1. PK/PD: TOWARDS DEFINITIVE CRITERIA PK/PD in clinical Practice: new level of PK/PD Francesco Scaglione Department of Pharmacology, Toxicology and Chemotherapy, University of Milan, Milan, Italy

2. PK/PD results and evolution 2000 Persistend effect Time/Conc. dependent activity } Improvement of dose and intervals } Outcome resistance ?

3. Several objectives of PK/PD Phase 2-3 clinical trial resistance Improvement of therapy

4. PK/PD evolution Custom-made therapy 2000

5. Effect over the time; the time; Peculiar Effects Effect over the time; the time; Peculiar Effects ADMEADME In Vitro and in vivo activity In Vitro and in vivo activity Pharmacology : what for physician? 0 2 4 6 8 10 12 14 16 18 20 01 23456789101112 time h concentration (µg/ml)

6. Considerations when choosing an antibacterial agent Pathogen MIC Drug Absorption Distribution Metabolism Excretion Optimal dosing regimen Concentration at infection site Outcome Clinical efficacy Bacterial eradication Compliance with dosing regimen Tolerability Rate of resolution Prevention of resistance PD Time- vs concentration- dependent killing Bactericidal vs bacteriostatic activity Tissue penetration Persistence of antibacterial effect PK Microbiology Mechanism of action Antibacterial spectrum

7. Time (hours) 0 MIC Peak/MIC AUC/MIC Time >MIC PAE PK/PD parameters affecting efficacy Concentration

8. Improving the probability of positive outcomes IMPROVING THE ODDS HOST BUG DRUG

9. PK/PD parameters determining efficacy Absorption Absorption Serum levels Serum levels Distribution and penetration to site of infection Distribution and penetration to site of infection Intracellular penetration Intracellular penetration Relationship of PK parameters to MIC Relationship of PK parameters to MIC

10. Infections are treated with the same dosing regimen irrespective of the absolute susceptibility of the microrganisms as well as the PK of the actual patient In clinical practice

11. Aminoglycoside dosing characteristics for 78 patients with pneumonia caused by gram-negative bacteria Variable Before IPM (n = 78) After IPM (n = 60) Aminoglycoside dose (mg) a a 105 (90-140)230 (175-320) C max (µg/ml) a a 5.3 (3.9-6.3)6.7 (5.2-7.6) C min (µg/ml) a a 0.6 (0.3-1.1)0.8 (0.5-1.1) a Values are medians (interquartile ranges). Adapted from Angela D. M. Kashuba; AAC 1999

12. Aminoglycoside pharmacokinetic and pharmacodynamic variables for 78 patients with pneumonia caused by gram-negative bacteria VariableMedian (interquartile range) Aminoglycoside CL (ml/min/1.73 m 2 ) Aminoglycoside half-life (h) AUC 0-24 (µg · h/ml) First C max /MIC Second C max /MIC 71.5 (50.4-91.3) 3.5 (2.6-5.0) 52.2 (34.5-77.5) 3.6 (1.4-6.2) 3.7 (1.9-6.9) Adapted from Angela D. M. Kashuba; AAC 1999

13. Peak level of tobramycin 3mg/kg in ten patients in ICU

14. Trauma FACTORS INVOLVED IN INFLAMMATION Complement Necrosis Bacteria PMN MN Lymphocytes TNF-  IL - 1 IL - 6 PAF PGE LTC TXA Protease oxygen Radicals endothelial Damage Increase of capillary permeability Oedema

15. VARIATIONS OF INTERSTITIAL FLUID DURING INFECTIONS blood INTERSTITIAL FLUID Cells

16. THEORETICAL CONCENTRATION OF AN ANTIBIOTIC Time Serum Interstitial fluid Concentration Large volume compartment

17. 01234567 0 10 20 30 40 50 days L Vd of Tobramicin in 13 patients admitted in ICU

18. 01234567 0.0 2.5 5.0 7.5 10.0 days mg/L Serum peak of Tobramicin in 13 patients admitted in ICU

19. ‘Time above MIC’ Concentration M IC 1 Time M IC 2 Time Over MIC Peak/MIC

20. Ideal approach to adjust the dose  Initial dosing regimen(chosen by patient’s physician)  Blood sampling( two or more post- distributional sample)  Pharmacokinetic analysis (peak,AUC,CL)  Adjust dose or/and intervals (PK/PD)  Redetermine concentrations  Adjust again ?

21. First problem PK approach to adjust the dose is poor applicable for routinely use (at moment)  N°samples  Personnel  Costs  Microbiology

22. second problem PK/PD breakpoints betalactams (ceftriaxone) aminoglicosides quinolones glicopeptides macrolides tetraciclines

23. Program to customize the therapy in our hospital  Isolation of the pathogen and MIC  Design therapy traditionally(by patient’s physician)  Pharmacokinetic  Adjust dose or interval using PK/PD  Redetermine concentrations

24. PK/PD values adopted Aminoglicosides Peak/MIC  8 Quinolones peak/MIC  10 Betalactams peak/MIC  4 and T>MIC  70% same value for monotherapy or combination

25. Sampling time Aminoglicosides Peak : 0.5 h from end 30 min infusion Quinolones peak : 0.5 h from end 60 min infusion Betalactams peak :0.5 h from end 30 min infusion And T>MIC : 5.6 hours from start infusion

26. Concentrations of ceftazidime and cefotaxime in serum 0 5 10 15 20 25 30 35 40 45 50 55 60 65 mg/L C 0.5 h C 5.6 h

27. Peak levels of amikacin 0 10 20 30 40 mg/L

28. PK/PD dose adjustment Levofloxacin 500 mg to 750 OD or BID Ciprofloxacin 500mg to 750 BID Cefotaxime-Ceftazidime 2g q 8 to 2g q6 Amikacin 15 mg/kg OD to 20 mg/kg OD* * Patients are daily monitored for safety

29. preliminary results October 2000 – April 2001 Patients included 680 Evaluated for PK/PD 223 (32.8%) Dose or interval adjusted 84 (37.7%) Adjustment failed in 6 (5 cipro -1 amikacin)

30. diagnosis Nosocomial pneumonia 105 Sepsis 44 upper UTI 57 Necrotizing Fascitis 8 Others 9

31. Organisms isolated Pseudomonas aeruginosa 87 Staphylococcus aureus 42 Enterobacter species 33 Klebsiella species 15 Escherichia coli 14 Haemophilus influenzae 11 Serratia marcescens 7 Streptococcus pneumoniae4 Stenotrophomonas spp 4 Legionella species2 Citrobacter species2 Acinetobacter1 Proteus species1

32. outcome Length hospitalization - days* failure PK/PD analysed 11 (7-16) 39/223 (17.5%) PK/PD Not analysed 16 (9-23 ) 147/457 (31.9 %) *From the diagnosis of infection

33. 0255075100125150175 0 5 10 15 20 hours to adjust doses hospitalization days correlation between time to adjust the dose and hospitalisation days

34. Conclusions I The PK/PD approach may:  improve the outcome  shorten the time to clinical improvement  Reduce the length of hospitalisation

35. Conclusions II The initial higher costs for analysis and personnel are compensate for the reduction of the hospitalisation, with a financial gain

36. Conclusions III Can PK/PD be used in everyday clinical practice? yes