1. WHICH PK-PD MEASURE FOR WHICH DRUG? Sujata M. Bhavnani, Pharm.D, MS Institute for Clinical Pharmacodynamics Ordway Research Institute Latham, New York The Life and Times of Dr. William A. Craig

2. ROAD MAP Objectives To provide a review of the PK-PD measure associated with efficacy in animal infection models To review an example where consideration of the PK-PD measure most closely associated with efficacy did not completely tell the entire story

3. THINGS DR. CRAIG HAS TAUGHT US Factors that Influence the Magnitude of the PK-PD Measure Associated with Efficacy Major EffectMinor Effect Infecting pathogenResistant organisms Drug classDosing regimen Protein binding Site of infection Presence or absence of neutrophils Starting inoculums Data by WA Craig, shamelessly stolen by PG Ambrose and given to SM Bhavnani

4. Z Z EXPOSURE & RESPONSE IN MICE Ceftazidime and Klebsiella pneumoniae Craig WA. Interrelationship between pharmacokinetics and pharmacodynamics in determining dosing regimens for broad spectrum cephalosporins. Diagn Micro Infect Dis 1995;22:89-96.

5. EXPOSURE & RESPONSE IN MICE Amoxicillin and Pneumococci Andes DR and Craig WA. In vivo activities of amoxicillin and amoxicillin-clavulanate against Streptococcus pneumoniae: application to breakpoint determinations. Antimicrob Agents Chemother. 1998;42:2375-2379.

6. Z Z Andes DR and Craig WA. Pharmacodynamic activity of dorpenem against multiple bacteria in a murine-thigh infection model. 2003 ICAAC, Abstract A-308. EXPOSURE & RESPONSE IN MICE Doripenem Against Pneumococci

7. EXPOSURE & RESPONSE IN MICE Impact of β-Lactams on % Time > MIC One of hundreds of Dr. Craig’s slides for which I cannot find the correct reference.

8. THE PK-PD GOAL OF THERAPY(% T>MIC) Beta-Lactams ClassOrganismStasisMaximum Kill PenicillinGram-negative30-4060-70 Pneumococci25-3535-50 Staphylococci20-3040-50 CephalosporinGram-negative40-5070-80 Pneumococci35-4040-50 Staphylococci20-3040-50 CarbpenemGram-negative20-3040-50 Pneumococci15-2530-45 Staphylococci10-2025-40 Data by WA Craig, yet another slide shamelessly stolen by PG Ambrose and given to SM Bhavnani

9. EXPOSURE & RESPONSE IN MICE Impact of ESBL-Producing Enterobacteriaciae on % Time > MIC for Cephalosporins 1 Ambrose PG, Bhavnani SM, Jones RN, Craig WA, Dudley MN. Use of PK-PD and Monte Carlo simulation as decision support for the re-evaluation of NCCLS cephem susceptibility breakpoints for Enterobacteriaceae. 44th ICAAC, Washington, DC, October 30-November 2, 2004 [Abstract No. A-138]. 1. Ceftazidime, ceftriaxone, cefepime and cefotaxime.

10. EXPOSURE & RESPONSE IN MICE Aminoglycosides and Pseudomonas aeruginosa & Serratia marcescens Q 6 hrQ 12 hrQ 24 hrControl 110100100010000 -4 -2 0 2 4 AUC:MIC Ratio Change in Log (CFU/g) over 24 hrs R 2 =0.852 0.11101001000 Cmax:MIC Ratio R 2 =0.826 % Time > MIC R 2 =0.766 020406080100 Craig WA, Andes DR, Bhavnani SM, Drusano GL, Ambrose PG. Pharmacokinetics-pharmacodynamics of amikacin against gram-negative Bacilli in a murine-thigh infection model and examination of the PK-PD variance in humans. 44 th Annual Meeting of the Infectious Diseases Society of America, Toronto, Ontario, Canada, October 12-15, 2006. Neutropenic mice were inoculated with 10 6 CFU/thigh of either P. aeruginosa (MIC = 4 mg/L) or S. marcescens (MIC = 8 mg/L)

11. EXPOSURE & RESPONSE IN MICE Quinolones vs. Gram-Negative Bacilli AUC 0-24 :MIC Ratio 2.510251002501000 Mortality (%) 0 20 40 60 80 100 Craig WA. Pharmacodynamics of Antimicrobials: General Concepts and Applications. In: Nightingale CH, Murakawa T, Ambrose PG ed. Antimicrobial Pharmacodynamics in Theory and Practice. New York, Marcel Dekker Publishers, 2002.

12. Z Z EXPOSURE & RESPONSE IN MICE Levofloxacin vs. Pneumococci Andes & Craig, Int J Antimicrob Agents, 2002

13. PRE-CLINICAL PK-PD ANALYSES Results of Dose-Fractionation Studies van Ogtrop ML, Andes D, Stamstad TJ, Conklin B, Weiss WJ, Craig WA, and Vesga O. In vivo pharmacodynamic activities of two glycylcyclines (GAR-936 and WAY 152,288) against various gram-positive and gram-negative bacteria. Antimicrob. Agents Chemother. 2000 44: 943-949. EXPOSURE & RESPONSE IN MICE Tigecycline versus Staphylococcus aureus

14. Ambrose PG, Forrest A, Craig WA, Rubino CM, Chavnani SM, Drusano GL, Heine HS. Pharmacokinetics- Pharmacodynamics of Gatifloxacin in a Lethal Murine Bacillus anthracis Inhalation Infection Model. Antimicrob Agents Chemother. 2007;51:4351-4355 EXPOSURE & RESPONSE IN VIVO Gatifloxacin Against Bacillus anthracis 6-8 week old non-neutropenic female BALB/c mice received aerosol challenges of 50 to 100 times the established 50% lethal dose (3.4 x 104 CFU) of B. anthracis (Ames strain, gatifloxacin MIC = 0.125 mg/L)

