Basic Concepts of PK/PD -pharmacodynamic indices- Johan W. Mouton MD PhD FIDSA Professor pharmacokinetics and pharmacodymamics

Basic Concepts of PK/PD -pharmacodynamic indices- Johan W. Mouton MD PhD FIDSA Professor pharmacokinetics and pharmacodymamics

This patient needs antibiotics. But which ones?

Intensive care patient Ceftazidime, P. aeruginosa infection Which of the following dosing regimens is best? A. 1000 mg q12h B. 500 mg q6h C 2000 mg q12h D 1000 mg q8h

Dosing should be such that the level of antmicrobial activity is associated with a high likelihood of therapeutic success. therapeutic success DOSE

Dose Finding - The Past

Efficacy of the drug Potency of a drug (MIC) Exposure to the bug In vivo (PK)

ACTVITY in vitro (MIC) Other factors Mouton et al., Drug Resistance Updates 2011 CONCENTRATIONS in vivo (PK) ANTMICROBIAL EFFICACY (Microbiological Cure) CLINICAL EFFICACY (Clinical Cure) DOSING regimen

conc mg/l 10 8 6 4 2 PK MIC X-acin 500 mg 0 0 4 8 12 16 20 24 time h Lowest concentration with no visible growth after 18 hour incubation.25.5 1 2 4 8 MIC = 2 mg/l

Pharmacokinetic Parameter (and Dose) Thus, we have to: MIC Establish a relationship between the MIC in vitro and concentrations in vivo (thus, dosing regimens) Determine which dosing regimens are optimal for Treatment in relation to the MIC

Any idea where we are today? No idea may be a mouse? Might be a human, though

An elephant. Today it is an elephant!

4. Mortality or dcfu

PK/PD dose fractionation studies Neutropenic mouse thigh model Various doses and dosing regimens (q1 to q24) Outcome parameter: cfu counts after 24 h Plot PK parameter and/or PK/PD index (AUC, Peak, %ft>mic) to effect

concentration Pharmacokinetic parameters : Measures of Exposure AUC Area under the concentration-time curve Integrated concentration over time time

concentration Pharmacokinetic parameters : Measures of Exposure AUC time AUC is usually linearly related to Dose

concentration Pharmacokinetic parameters : Measures of Exposure AUC time AUC is usually linearly related to Dose Dose x 2 = AUC x 2 Dose x 4 = AUC x 4

dlogcfu -1-2 -3 Based on data from Craig WA 3 2 1 0 K. pneumoniae, imipenem 10 0 10 1 10 2 AUC mg.h/l Every point = one mouse thigh dlogcfu = logcfu (t=24h) logcfu (t=0h in controls) = net effect of treatment

For K.pneumoniae, there is no clear relation between AUC (or total daily dose) of imipenem and efficacy in an in vivo model of infection

concentration PEAK Pharmacokinetic parameters : Measures of Exposure AUC T > MIC time Mouton et al. 2007 21-44 In Antimicrobial Pharmacodynamics in Theory and Clinical Practice AUC and Peak are usually linearly related to Dose MIC

Time > MIC dependent on dose frequency Concentration mg/l 100 12.5 q6 80 60 40 20 25 q12 50 q24 0 0 6 12 18 24 Mouton et al Clin Res Updates 2011 14:107 Time (h) MIC 2 mg/l total length of bars corresponds to Time > MIC

dlogdcfu 3 2 1 0-1 -2-3 K. pneumoniae, imipenem Based on data from Craig WA 10 100 %ftime > MIC

For beta-lactams, there is a direct relation between Time > MIC and efficacy

cfu 10 8 6 4 2 Levofloxacin in S. pneumoniae infection in mice cfu 0 0 20 40 60 80 100 T >mic % 0 1 2 Relationship between T>MIC, Peak, AUC 10 8 6 4 2 0 log (peak) mg/l Each dot represents one mouse / dosingregimen. Based on data from Scaglione & Mouton, 2001, 2003 cfu 10 8 6 4 2 0 1 2 log (auc) mg.h/l

Andes IJAA 2002 PK/PD relationship is Class Dependent Log 10 CFU/Thigh at 24 Hrs 10 Log 10 CFU/Thigh at 24 Hrs 8 6 4 2 0 10 100 1000 10 9 8 7 6 5 4 24-Hr AUC/MIC 1 10 100 1000 Peak/MIC 0 25 50 75 100 Time Above MIC 3 2 10 100 1000 1 10 100 1000 0 25 50 75 100 24-Hr AUC/MIC Peak/MIC Time Above MIC levofloxacin ceftazidim

