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Kill Curve Analysis

Kill Curve Analysis. Hartmut Derendorf, PhD University of Florida. Drug Delivery Pharmacokinetics Pharmacodynamics. ?. Biopharmaceutics. ?. PK-PD-Modeling. Biomarker vs. Surrogate Endpoint. Biomarker

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Kill Curve Analysis

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  1. Kill Curve Analysis Hartmut Derendorf, PhD University of Florida

  2. Drug Delivery Pharmacokinetics Pharmacodynamics ? Biopharmaceutics ? PK-PD-Modeling

  3. Biomarker vs. Surrogate Endpoint Biomarker Drug- or disease-induced measurable physiological, pathophysiological or biochemical change Surrogate Endpoint Biomarker that has predictive value for therapeutic outcome

  4. E = intensity of effect Emax = maximum effect C = concentration EC50 = concentration at 0.5 Emax Emax - model

  5. Emax - model EC50

  6. ln EC50 - 2 Emax - model

  7. E = intensity of effect Emax = maximum effect C = concentration EC50 = concentration at 0.5 Emax n = shape (slope) factor Sigmoid Emax - model

  8. Sigmoid Emax - model normal plot semilogarithmic plot

  9. Pharmacodynamics of Anti-infective Agents • in vitro studies • steady state • dilution models • diffusion models • animal studies • clinical studies

  10. Noncompartmental PK-PD Models • Time above MIC • Cmax/MIC • AUC24/MIC • Area under the inhibitory curve (AUIC) • - based on reciprocal serum inhibitory titers • - calculated as AUC24/MIC for C>MIC • AUC above MIC

  11. 16 • Time above MIC • Cmax/MIC • AUC24/MIC • AUIC • AUC above MIC Cmax AUC > MIC 12 8 Concentration (µg/mL) MIC 4 0 24 12 0 6 18 Time (hours) t > MIC

  12. Ceftazidime K. pneumoniae in neutropenic mice Craig 2002

  13. Temafloxacin S. pneumoniae in neutropenic mice Craig 2002

  14. Pharmacodynamics conc. vs effect Pharmacokinetics conc. vs time 0.4 Conc. Effect 0.0 Time 0 25 Conc. (log) 10 -3 PK/PD effect vs time 1 Effect 0 Time 0

  15. Concentration-dependent vs. Time-dependent Craig 1991

  16. Kill Curves flask reservoir tubing connector pump waste Auto-dilution system

  17. PK-PD Model Maximum Growth Rate Constant k Maximum Killing Rate Constant k-kmax Initially, bacteria are in log growth phase

  18. PK-PD Model In animals Bacterial survival fraction of P. aeruginosa in a neutropenic mouse model at different doses (mg/kg) of piperacillin (Zhi et al., 1988)

  19. Single Dose Piperacillin vs. E. coli

  20. Dosing Interval Piperacillin (2g and 4g) vs. E. coli q24h q8h q4h

  21. FDA Draft-Guidance for Industry (1997) Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products New Dosage Form of a Previously Studied Drug In some cases, modified release dosage forms may be approved on the basis of pharmacokinetic data linking the new dosage form from a previously studied immediate-release dosage form. Because the pharmacokinetic patterns of controlled-release and immediate release dosage forms are not identical, it is generally important to have some understanding of the relationship of blood concentration to response to extrapolate to the new dosage form.

  22. 500 mg IR Plasma and free tissue levels n = 12 (means +/- S.D.)  total plasma concentrations  free tissue concentrations

  23. Plasma and free tissue levels 500 mg MR 750 mg MR n = 12 (means +/- S.D.)  total plasma concentrations  free tissue concentrations

  24. 750 mg MR bid vs 500 mg IR tid

  25. 500 mg MR bid vs 500 mg IR tid

  26. Conclusion Microdialysis has opened the door to get better information about the drug concentrations at the site of action. This, in combination with appropriate PK/PD-models, will allow for better dosing decisions than traditional approaches based on blood concentrations and MIC.

  27. PK/PD in Drug Development Streamlining Rational Approach Cost Saving Time Saving

  28. Questions • What are some of the limitations of MICs? • What is the difference between AUC/MIC vs. AUIC? • Should one use total or unbound concentrations to calculate PK/PD-indices? • Why do peak concentrations correlate with aminoglycoside activity but not with beta-lactam activity? • Is AUC/MIC a reasonable PK/PD-index for a macrolide?

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