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WP2: Development of a library of PK-PD indices and EDR targets

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Presentation on theme: "WP2: Development of a library of PK-PD indices and EDR targets"— Presentation transcript:

1 WP2: Development of a library of PK-PD indices and EDR targets
Paul M. Tulkens, MD, PhD Cellular and Molecular Pharmacology & Centre for Clinical Pharmacy Louvain Drug Research Institute Université catholique de Louvain, Brussels, Belgium On behalf of UCL – EXPRIMO – UHOUS MON4STRAT kick-off meeting Liège, Belgium, 1 April2014 01/04/2014 MONT4STRAT Kick-off meeting

2 MONT4STRAT Kick-off meeting
In a nutshell… This is the old number ! 01/04/2014 MONT4STRAT Kick-off meeting

3 MONT4STRAT Kick-off meeting
The objectives… 01/04/2014 MONT4STRAT Kick-off meeting

4 MONT4STRAT Kick-off meeting
The tasks… Task 1.1 – Selection of best PK/PD targets for efficacy [M1-M3] analysis of pertinent literature and selection of best indices in terms of fT>MIC and Ctrough /MIC ratios commonly proposed for -lactams (for sake of objectivity, other indices often proposed such AUC24h/MIC will also be critically examined). construction of models describing free serum concentration patterns corresponding to the current regimens (doses and schedule) of the -lactams included in the study (piperacillin-tazobactam, ceftazidime, cefepime, imipenem-cilastatin, meropenem) for treating HAP/VAP patients stratified according to the main underlying pathologies affecting pharmacokinetics (literature data and data available from previous studies of the applicants) Note: systematically introducing free concentration for PK represents a progress beyond the current state of the art that can be later extended to -lactams with high protein binding (e.g., ertapenem, ceftriaxone…) and other antibiotics. coupling of these models to expected variability in susceptibility of target organisms (epidemiological data pertinent to HAP/VAP; EUCAST “S” and “R” breakpoints) selection for each -lactam of the optimal PK/PD profile for efficacy and definition of the corresponding regimens 01/04/2014 MONT4STRAT Kick-off meeting

5 Selection of the best indices for efficacy: point #1
For susceptible organisms (with typically low MICs), the maximal efficacy efficacy of -lactams is obtained even at the lowest serum concentration following a conventional IV administration This explains why no or little concentration-dependent effect is seen (in sharp contrast with aminglycosides, e.g.) Thus, time and not concentration becomes the predominant driver for activity -lactams in the conditions of clinical use and for organisms with low MICs 24h-concentration-dependence of the activity of 2 typical -lactams (left) and an aminglycoside (right) towards typical susceptible Gram-positive (top) and Gram-negative (bottom) organisms. Dotted vertical lines: MIC (S. aureus: oxacillin: 0.25 mg/L; gentamicin: 0.25 mg/L; P. aeruginosa: meropenem: 1 mg/L; gentamicin: 2 mg/L); yellow zones: Cmin-Cmax range as typically observed in patients with conventional (discontinuous) administration; horizontal dotted line: static effect 01/04/2014 MONT4STRAT Kick-off meeting

6 Question #1: what about organisms with decreased susceptibility ?
time is predominant time or concentration ? concentration ? EUCAST breakpoint: S  2 – R > 8 01/04/2014 MONT4STRAT Kick-off meeting

7 Question #2: how to integrate the variations in PK
step 2: define the worse scenario for specific populations step 1: define the PK for the target populations 01/04/2014 MONT4STRAT Kick-off meeting

8 EUCAST breakpoint for S. aureus
Question #3: how to integrate the variations of MICs and the EUCAST breakpoints step 3: apply MICs and check the EUCAST breakpoint The ceftaroline EUCAST breakpoint for S. aureus is 1 mg/L ! 01/04/2014 MONT4STRAT Kick-off meeting