T>MIC Penicillins Cephalosporins Carbapenems Monobactams Tribactams Relationship PkPd and Effect AUC Aminoglycosides Fluoroquinolones Metronidazole Lipopeptides Ketolides Macrolides Clindamycin Streptogramins Glycopeptides Glycylcyclines Oxazolidinones Tetracyclines Azoles

Relationship AUC and effect What has the MIC to do with this? Scaglione et al., AAC 2003

Andes et al ISHAM 2003 Fluconazole efficacy in mice Dose vs MIC

PEAK Pharmacokinetic parameters : Measures of Exposure AUC T > MIC Mouton et al. 2007 21-44 In Antimicrobial Pharmacodynamics in Theory and Clinical Practice AUC and Peak are usually linearly related to Dose MIC

'Normalizing pk/pd relationships' Pharmacokinetic parameter Pharmacodynamic index (AUC/MIC, Peak/MIC, T>MIC) MIC

Fluconazole Pharmacodynamics Against Isogenic Strain Pairs of Susceptible and Resistant C. albicans Change in Log10 CFU/Kidneys 0.0-0.5-1.0-1.5-2.0-2.5-3.0-3.5 0.1 1 10 100 1000 Andes et al ISHAM 2003 24-h Total Dose 1649 MIC 0.25 2183 MIC 4.0 - CDR 1002 MIC 1.0 2823 MIC 32 - MDR1, ERG 11 2-76 MIC 1.0 12-99 MIC 64 - CDR, MDR1, ERG 11 412 MIC 0.25 2307 MIC 128 - CDR, ERG 11 580 MIC 0.50 2438 MIC 32 FH1 MIC 1.0 FH5 MIC 4.0 - CDR R 2 = 84% 0.01 0.1 1 10 100 100010000 24-hr AUC/MIC

extinction 0.4 0.3 0.2 0.1 0.0-0.1-6 -5-4 -3-2 -1 0 1 2 3 4 5 6 2log fluconazole mg/l In vitro effect at fixed concentrations prob cure MIC 1.0 0.8 0.6 0.4 0.2 conc mg/l 0.0 1 10 100 1000 fluconazole (auc/mic) 10 8 6 4 2 0 0 4 8 12 16 20 24 time h In vivo CT profile dynamic concentrations Response Curve

prob cure 1.0 0.8 0.6 0.4 0.2 Probability of cure after treatment with fluconazole Oropharyngeal Candidiasis n=132 EC50 43.69 R² 0.9938 0.0 1 10 100 1000 AUC/MIC mg.h/l Rodriguez- Tudela et al, AAC 2007 Prob cure correlates with AUC/MIC POSITIVE correlation with EXPOSURE INVERSE correlation with MIC Pharmacodynamic index (AUC/MIC)

Why is the term pk/pd index used instead of pk/pd parameter? -a ratio (e.g.) of two independent parameters, not a parameter by itself Mouton et al, J Antmicrob Chemother 2005 55:601. Available from ISAP site (www.isap.org)

Thus, 2 factors influence the value of the pk/pd index: MIC and its Errors/variation Pharmacokinetics and its variation

Kahlmeter et al, JAC 2003

Growth and/or kill rate dependent : strain, species medium composition, brand MH, supplements, ISO number of bacteria inoculum 5.10 5 (CLSI) vs 10 5 (BSAC) temperature (35 o vs 37 o ) growth phase CO 2 etc.

The reference method 2003 20 june DIN Berlin CEN TC140/WG10 2004 22 april DIN Berlijn Combined meeting with ISO ISO/TC 212 WG4 Vienna Agreement 2005 Vote on first draft and comments by all Member Countries 2006 Final version 27 October 2006, 8th CEN, 6th ISO meeting ISO 20776-1 2007 Final version validation ISO 20776-2.

The reference method - Microdilution Microdilution, 0.1 ml Mueller Hinton (1941, Corn starch) Inoculum 5 (2-8).10E5 cfu/ml 36 + 1 o C 18 + 2 h incubation

The reproducibility of the MIC test is within 2 2fold dilutions. The variation introduced in the AUC/MIC and Peak/MIC values by the MIC is there for at least 0.5 tot 2 x the pk/pd index value!

