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Anti-fungal therapeutic drug monitoring and azole dose modification

Anti-fungal therapeutic drug monitoring and azole dose modification. Tim Felton. Contents. Triazoles – an overview Therapeutic drug monitoring (TDM) Specific drugs. Triazoles. Bind cytochrome P450-enzyme lanosterol 14-  demethylase Inhibits the conversion of lanosterol to ergosterol

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Anti-fungal therapeutic drug monitoring and azole dose modification

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  1. Anti-fungal therapeutic drug monitoring and azole dose modification Tim Felton

  2. Contents • Triazoles – an overview • Therapeutic drug monitoring (TDM) • Specific drugs

  3. Triazoles • Bind cytochrome P450-enzyme lanosterol 14- demethylase • Inhibits the conversion of lanosterol to ergosterol • Fluconazole • Itraconazole • Voriconazole • Posaconazole • (Isavuconazole)

  4. Emergence of resistance Therapeutic window

  5. Exposure Peak Concentration AUC MIC Time>threshold

  6. Indications for TDM • Variable pharmacokinetics

  7. PK-PD: the black arts DOSE OUTCOME OF CLINICAL INTEREST/IMPORTANCE BIOMARKER • Quantifiable • Linked to pathogenesis • Linked to an outcome • of clinical interest • Survival • Resolution of clinical syndrome Conc Dose PHARMACOKINETICS PHARMACODYNAMICS

  8. Pharmacokinetic variability Voriconazole Concentration (mg/L) Toxic Sub-therapeutic Time (hours)

  9. Pharmacokinetic variability Hope WW. AAC. 2012. In press

  10. Pharmacokinetic variability Howard S. TDM. 2012. 34:72-76

  11. 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. Pharmacogenomics

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

  14. Saturation of metabolism Dosage escalation from 200 mg bd to 300 mg bd

  15. Indications for TDM • Variable pharmacokinetics • Clinically relevant exposure–response relationships

  16. Indications for TDM • Variable pharmacokinetics • Clinically relevant exposure–response relationships

  17. Experimental IPA in rabbits Berenguar et al, AAC 1994;38:1303-8

  18. Exposure-trough conc. Hope WW AAC. 2012. 56:526-31.

  19. 0 1 2 3 4 5 6 7 8 9 10 Voriconazole trough concentrations (mg/L) Clinical IPA Effect 1.00 0.90 0.80 0.70 0.60 Probability effect 0.50 0.40 0.30 0.20 0.10 0.00 Pascual et al. CID. 2008. 46:201-11

  20. Indications for TDM • Variable pharmacokinetics • Clinically relevant exposure–response relationships • Clinically relevant exposure–toxicity relationships

  21. Concentration-toxicity Lestner J M. CID. 2009. 49:928-930

  22. Clinical IPA Effect Toxicity 1.00 0.90 0.80 0.70 0.60 Probability effect or toxicity 0.50 0.40 0.30 0.20 0.10 0.00 0 1 2 3 4 5 6 7 8 9 10 Voriconazole trough concentrations (mg/L) Pascual et al. CID. 2008. 46:201-11

  23. Indications for TDM • Variable pharmacokinetics • Clinically relevant exposure–response relationships • Clinically relevant exposure–toxicity relationships • Narrow therapeutic window

  24. Clinical IPA Therapeutic window Effect Toxicity 1.00 0.90 0.80 0.70 0.60 Probability effect or toxicity 0.50 0.40 0.30 0.20 0.10 0.00 0 1 2 3 4 5 6 7 8 9 10 Voriconazole trough concentrations (mg/L) Pascual et al. CID. 2008. 46:201-11

  25. Indications for TDM • Variable pharmacokinetics • Clinically relevant exposure–response relationships • Clinically relevant exposure–toxicity relationships • Narrow therapeutic window • Unable to rapidly assess response • Serious/poor prognostic disease • Drug–drug interactions • Compliance • Dosage adjustment

  26. Specific dugs • Fluconazole • Itraconazole • Voriconazole • Posaconazole • Indication • Pharmacology/pharmacokinetics • Exposure–response relationship • Exposure–toxicity relationship • TDM target

  27. 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

  28. 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

  29. Itraconazole • Indication • Prophylaxis of IFI • Treatment of IPA • Treatment of CPA • Treatment of ABPA

  30. Itraconazole • Pharmacology/pharmacokinetics • Highly lipophilic and protein bound •  capsule solubility in acidic environment • Different manufactures' capsules behave differently •  absorption with PPI and H2-antagonists • Suspension (cyclodextrin) 20-50% higher bioavailability • Non-linear (probably) • Extensive variability • Active metabolite (OH-itraconazole) (bioassay/HPLC) • CYP3A4

  31. 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)

  32. 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

  33. Itraconazole • Tips to improve low levels • Usually poor absorption • Capsule with food or acid drink? • Stop PPI or H2-antagonist (if possible) • Compliance • Consistently prescribe the same preparation • Check for drug interactions • Increase to capsule 300mg twice daily or change to suspension 200mg twice daily • Check serum levels again!

  34. Itraconazole • Tips to reduce high levels +/- toxicity • Usually saturated clearance • Stop drug for 1-2 weeks • Re-start at a lower dose • Check serum levels again!

  35. 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

  36. Voriconazole • Exposure–response relationship • In-vivo, in-vitro and clinical data • Exposure–toxicity relationship • Gradual increase in probability with increasing concentration • Abnormal LFTs, visual disturbance, photosensitivity, confusion etc Pascual et al. CID. 2008:46;201-11

  37. 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

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. Indications for TDM • Variable pharmacokinetics • Clinically relevant exposure–response relationships • Clinically relevant exposure–toxicity relationships • Narrow therapeutic window • Unable to rapidly assess response • Serious/poor prognostic disease • Drug–drug interactions • Compliance • Dosage adjustment

  44. Emergence of resistance Therapeutic window

  45. Conclusions • TDM required for itraconazole and voriconazole • Probably for posaconazole • TDM should • Improve outcomes • Reduce emergence of resistance • BUT there is an associated cost

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