9 MONT4STRAT Kick-off meeting
The tasks… Task 1.2 – Integration of requirements for mitigation of low-level EDR – [M2-M6] Partners involved: UCL, EXPRIMO, UHOUS analysis of which element needs to be introduced in the PK/PD index for efficacy to achieve effective mitigation of low-level emergence of EDR (Cmax/MIC, Ctrough/MIC, fT>MIC, AUC24h/MIC) definition of best dosing/schedule compromise for each β-lactam for organisms of different susceptibilities as defined by MICs and in relation to EUCAST breakpoints Model building using established decision-optimization methods used in drug assessment (such as “clinical utility index”) with weighing the benefit/risk ratios of each constituting part (in collaboration with clinicians involved in WP6 and WP7). Post-hoc examination of the models and of the corresponding regimen recommendations for compatibility with acceptable clinical conditions of use (all recommendations for dosages that exceed what is included in the drug labelling [as per the current EU SmPCs] will be flagged as experimental for appreciation and discussions of acceptability by the clinical investigators). 01/04/2014 MONT4STRAT Kick-off meeting

10 Which resistance do we need to avoid ?
essentially, resistance that correspond to a "crossing" of the EUCAST breakpoint 01/04/2014 MONT4STRAT Kick-off meeting

11 MONT4STRAT Kick-off meeting
Question: what do we need to prevent the emergence of low-level resistance ? Is 50 % of fT>MIC sufficient ? 01/04/2014 MONT4STRAT Kick-off meeting

12 MONT4STRAT Kick-off meeting
Question: what do we need to prevent the emergence of low-level resistance ? Perhaps, we need 100 % of fT>MIC ! 01/04/2014 MONT4STRAT Kick-off meeting

13 MONT4STRAT Kick-off meeting
Question: what do we need to prevent the emergence of low-level resistance ? our patient with his increased Vd and clearance will never make it without reducing the administration interval... Perhaps, we need 100 % of fT>MIC ! 01/04/2014 MONT4STRAT Kick-off meeting

14 MONT4STRAT Kick-off meeting
Question: what do we need to prevent the emergence of low-level resistance ? Like this ! (every 5 h) Perhaps, we need 100 % of fT>MIC ! 01/04/2014 MONT4STRAT Kick-off meeting

15 Question: what do we need to prevent the emergence of low-level resistance ?
But, perhaps, the Cmax/MIC ratio is critical ! (but how much ? perhaps 4-fold ?) 01/04/2014 MONT4STRAT Kick-off meeting

16 our patient with an increased Vd and clearance will not make it !
Question: what do we need to prevent the emergence of low-level resistance ? our patient with an increased Vd and clearance will not make it ! 01/04/2014 MONT4STRAT Kick-off meeting

17 unless he/she receives a 1.7-fold larger dose !
Question: what do we need to prevent the emergence of low-level resistance ? unless he/she receives a 1.7-fold larger dose ! 01/04/2014 MONT4STRAT Kick-off meeting

18 MONT4STRAT Kick-off meeting
The tasks… Task 1.3 – Analysis and integration of PK data with respect to neurological adverse effects of β-lactams [M1-M6] Partners involved: UCL, EXPRIMO, UHOUS analysis of literature data and search through applicants’ data base for links between occurrence of neurological adverse effects, serum concentrations, dosing, and known perturbations of excretory functions for building of PK/toxicodynamic (PK/TD) profiles of the -lactams included in the study comparison of PK/TD (this task) and PK/PD profiles (tasks 1.1 and 1.2) for best definition of trade-off in patients with stratification on basis of risk factors (e.g., impairment of excretory functions; high MICs requiring elevated dosages, …). 01/04/2014 MONT4STRAT Kick-off meeting

19 Question: which PK parameter is associated with neurotoxicity ?
probably the peak ... but also factors related to the molecule carbapenems > cephalosporins > penicillins ? degradation products (cefepime ?) and factors related to the patient slower elimination (renal insufficiency ...) permeability of the blood-brain barrier This may lead us to very complex algorithm ... 01/04/2014 MONT4STRAT Kick-off meeting

20 What may emerge from all that...
fT>MIC will probably predict the efficacy up to an MIC 2-4-fold the EUCAST breakpoint 100 % fT>MIC will probably be required to prevent emergence of resistance patients with increased Vd and clearance will need particular attention Large peaks will probably need to be avoided to mitigate neurotoxicity issues (mainly carbapenems) frequent administration rather than increase of doses will probably be preferred Prolonged drug exposure (decreased clearance) could be beneficial if proven non-neurotoxic the definition of the PK parameters associated with toxicity will probably need revision during the study 01/04/2014 MONT4STRAT Kick-off meeting

21 Ask questions and MAKE SUGGESTIONS
01/04/2014 MONT4STRAT Kick-off meeting

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