Why is outcome of beta-lactams %ft>mic related? And aminoglycosides AUC related?

log10 cfu 10 8 6 4 2 0 0 2 4 6 Mouton et al. AAC 2007 51:3449 In vitro activity of ceftazidime exposure-response relationship Time h 0 mg/l 0,125 mg/l 0,5 mg/l 1 mg/l 2 mg/l 4 mg/l 16 mg/l 64 mg/l Incubate inoculum at increasing concentrations Sample every two h

log10 cfu 10 8 6 4 2 0 0 2 4 6 Time h Modelling Kill Kinetics 0 mg/l 0,125 mg/l 0,5 mg/l 1 mg/l 2 mg/l 4 mg/l 16 mg/l 64 mg/l observed killrate h -1 4 3 2 1 0-1 R² 0.9941 Killrates -2 0.01 0.1 1 10 100 Concentration ceftazidim (mg/l) Mouton et al. AAC 2007 51:3449 E = Emax * C^γ / (C^γ + EC^γ )

Mouton JW Thesis 1993 ceftazidime Patterns of activity: Kill curves of P. aeruginosa tobramycin

killrate h -1 5 4 3 2 1 0-1 Steep Figure 44 meropenem -2-3 -2-1 0 1 2 10 log (conc meropenem) mg/l 1a killrate h -1 18 13 8 3 tobramycin Shallow 3.59 h -1 13.4 h -1-2 -2-1 0 1 2 3 10 log (conc tobramycin) mg/l high : steep slope low: shallow slope 'concentration independent' 'concentration dependent' Mouton & Vinks Clin Pharmacokinet 2005 44:201 1b

Conclusions The overall effect of antimicrobial therapy is dependent on exposure AND MIC The effect differs by antibiotic class Beta-lactams : %ft>mic related Most others : AUC related Exposure response relationship can be explained by the pd characteristics Fast vs slow kill (speed of killing) Maximum kill rate (extend of killing) Concentration effect (hill slope) Adjust dosing regimens based on pkpd! For beta-lactams : adjust dose : frequency matters! For most others : adjust frequency

PHARMACOKINETIC parameters

AUC Definition :The Area under the Concentration-time curve over 24 hours. Note:.. It should be stated how the AUC is determined : based on (log) linear trapezoideal rule, based on clearance, or based on microconstants. Dimensions : concentration x time e.g. mg.h/l or g.h/ml Mouton et al, J Antmicrob Chemother 2005. Available from ISAP site

concentration 200 100 0 0 10 20 30 40 AUC 0-24 = 3033 AUC inf = 5100 AUC 0-24 sd = 1361 AUC inf sd =1700 time Mg.h/L

AUC 0-24h or AUC Steady State? WHICH AUC? (log) trapezodeal rule? Derived? (A/ +B/ or other)

AUC/MIC Definition : The area under the concentration-time curve over 24 hours in steady state divided by the MIC.. Note :.For unbound fraction of the drug, use fauc/mic Dimensions : no dimensions Mouton et al, J Antmicrob Chemother 2005 Available from ISAP site

Definition :The Area under the inhibitory curve over 24 hours. Note: the AUIC should be reserved for those cases where actual inhibitory titers have been measured and used in the calculations. The AUIC is not equal to the AUC/MIC. See also Flaherty et al, AAC 1988;32(12):1825-29; Hyatt JM et al AAC 1994;38(12):2730-7; Occhipinti DJ et al, AAC 1997;41(11):2511-7. Dimensions : none AUIC Mouton et al, J Antmicrob Chemother 2005 Available from ISAP site

Peak/MIC Definition : the peak level divided by the MIC. Dimensions : no dimensions. Mouton et al, J Antmicrob Chemother 2005 Available from ISAP site

concentration mg/l concentration mg/l concentration mg/l 2.0 1.5 1.0 0.5 simulation of 1.25 mg/kg q1h simulated conc. measured conc. 0.0 0 1 2 3 4 5 6 7 8 10 8 6 4 2 time (h) simulation 10 mg/kg + 1.25 mg/kg q1h simulated conc. 0 0 4 8 12 16 20 24 10 8 6 4 2 time (h) simulation 10 mg/kg + 1.25 mg/kg q1h simulated conc. 0 0 4 8 12 16 20 24 time (h) Scaglione et al, AAC 2003 WHICH PEAKLEVEL? fig 2a fig 2b fig 2c After the 1st, 2nd or later dose? If more than one compartment, the peak level in compartment 1, 2 or even 3?

fraction unbound 1.0 0.9 0.8 0.7 0.6 0.1 1 10 100 fig 1 Scaglione et al, AAC 2003 concentration mg/l fu lev fu cip

Time > MIC Definition : the % of time above the MIC over a period of 24 hours. Note : if the period is other than 24 h, this should be stated explicitly. Dimensions : %. Mouton et al, J Antmicrob Chemother 2005 Available from ISAP site

Variation in methods, definitions Variation in estimation Variation in population

For all indices : how are they determined how are they calculated what is the error? Only when these questions have been answered do we know the true impact and value of the index.