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PK/PD: TOWARDS DEFINITIVE CRITERIA

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. PK/PD results and evolution. }. }. Improvement of dose and intervals. Outcome resistance.

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PK/PD: TOWARDS DEFINITIVE CRITERIA

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  1. PK/PD: TOWARDS DEFINITIVE CRITERIA PK/PD in clinical Practice: new level of PK/PD Francesco ScaglioneDepartment of Pharmacology, Toxicologyand Chemotherapy, University of Milan, Milan, Italy

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

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

  4. PK/PD evolution 2000 Custom-made therapy

  5. Pharmacology : what for physician? 20 18 16 14 12 concentration (µg/ml) 10 A D M E 8 6 4 2 0 In Vitro and in vivo activity 2 3 4 5 6 7 8 9 10 11 12 0 1 time h Effect over the time; Peculiar Effects

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

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

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

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

  10. In clinical practice 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

  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 105 (90-140) 230 (175-320) Cmax (µg/ml)a 5.3 (3.9-6.3) 6.7 (5.2-7.6) Cmin (µg/ml)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 CL (ml/min/1.73 m2) 71.5 (50.4-91.3) Aminoglycoside half-life (h) 3.5 (2.6-5.0) AUC0-24 (µg · h/ml) 52.2 (34.5-77.5) First Cmax/MIC 3.6 (1.4-6.2) Second Cmax/MIC 3.7 (1.9-6.9) Aminoglycoside pharmacokinetic and pharmacodynamic variables for 78 patients with pneumonia caused by gram-negative bacteria Variable Median (interquartile range) Adapted from Angela D. M. Kashuba; AAC 1999

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

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

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

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

  17. Vd of Tobramicin in 13 patients admitted in ICU 50 40 L 30 20 10 0 0 1 2 3 4 5 6 7 days

  18. Serum peak of Tobramicin in 13 patients admitted in ICU 10.0 mg/L 7.5 5.0 2.5 0.0 0 1 2 3 4 5 6 7 days

  19. Time Over MIC Peak/MIC Concentration M IC2 M IC1 Time ‘Time above 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 problemPK approach to adjust the dose is poor applicable for routinely use(at moment) • N°samples • Personnel • Costs • Microbiology

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

  23. Program to customize the therapyin 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 65 60 55 50 45 mg/L 40 35 30 25 20 15 10 5 0 C 0.5 h C 5.6 h

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

  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 Sepsis44 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 pneumoniae 4 Stenotrophomonas spp 4 Legionella species 2 Citrobacter species 2 Acinetobacter 1 Proteus species 1

  32. outcome *From the diagnosis of infection

  33. correlation between time to adjust the dose and hospitalisation days 20 15 hospitalization days 10 5 0 0 25 50 75 100 125 150 175 hours to adjust doses

  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

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