6 h

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CONCLUSIONS

• PK/PD of antibiotic is aimed to develop a more effective dosage regimen– To obtain successful treatment while avoiding the toxicity

and the emergence of antibiotic resistance.

• Optimalization of PK/PD can be obtained either by increasing the dose or extending the duration of infusion

• Strategy for improving the PK/PD is determined by the killing pattern of antibiotics