15. Use of Pharmacokinetics-Pharmacodynamics and Monte Carlo Simulations as Decision Support for Determination of Penicillin VK Susceptibility Breakpoints for Streptococcus pneumoniae THE PK-PD GOAL OF THERAPY Various Drug Classes That I Did Not Have Time to Mention ClassOrganismBacterial endpoint Net bacterial stasis Maximum kill MacrolidesPneumococci20-3540-50 ClindamycinPneumococci20-3540-50 Staphylococci30-4060-80 TetracyclinesStaphylococci60-8090-120 LinezolidStaphylococci80-90100-150 VancomycinStaphylococci150-320400-800

16. We evaluated the effect on H. influenzae of delivering the same cumulative dose three different ways: oSimulated sustained release single dose oSimulated divided doses over 3 days oSimulated divided doses over 5 days The pharmacokinetic profile in gerbils was humanized to better reflect the human pharmacokinetic profile Two strains were studied, MIC values of 0.5 and 2 mg/L AZITHROMYCIN Mongolian Gerbil-Otitis Infection Model Okusanya OO, Forrest A, Booker BM, Bhavnani SM, Girard D, Ambrose PG. Pharmacokinetics and pharmacodynamics of azithromycin in gerbils with Haemophilus influenzae middle ear infection. Presented at 106th American Society for Clinical Pharmacology and Therapeutics, 2005

17. AZITHROMYCIN IN THE GERBIL-OTITIS MODEL Exposure-Response Relationship: Single Dose Okusanya OO, Forrest A, Booker BM, Bhavnani SM, Girard D, Ambrose PG. Pharmacokinetics and pharmacodynamics of azithromycin in gerbils with Haemophilus influenzae middle ear infection. Presented at 106th American Society for Clinical Pharmacology and Therapeutics, 2005

18. AZITHROMYCIN IN THE GERBIL-OTITIS MODEL Exposure-Response Relationship: 3-Day Regimen Okusanya OO, Forrest A, Booker BM, Bhavnani SM, Girard D, Ambrose PG. Pharmacokinetics and pharmacodynamics of azithromycin in gerbils with Haemophilus influenzae middle ear infection. Presented at 106th American Society for Clinical Pharmacology and Therapeutics, 2005

19. AZITHROMYCIN IN THE GERBIL-OTITIS MODEL Exposure-Response Relationship: 5-Day Regimen Okusanya OO, Forrest A, Booker BM, Bhavnani SM, Girard D, Ambrose PG. Pharmacokinetics and pharmacodynamics of azithromycin in gerbils with Haemophilus influenzae middle ear infection. Presented at 106th American Society for Clinical Pharmacology and Therapeutics, 2005

20. IMPLICATIONS Azithromycin in the Gerbil-Otitis Model Front-loading the exposure results in a more rapid and complete bacterial kill Extending the therapy duration increases the exposure intensity required to effect bacterial eradication Having the highest exposure at the time of greatest bacterial count results in the greatest kill possible  Optimizes the likelihood of positive clinical outcome,  This reduces the likelihood of spontaneous mutation, and  Should eliminate a preexisting resistant subpopulation

21. CONCLUSIONS Applications and Path Forward By understanding the PK-PD measure and magnitude associated with efficacy, we have been able to assess the translational value of these data Non-clinical and clinical are generally concordant ! Identification of the PK-PD measure associated with efficacy early in drug development provides the opportunity to positively impact the selection of dosing regimens for further clinical study Decreases risk of drug development failure Application of these principles has provided a paradigm for the evaluation of susceptibility breakpoints Better definitions of susceptibility will better influence prescribing

22. Thank you Dr. Craig for all that have you done!!!

23. EXPOSURE & RESPONSE IN MICE Penicillin and Pneumococci Forrest A, Rubino CM, Craig Craig WA. Andes DR. Sorgel F, Kinzig-Schippers M, Rodamer M, Jones RN, Ambrose PG. Use of Pharmacokinetics-Pharmacodynamics and Monte Carlo Simulations as Decision Support for Determination of Penicillin VK Susceptibility Breakpoints for Streptococcus pneumonia. 2007 ICAAC, Abstract A-782. Use of Pharmacokinetics-Pharmacodynamics and Monte Carlo Simulations as Decision Support for Determination of Penicillin VK Susceptibility Breakpoints for Streptococcus pneumoniae Studied Strain of S. pneumoniae EffectExposure SP ATCC 10813 SP CDC 145 SP CDC 146 Stasisf%T>MIC23.920.020.3 mg/kg/6h2696110 2 log 10 Killf%T>MIC35.632.331.2 mg/kg/6h87.8736567

24. EXPOSURE & RESPONSE IN MICE Linezolid and Staphylococcus aureus Andes D, van Ogtrop ML, Peng J, Craig WA, In vivo pharmacodynamic of a new oxazolidinone (linezolid. Antimicrob. Agents Chemother. 2000 46: 3484-3489.

25. EXPOSURE & RESPONSE IN MICE Doxycycline and Streptococcus pneumoniae Andes D, Craig WA. In: Nightingale CH, Murakawa T, Ambrose PG, Drusano GL. ed. Antimicrobial Pharmacodynamics in Theory and Practice. New York, Marcel Dekker Publishers, 2 nd Ed. 2006.