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Advances Against Aspergillosis Istanbul, 2012 Anti-fungal therapeutic drug monitoring and azole dose modification Tim Felton.

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Presentation on theme: "Advances Against Aspergillosis Istanbul, 2012 Anti-fungal therapeutic drug monitoring and azole dose modification Tim Felton."— Presentation transcript:

1 Advances Against Aspergillosis Istanbul, 2012 Anti-fungal therapeutic drug monitoring and azole dose modification Tim Felton

2 Advances Against Aspergillosis Istanbul, 2012 Contents Triazoles – an overview Therapeutic drug monitoring (TDM) Specific drugs

3 Advances Against Aspergillosis Istanbul, 2012 Triazoles Bind cytochrome P450-enzyme lanosterol 14- demethylase Inhibits the conversion of lanosterol to ergosterol Fluconazole Itraconazole Voriconazole Posaconazole (Isavuconazole)

4 Advances Against Aspergillosis Istanbul, 2012 Therapeutic window Emergence of resistance

5 Advances Against Aspergillosis Istanbul, 2012 Peak Concentration Time>threshold AUC Exposure MIC

6 Advances Against Aspergillosis Istanbul, 2012 Indications for TDM 1.Variable pharmacokinetics

7 Advances Against Aspergillosis Istanbul, 2012 PK-PD: the black arts DOSE BIOMARKER OUTCOME OF CLINICAL INTEREST/IMPORTANCE Survival Resolution of clinical syndrome Quantifiable Linked to pathogenesis Linked to an outcome of clinical interest PHARMACOKINETICSPHARMACODYNAMICS Conc Dose

8 Advances Against Aspergillosis Istanbul, 2012 Pharmacokinetic variability Toxic Sub- therapeutic Voriconazole Concentration (mg/L) Time (hours)

9 Advances Against Aspergillosis Istanbul, 2012 Hope WW. AAC. 2012. In press Pharmacokinetic variability

10 Advances Against Aspergillosis Istanbul, 2012 Howard S. TDM. 2012. 34:72-76 Pharmacokinetic variability

11 Advances Against Aspergillosis Istanbul, 2012 Pharmacokinetic variability Absorption –Vomiting –Diet –Genetic differences in drug- transport/gut-metabolism –Concomitant medications Distribution –Amount of body fat –Presence of extravascular fluid collections –Hypoalbuminaemia Metabolism –Hepatic dysfunction –Genetic differences in drug- metabolism –Concomitant medications Excretion –Hepatic dysfunction –Renal insufficiency –Genetic differences in drug- elimination pathways

12 Advances Against Aspergillosis Istanbul, 2012 Pharmacogenomics

13 Advances Against Aspergillosis Istanbul, 2012 Absorption Time (hours) Suspension (fasted) Suspension (high-fat meal) Suspension (non-fat meal) Courtney R. Br J Clin Pharmacol 2004:218–222.

14 Advances Against Aspergillosis Istanbul, 2012 Saturation of metabolism 6 mg/kg i.v 2 dosages 4 mg/kg b.d. i.v 200 mg bd oral

15 Advances Against Aspergillosis Istanbul, 2012 Saturation of metabolism Dosage escalation from 200 mg bd to 300 mg bd

16 Advances Against Aspergillosis Istanbul, 2012 Indications for TDM 1.Variable pharmacokinetics 2.Clinically relevant exposure–response relationships

17 Advances Against Aspergillosis Istanbul, 2012 Exposure-response relationship Warn PA. AAC. 2012. In press

18 Advances Against Aspergillosis Istanbul, 2012 Indications for TDM 1.Variable pharmacokinetics 2.Clinically relevant exposure–response relationships

19 Advances Against Aspergillosis Istanbul, 2012 Experimental IPA in rabbits Berenguar et al, AAC 1994;38:1303-8

20 Advances Against Aspergillosis Istanbul, 2012 Hope WW AAC. 2012. 56:526-31. Exposure-trough conc.

21 Advances Against Aspergillosis Istanbul, 2012 In-vitro alveolus model of IPA Jeans. A. JID. 2012. In press

22 Advances Against Aspergillosis Istanbul, 2012 Clinical IPA Pascual et al. CID. 2008. 46:201-11 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 0.80 0.90 1.00 Probability effect Effect

