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WHICH PK-PD MEASURE FOR WHICH DRUG?

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

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WHICH PK-PD MEASURE FOR WHICH DRUG?

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

  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 Data by WA Craig, shamelessly stolen by PG Ambrose and given to SM Bhavnani

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

  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 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 Cephalosporins1 1. Ceftazidime, ceftriaxone, cefepime and cefotaxime. 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].

  10. R2=0.852 R2=0.826 R2=0.766 4 2 Change in Log (CFU/g) over 24 hrs 0 -2 -4 0 20 40 60 80 100 1 10 100 1000 10000 0.1 1 10 100 1000 AUC:MIC Ratio Cmax:MIC Ratio % Time > MIC EXPOSURE & RESPONSE IN MICE Aminoglycosides and Pseudomonas aeruginosa & Serratia marcescens • Neutropenic mice were inoculated with 106 CFU/thigh of either P. aeruginosa (MIC = 4 mg/L) or S. marcescens (MIC = 8 mg/L) Q 6 hr Q 12 hr Q 24 hr Control 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. 44th Annual Meeting of the Infectious Diseases Society of America, Toronto, Ontario, Canada, October 12-15, 2006.

  11. 100 80 60 Mortality (%) 40 20 0 2.5 10 25 100 250 1000 AUC0-24:MIC Ratio EXPOSURE & RESPONSE IN MICEQuinolones vs. Gram-Negative Bacilli 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. EXPOSURE & RESPONSE IN MICELevofloxacin vs. Pneumococci Z Andes & Craig, Int J Antimicrob Agents, 2002

  13. 3 R2 = 96% R2 = 89% R2 = 87% 2 1 0 ΔLog10 CFU/Thigh -1 -2 -3 -4 0 20 40 60 80 100 0.1 1 10 1 10 100 % Time>MIC Cmax:MIC Ratio AUC0-24:MIC Ratio PRE-CLINICAL PK-PD ANALYSESResults of Dose-Fractionation Studies EXPOSURE & RESPONSE IN MICE Tigecycline versus Staphylococcus aureus 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.

  14. 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) 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

  15. THE PK-PD GOAL OF THERAPY Various Drug Classes That I Did Not Have Time to Mention Use of Pharmacokinetics-Pharmacodynamics and Monte Carlo Simulations as Decision Support for Determination of Penicillin VK Susceptibility Breakpoints for Streptococcus pneumoniae

  16. AZITHROMYCIN Mongolian Gerbil-Otitis Infection Model • We evaluated the effect on H. influenzae of delivering the same cumulative dose three different ways: • Simulated sustained release single dose • Simulated divided doses over 3 days • Simulated 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 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 Use of Pharmacokinetics-Pharmacodynamics and Monte Carlo Simulations as Decision Support for Determination of Penicillin VK Susceptibility Breakpoints for Streptococcus pneumoniae 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.

  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, 2nd Ed. 2006.

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