Is monitoring of azole concentrations of clinical value in patients with haematological malignancies?

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1 Is monitoring of azole concentrations of clinical value in patients with haematological malignancies? J Peter Donnelly PhD Department of Haematology Radboud University Nijmegen Medical Centre Nijmegen, The Netherlands

2 Route Oral, parenteral or ssssubcutaneousss

3 Setting Outpatient Inpatient

4 Strategies for treating IFD Signs & symptoms No No Persistent febrile neutropenia Yes Radiological signs Radiological signs Mycology Negative Positive biomarker Negative Negative Negative Positive Biomarker or microscopy or culture EORTC/MSG Possible Probable Strategy Prophylaxis Pre-emptive therapy Empirical therapy Pre-emptive therapy Directed therapy Directed therapy IV or oral azole

5 ECIL recommendations Azole Prophylaxis 1 st line therapy Salvage therapy Itraconazole Oral BI IV then oral CIII IV then Oral IV Oral Oral CIII Voriconazole Oral IV then oral AI IV then oral IV Oral CIII Oral BII Posaconazole Oral AI Oral Oral BII

6 Some questions to ask oral or IV administration of the azole? treatment or prophylaxis? If treatment is it for fever, suspected IFD, possible IFD or probable/proven IFD? is there no other alternative to the azole?

7 Clinical value TDM harms helps

8 What do we want to know? Is the patient taking the medication? Is the patient absorbing the medication? Are the levels likely to result in toxicity? Are the levels optimum for efficacy?

9 is the patient taking the azole?

10 Are you taking the medication?

11 Minimum levels Azole Itraconazole Voriconazole Posaconazole Trough levels 1-2 mg/l 1 2 mg/l mg/l

12 Consequences of non compliance You taken your medication? Yep but it sure is hard to swallow!

13 Is the azole being absorbed?

14 Posaconazole levels and prophylaxis Lebeaux et al. Antimicrob Chemother Ag 2009; 53:

15 Improving the absorption of posaconazole High fat Carbonated drinks PPIs

16 TDM of oral voriconazole Ueda et al Int J Hematol. 2009;89:592-9

17 Consequences of low levels Azole Itraconazole Voriconazole Posaconazole Action Increase dose or switch to IV Increase dose or switch to IV Increase dose

18 Levels likely to result in toxicity

19 Toxic levels Azole Trough levels Itraconazole >10 mg/l Voriconazole Posaconazole > 6 mg/l No data

20 Voriconazole levels and toxicity Pascual et al. Clin Infect Dis 2008; 46:

21 Voriconazole levels and toxicity Ueda et al Int J Hematol. 2009;89:592-9

22 Dosage and levels of patients Pascual et al. Clin Infect Dis 2008; 46:

23 Dosage and levels of patients Pascual et al. Clin Infect Dis 2008; 46:

24 Consequences of toxic levels Azole Itraconazole Voriconazole Posaconazole Action Lower dose, suspend treatment OR change to another drug Lower dose, suspend treatment OR change to another drug Lower dose, suspend treatment OR change to another drug

25 Levels optimum for efficacy

26 Therapeutic levels Azole Itraconazole Voriconazole Posaconazole Trough levels >1-2 - <10 mg/l >1-2 - <6 mg/l > mg/l

27 Dosage and levels of patients Pascual et al. Clin Infect Dis 2008; 46:

28 Voriconazole levels and outcome Pascual et al. Clin Infect Dis 2008; 46:

29 Consequences of toxic levels Azole Itraconazole Voriconazole Posaconazole Action Increase dose or switch to IV Increase dose or switch to IV Increase dose

30 What is needed for effective monitoring

31 Dutch voriconazole study am pm Action: increase dose to 5 mg/kg

32 Dutch voriconazole study am pm Action: decrease dose to 4 mg/kg

33 Dutch voriconazole study am pm Twice weekly if in hospital

34 Cost-effectiveness of TDM of azole drugs TDM of voriconazole is useful (C3) TDM of itraconazole can be useful (C3) TDM of posaconazole (no data) Recommendations: Voriconazole therapy must be guided by TDM. TDM can be useful to guide therapy of itraconazole. Touw et al. EJHP Science 2007; 4:

35 Clinical ordering of voriconazole levels Lack of information on dose and sample timing Delay in delivery to the laboratory Lack of clinical details No follow up samples Problem with Fridays Lack of synchronisation between sample cycling and dosing cycling Failure to see TDM as a care pathway Miyakis et al. Ther Drug Monit 2010; epub

36 Care pathway for TDM azole level Too low In range Too high Increase exposure Decrease exposure Increase dose Switch to IV If all else fails switch level to other drug Decrease dose Suspend therapy Too low In range Too high

37 Final question Will the results of the azole assay add more to the clinical decision making process than sound clinical judgment alone? Yes for compliance Yes for absorption No for efficacy Perhaps for toxicity