23 Advances Against Aspergillosis Istanbul, 2012 Indications for TDM 1.Variable pharmacokinetics 2.Clinically relevant exposure–response relationships 3.Clinically relevant exposure–toxicity relationships

24 Advances Against Aspergillosis Istanbul, 2012 Lestner J M. CID. 2009. 49:928-930 Concentration-toxicity

25 Advances Against Aspergillosis Istanbul, 2012 Clinical IPA Pascual et al. CID. 2008. 46:201-11

26 Advances Against Aspergillosis Istanbul, 2012 Indications for TDM 1.Variable pharmacokinetics 2.Clinically relevant exposure–response relationships 3.Clinically relevant exposure–toxicity relationships 4.Narrow therapeutic window

27 Advances Against Aspergillosis Istanbul, 2012 Clinical IPA Pascual et al. CID. 2008. 46:201-11 Therapeutic window

28 Advances Against Aspergillosis Istanbul, 2012 Indications for TDM 1.Variable pharmacokinetics 2.Clinically relevant exposure–response relationships 3.Clinically relevant exposure–toxicity relationships 4.Narrow therapeutic window 5.Unable to rapidly assess response 6.Serious/poor prognostic disease 7.Drug–drug interactions 8.Compliance 9.Dosage adjustment

29 Advances Against Aspergillosis Istanbul, 2012 Specific dugs Fluconazole Itraconazole Voriconazole Posaconazole Indication Pharmacology/pharmacokinetics Exposure–response relationship Exposure–toxicity relationship TDM target

30 Advances Against Aspergillosis Istanbul, 2012 Fluconazole Indication –Prophylaxis –Empirical therapy –Treatment of superficial and invasive candidiasis Pharmacology/pharmacokinetics –Linear PK –High bioavailability Exposure–response relationship –Well defined Rodríguez-Tudela J L. AAC. 2007. 51:3599-3604

31 Advances Against Aspergillosis Istanbul, 2012 Fluconazole Exposure–toxicity relationship –High LFTs, nausea, vomiting, seizures at high dosages TDM target –Wide therapeutic index –Treatment of isolates with reduced susceptibility –Poor absorption –Paediatric patients

32 Advances Against Aspergillosis Istanbul, 2012 Itraconazole Indication –Prophylaxis of IFI –Treatment of IPA –Treatment of CPA –Treatment of ABPA

33 Advances Against Aspergillosis Istanbul, 2012 Itraconazole Pharmacology/pharmacokinetics –Highly lipophilic and protein bound – capsule solubility in acidic environment –Different manufactures' capsules behave differently – absorption with PPI and H 2 -antagonists –Suspension (cyclodextrin) 20-50% higher bioavailability –Non-linear (probably) –Extensive variability –Active metabolite (OH-itraconazole) (bioassay/HPLC) –CYP3A4

34 Advances Against Aspergillosis Istanbul, 2012 Itraconazole Exposure–response relationship –Peak itraconazole levels and successful outcome of mucosal candidiasis in patients with AIDS –In vivo data Exposure–toxicity relationship –Gastrointestinal intolerance, hypokalaemia, fatigue, ankle oedema, cardiac failure and deranged LFTs –Nausea more common with suspension (cyclodextrin)

35 Advances Against Aspergillosis Istanbul, 2012 Itraconazole TDM target –200mg b.i.d. –Trough concentration –Lower level Prophylaxis in neutropenia & treatment of oesophageal candidasis in HIV 0.5mg/L HPLC or 5mg/L bioassay –Upper level 17mg/L (bioassay)due to high probability of toxicity

36 Advances Against Aspergillosis Istanbul, 2012 Itraconazole Tips to improve low levels –Usually poor absorption 1.Capsule with food or acid drink? 2.Stop PPI or H 2 -antagonist (if possible) 3.Compliance 4.Consistently prescribe the same preparation 5.Check for drug interactions 6.Increase to capsule 300mg twice daily or change to suspension 200mg twice daily 7.Check serum levels again!

37 Advances Against Aspergillosis Istanbul, 2012 Itraconazole Tips to reduce high levels +/- toxicity –Usually saturated clearance 1.Stop drug for 1-2 weeks 2.Re-start at a lower dose 3.Check serum levels again!

