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A Critical Review of PK/PD in Animal Models

A Critical Review of PK/PD in Animal Models. David R. Andes, M.D. William A. Craig, M.D. University of Wisconsin USA. Animal Versus In-Vitro Models. Infection of specific body sites Interaction of multiple host factors Growth environment less favorable than broth

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A Critical Review of PK/PD in Animal Models

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  1. A Critical Review of PK/PD in Animal Models David R. Andes, M.D. William A. Craig, M.D. University of Wisconsin USA

  2. Animal Versus In-Vitro Models • Infection of specific body sites • Interaction of multiple host factors • Growth environment less favorable than broth • Faster drug elimination than in humans, but can still simulate human pharmacokinetics by inducing renal impairment or computer-controlled drug administration

  3. Use of Animal Models in PK/PD Evaluation of Anti-Infective Agents • Relationship between serum and tissue concentrations

  4. Plasma Cf muscle Cf lung CeftriaxoneTotal plasma and free tissue levels in rats 50 mg/kg 75 mg/kg de la Pena et al., 2000

  5. Use of Animal Models in PK/PD Evaluation of Anti-Infective Agents • Relationship between serum and tissue concentrations • Time-course of antimicrobial activity in vivo

  6. Effect of Increasing Concentrations on Killing of Pneumococci in Thighs of Neutropenic Mice Craig et al, ICAAC 2000

  7. In-Vivo Postantibiotic Effects of Cefotaxime in Murine Thigh Model

  8. In Vivo PAE for Azithromycin with Streptococcus pneumoniae ATCC 10813 in Thighs of Neutropenic Mice

  9. Use of Animal Models in PK/PD Evaluation of Anti-Infective Agents • Relationship between serum and tissue concentrations • Time-course of antimicrobial activity in vivo • PK/PD parameters correlating with efficacy • Magnitudes of the PK/PD parameter required for efficacy

  10. PK/PD In-vivo Model Variables • Animal • Infection Site • Kinetics and protein binding • Endpoint • CFU (allows use of fewer animals) • Survival • Time Point

  11. PK/PD In-vivo Model Variables • Immune State • Normal • Neutropenic • Organism/Strain • Dosing Regimen • Fractionation • Single Interval • Duration of Therapy • Antimicrobial Class

  12. Relationship Between PK/PD Parameters and Efficacy for Ceftazidime against Klebsiella pneumoniae in a Murine Pneumonia Model

  13. Correlation of PK/PD Parameters with Efficacy of Levofloxacin against Streptococcus pneumoniaein Thighs of Neutropenic Mice

  14. Relationships Between PK/PD Parameters and Efficacy of ABT-773 withStreptococcus pneumoniae ATCC 10813

  15. Impact of DosingFrequency on Static Dose for Macrolides, Azalides and Ketolides with Streptococcus pneumoniae ATCC 10813

  16. Impact of Dose Fractionation on the Efficacy of Glycopeptides in a Murine Peritonitis Model ED50 (mg/kg) Drug 1 2 4 8 12 24 Vancomycin 0.65 0.82 1.27 1.25 6.00 6.79 Teicoplanin 0.45 0.83 1.22 1.75 3.13 5.67 Knudsen JD, et al. AAC 2000;44:1247-54

  17. Pharmacodynamics of Lomefloxacin in a Neutropenic Rat Model of Pseudomonas • Dose-fractionation (q24, 12, 6) • AUC/MIC pharmacodynamically linked with doses with peak/MIC < 10:1 • Peak/MIC pharmacodynamically linked with doses with peak/MIC > 10:1 Drusano GL, et al AAC 1993;37:483-90

  18. Half-lives in Mice and Humans Half-life in Minutes Drug Mice Humans Amikacin 17 104 PCN 5 30 Imipenem 8 60 Cefazolin 15 108 Ciprofloxacin 32 240 Minocycline 120 1080

