1 / 33

Pharmacodynamic Indices

Pharmacodynamic Indices. Johan W Mouton. Canisius-Wilhelmina Hospital Nijmegen, The Netherlands. PEAK / MIC AUC / MIC TIME > MIC. PEAK. AUC. MIC. TIME > MIC. PK/PD. Neutropenic mouse thigh model Various doses and dosing regimens (q1 to q24) Outcome parameter: cfu counts after 24 h

mary
Download Presentation

Pharmacodynamic Indices

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Pharmacodynamic Indices Johan W Mouton Canisius-Wilhelmina Hospital Nijmegen, The Netherlands

  2. PEAK / MIC AUC / MIC TIME > MIC PEAK AUC MIC TIME > MIC

  3. PK/PD • Neutropenic mouse thigh model • Various doses and dosing regimens (q1 to q24) • Outcome parameter: cfu counts after 24 h • Plot PD index (AUC, Peak T>MIC) to effect

  4. K. pneumoniae, imipenem

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

  6. K. pneumoniae, imipenem

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

  8. Scaglione et al, ICAAC 1999

  9. Pharmacodynamic Indicespredictive for efficacy T>MIC AUC (Peak)/MIC Penicillins Aminoglycosides Cephalosporins Fluoroquinolones Carbapenems Metronidazole Monobactams Daptomycin Tribactams Ketolides Clindamycin Macrolides Oxazolidinones Azithromycin Clindamycin Streptogramins Glycopeptides Glycylcyclines Tetracyclines

  10. Kill curves of ceftazidime, P. aeruginosa

  11. Mouton & Vinks, 2003

  12. Kill curves of tobramycin, P. aeruginosa

  13. Antibiotics showing increasing effect (killing) over a wide range of concentrations are called ‘concentration dependent’. In vivo effects are usually AUC and/or Peak related. • Those with a limited range of increasing effect are called (wrongly) ‘concentration-independent’. In vivo effects are usually Time >MIC related.

  14. Pharmacokinetic parameter MIC Pharmacodynamic index

  15. The MIC

  16. MIC The MIC is a result of : • kill over time (kill rate) by the antibiotic • growth over time (growth rate) • for a certain number of micro-organisms (the inoculum) AT STATIC CONCENTRATIONS

  17. Growth and/or kill rate dependent : • strain, species • medium composition, brand • MH, supplements, ISO • number of bacteria • inoculum • 5.105 (NCCLS) vs 105 (BSAC) • temperature (35o vs 37o) • growth phase • CO2 • etc.

  18. Mouton, icaac 2000

  19. The MIC of the control strain should be within one two-fold dilution of the expected MIC

  20. PHARMACOKINETIC parameters

  21. 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, Int J Antimicrob Agents april 2002

  22. AUC 0-24 = 3033 AUC inf = 5100 AUC 0-24 sd = 1361 AUC inf sd =1700 Mg.h/L

  23. WHICH AUC? • AUC 0-24h or AUC  • Steady State? • (log) trapezodeal rule? • Derived ? (A/ +B/ or other)

  24. Peak/MIC Definition : the peak level divided by the MIC. Dimensions : no dimensions. Mouton et al, Int J Antimicrob Agents april 2002

  25. WHICH PEAKLEVEL? • After the 1st, 2nd or later dose? • If more than one compartment, the peak level in compartment 1, 2 or even 3?

  26. Scaglione et al, icaac 1999

  27. Scaglione et al, unpubl.

  28. 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, Int J Antimicrob Agents april 2002

  29. Concentration-time profile of beta-lactam Vd = 20 L, Ka = 1.2 h-1, Ke = 0.3 h-1

  30. Monte Carlo Simulation of beta-lactam Vd = 20 L, Ka = 1.2 h-1, Ke = 0.3 h-1, VC=20% 4h 10h Mouton, Int J Antimicrob Agents april 2002

  31. Mouton et al, Clin Pharmacokin 2000

  32. Amoxicillin/clavulanic acid Mouton & Punt, JAC 2001

  33. For all indices : how are they determined how are they calculated what is the error?

More Related