38 Advances Against Aspergillosis Istanbul, 2012 Voriconazole Indication –Disseminated candidasis –IPA and CPA Pharmacology/pharmacokinetics –Excellent bioavailabilty (96%) –IV preparation – cyclodextrin (potentially nephrotoxic) –Marked PK variability (100-fold) –Sex, age and CYP2C19 genotype only partially explain –Weight important in paediatric patients –CYP2C19, 3A4 and 2C9 substrate Herbrecht R. NEJM. 2002. 347:408-15

39 Advances Against Aspergillosis Istanbul, 2012 Voriconazole Exposure–response relationship –In-vivo, in-vitro and clinical data Exposure–tox icity relationship –Gradual increase in probability with increasing concentration –Abnormal LFTs, visual disturbance, photosensitivity, confusion etc Pascual et al. CID. 2008:46;201-11

40 Advances Against Aspergillosis Istanbul, 2012 Voriconazole TDM target –200mg b.i.d. (i.v. loading dose) –Trough concentration –Lower level Trough 1mg/L associated with 70% probability of success –Upper level Less well established >6mg/L associated with high probability of CNS toxicity and hepatitis

41 Advances Against Aspergillosis Istanbul, 2012 Voriconazole Tips on use –Loading dose –Switch IV to oral Tips to improve low levels –Dosage escalation carefully by 50mg daily –Check levels every 1-2/52 Tips to reduce high levels +/- toxicity –Stop for 1 week or by TDM then reduce dosage –Stop omeprazole –Check levels

42 Advances Against Aspergillosis Istanbul, 2012 Posaconazole Indication –Salvage therapy IPA –Prophylaxis neutropenia and HSCT Pharmacology/pharmacokinetics –Only oral suspension –Linear PK to 800mg/day –Absorption saturated above 800mg/day –Better absorption with fatty food and low stomach pH –Long t½ with comparable average and trough levels –Variability Felton TW. CID. 2010;51:1383-1391

43 Advances Against Aspergillosis Istanbul, 2012 Posaconazole Exposure–response relationship –In-vivo (mouse IC and rabbit IPA) –Increased clinical response with increasing average and trough concentration Exposure–toxicity relationship –GI intolerance, abnormal LFT –No dose dependent Walsh T. CID. 2007. 44. 2-12

44 Advances Against Aspergillosis Istanbul, 2012 Posaconazole TDM target –400mg b.i.d –Trough concentration (but long t½ life) –Lower level >0.7mg/L Higher might be better if formulation/cost allowed! –Upper level Not known/defined

45 Advances Against Aspergillosis Istanbul, 2012 Posaconazole Tips to improve low levels –Fatty foods, milk or fatty food supplements –Stop enzyme inducers –Stop PPIs –Can try fractionating the regimen –Dosage escalation unhelpful above 800mg/day

46 Advances Against Aspergillosis Istanbul, 2012 Indications for TDM 1.Variable pharmacokinetics 2.Clinically relevant exposure–response relationships 3.Clinically relevant exposure–toxicity relationships 4.Narrow therapeutic window 5.Unable to rapidly assess response 6.Serious/poor prognostic disease 7.Drug–drug interactions 8.Compliance 9.Dosage adjustment

47 Advances Against Aspergillosis Istanbul, 2012 Therapeutic window Emergence of resistance

48 Advances Against Aspergillosis Istanbul, 2012 Conclusions TDM required for itraconazole and voriconazole Probably for posaconazole TDM should –Improve outcomes –Reduce emergence of resistance –BUT there is an associated cost

49 Advances Against Aspergillosis Istanbul, 2012 Fungal infection and allergy Invasive fungal infection –High mortality and morbidy Chronic fungal infection –High mortality and morbidy Fungal allergy –High morbidy

50 Advances Against Aspergillosis Istanbul, 2012 Fungal infection and allergy Triazole are the most commonly used treatment Increasing levels of triazole resistance

51 Advances Against Aspergillosis Istanbul, 2012 Saturation of metabolism

52 Advances Against Aspergillosis Istanbul, 2012 Saturation of metabolism


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