  19. Once-Daily Dosing of Aminoglycosides in Animals • Most studies demonstrating efficacy have been in medium-sized, non-neutropenic animals infected with P. aeruginosa • Most studies showing less efficacy with once-daily dosing have used small rodent and/or neutropenic animals infected with strains of Enterobacteriacea • However, studies simulating human kinetics in neutropenic rodents have demonstrated equal or enhanced efficacy with once-daily dosing for Enterobacteriacea as well as P. aeruginosa

  20. Pharmacokinetic/Pharmacodynamic Parameter Correlating with Efficacy of Amikacin Against Gram-Negative Bacilli in Thighs and Lungs of Neutropenic Mice with Normal and Impaired Renal Function Parameter Selected Organism Site Normal Renal Impaired K. pneumoniae Lung T>MIC Peak/MIC Thigh T>MIC Peak/MIC E. coli Thigh T>MIC AUC/MIC S. marcescens Thigh T>MIC AUC/MIC P. aeruginosa Thigh AUC/MIC AUC/MIC

  21. 3 Quinolones K. pneumoniae Thigh 2 Aminoglycosides P. aeruginosa Lung 4 B-lactams S. pneumoniae

  22. Time Above MIC Required for a Static Effect After 24-hrs of Therapy with Three ß-Lactam Classes Time Above MIC (Percent of Dosing Interval) Drug q1-3 h q4-6h q8-12h q24h Cephalosporins 35 ± 5 34 ± 6 36 ± 5 33 ± 6 Penicillins 30 ± 6 31 ± 5 30 ± 7 29 ± 6 Carbapenems 21 ± 5 20 ± 5 22 ± 6 20 ± 7

  23. Time Above MIC Required for a Bacteriostatic Effect with Four Cephalosporins Time Above MIC (% of Dosing Interval) Drug Enterobacteriaceae S. pneumoniae S.aureus Ceftiaxone (T) 62 (56-69) 64 (59-68) 46,49 Ceftriaxone (F) 38 (34-42) 39 (37-41) 24,26 Cefotaxime 38 (36-40) 38 (36-40) 22,25 Ceftazidime 36 (27-42) 39 (35-42) 20,25 Cefepime 35 (29-40) 37 (33-39) 21,24

  24. Survival/Mortality Studies • Mortality in control animals 80-100% by end of therapy • Animals treated for at least 48 hrs • Mortality assessed within 24 hrs of end of therapy • Pharmacokinetics included so PK/PD parameters could be estimated

  25. Relationship Between Bacteriologic Cure in Experimental Pneumococcal Meningitis and T>MBC for Beta-Lactams

  26. Magnitude of Static Dose (mg/kg) Required inThigh and Lung Models in Neutropenic Mice Infected with Klebsiella pneumoniae

  27. 24-Hr AUC/MIC for Static Doses of Gatifloxacin, Sitafloxacin and Gemifloxacin Against 6 Strains of Streptococcus pneumoniae

  28. Relationship Between 24 Hr AUC/MIC and Mortality for Fluoroquinolones against Gram-Negative Bacilli Craig, CID (in Press)

  29. Relationship Between 24 Hr AUC/MIC and Mortality for Fluoroquinolones against Streptococcus pneumoniae Craig, CID (in Press)

  30. Intracellular Concentrations ofFluoroquinolones vs Intracellular Pathogens • Tissue homogenate concentrations from multiple tissues are 2 to 8-fold higher than plasma levels • A variety of efficacy studies using survival as the end point have been conducted with fluoroquinolnes against both extracellular and intracellular pathogens. • The primary intracellular pathogens studied were M. tuberculosis, C. psittaci, L. pneumophila, and L. moncytogenes.

  31. Conclusions • Animal models have been very useful for determining which PK/PD parameter is the appropriate target and the magnitude required for bacteriologic cure and survival • Despite the variety of techniques and models, there is marked consistency in the PK/PD data in animals

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