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Pharmacotherapy of antifungal drugs

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  1. Pharmacotherapy of antifungal drugs Isabel Spriet Pharmacy Dpt, UZ Leuven

  2. The fungal ‘players’ • Opportunistic fungi • Normal flora • Candida spp. • Ubiquitious in our environment • Aspergillus spp. • Cryptococcus spp. • Mucor spp.

  3. Invasive fungal infections - Incidence • Solid organ transplant: 5-42% • Bone marrow transplant: 15-25% • ICU: 17% Singh N. Clin Infect Dis 2000;31:545-53 Vincent JL. Intens Care Med 1998; 24:206-216

  4. Candidemia – Mortality rate Hospital acquired pathogens and their associated mortality Edmond et al. CID 1999; 29:239-44.

  5. Invasive Aspergillosis – Mortality Rate Review of 1941 Patients from 50 Studies Lin S-J et al, CID 2001; 32:358-66

  6. Risk factors for fungal disease

  7. Fungal infections today A major change in the occurence, diagnosis and management of invasive fungal infections has arisen in the recent years.

  8. Licensed antifungals: a dynamic drug class To be expected: isovuconazole – anidulafungin – micafungin … Posaconazole Voriconazole Caspofungin Lipid amphotericin products Itraconazole Fluconazole Ketoconazole Flucytosine Amphotericin B 1950 1960 1970 1980 1990 2000

  9. OutlineProduct Overview • Spectrum • Therapeutic indications • Recommended dosages • Pharmacokinetics • Pharmacokinetic difficulties and problems • Tolerability and safety • Therapeutic drug monitoring?

  10. An ideal antifungal agent has… • Broad spectrum of activity (yeasts and moulds) • Rapidly and highly fungicidal, stable to resistance • Potent in vivo activity (even in neutropenia) • Good pharmacokinetics (AUC) • Both oral and parenteral formulations • Good penetration into all tissue compartments • Low toxicity, minimal drug-drug interactions • Cost effective

  11. Polyenes

  12. Amphotericin BTarget: fungal cell membrane • Ampho B binds ergosterol in the cell membrane • depolarisation: leakage of monovalent and divalent cations •  cell death • stimulates host immune response

  13. Amphotericin BSpectrum and Recommended dosage • Spectrum: • very broad range of activity: most Candida and Aspergillus spp. • active against most fungi except A. terreus, Fusarium spp. • Fungicidal • Amphotericin B: 1 mg/kg IV (after a test dose of 1 mg) • Lipid-based Amphotericin B • amphotericin B Lipid Complex: 5 mg/kg IV • liposomal amphotericin B: 3 mg/kg IV

  14. Amphotericin BPharmacokinetics • Low oral bioavailability: only IV administration • Extensive distribution • High concentrations in liver, spleen, bone marrow • No metabolism • Renal excretion • Halflife: about 5 days

  15. Amphotericin BTolerability and Safety • chills, rigors, fever (during infusion) • nausea, vomiting • cardio/respiratory reactions • phlebitis • can be explained by mode of action: ampho B stimulates host immune response with release of inflammatory cytokines

  16. Amphotericin BTolerability and Safety • Nephrotoxicity: incidence: 49-65% • Hypokalemia can be explained by mode of action: ampho B binds cholesterol in distal tubular membrane leading to wasting of Na+, K+ and Mg++

  17. Amphotericin BTolerability and Safety • Nephrotoxicity has been shown to significantly increase: • Length of hospital stay • Treatment costs • Prevention of nephrotoxicity • Fluids: saline, sodium bicarbonate • Low-dose vasoconstrictors (e.g. dopamine) • Alternate day dosing • Infusion rates (conventional ampho B: at least 6 hrs) • Lipid formulations Bates DW. CID 2001; 32: 686-93. Cagnoni PJ. J Clin Oncol 2000; 18: 2476-83. Greenberg RN. J Med Economics 2002; 2: 109-18.

  18. Azoles

  19. The azolesTarget: fungal cell membrane • Azoles inhibit ergosterol synthesis by inhibiting 14-α-demethylase • toxic sterol intermediates accumulate in the cell membrane leading to enhanced cellular permeability and inhibition of fungal growth

  20. Inhibits also human CYP450-dependent enzymes playing an important role in human hormone synthesis or drug metabolism DRUG INTERACTIONS!!!

  21. Fluconazole

  22. FluconazoleSpectrum, therapeutic indications, dosage • Spectrum: Candida spp. except C. krusei (C. glabrata: reduced susceptibility), Cryptococcus spp. • Indications and dosage: • Prophylaxis in neutropenic patients: fluco 200 mg • Treatment of Candida-infections: Charlier C. JAC 2006; 57:384-410.

  23. FluconazolePharmacokinetics Charlier C. JAC 2006; 57:384-410.

  24. FluconazolePharmacokinetics • Pharmacokinetic problems? • Majority unchanged renal excretion  glomerular filtration+ tubular reabsorption • Dose adjustments in severe renal failure • Removed by dialysis: 100 mg extra dose after IHD • Drug interactions: • Inhibits CYP2C9, CYP2C19 and CYP3A4 • cyclosporin – nephrotoxicity: TDM • midazolam: excessive sedation • phenytoin: TDM • tacrolimus – nephrotoxicity, neurotoxicity: TDM • warfarin: INR • Rifampicin induces fluconazole metabolism: • increase fluco dose with 25% Charlier C. JAC 2006; 57:384-410.

  25. FluconazoleTolerability and Safety • Generally very well tolerated: no adverse events • Side effects only occur in high doses (>400 mg/day) • Common: headache, nausea, abdominal pain • Elevated AST/ALT levels: generally mild • Reported in 10% of leukemia patients with fluco prophylaxis • Reported in 20% of ICU patients with fluco prophylaxis • Rare: case reports of fulminant hepatitis • Very rare: • neurotoxicity (high doses > 1200 mg/day), • prolongation of the QT interval Charlier C. JAC 2006; 57:384-410.

  26. FluconazoleTherapeutic drug monitoring? • No routine indications for measuring fluco levels • Predictable fluconazole PK and serum concentrations Charlier C. JAC 2006; 57:384-410.

  27. Voriconazole

  28. VoriconazoleSpectrum of activity • Invasive aspergillosis • fungicidal activity as great as ampho B • Invasive candidiasis • C. glabrata? • Fusarium, Penicillium, Scedosporium • Cryptococcus • in vitro activity > flucytosine or fluconazole • ! Zygomycetes: resistant to voriconazole • Breakthrough infections Mashmeyer G et al. Future Microbiol 2006; 1: 365-85.

  29. VoriconazoleRecommended dosage • Loading dose: 2 x 6mg/kg • Maintenance dose: 2 x 4 mg/kg • Infusion over 1hr • Adult Patients < 40 kg • Loading dose idem • Maintenance dose: 2 x 2 mg/kg or 2 x 100 mg • Child A and B cirrhosis (Child C: no data) • Loading dose idem • Maintenance dose: 2 x 2 mg/kg or 2 x 100 mg • Children (2-12 yrs) • 2 x 7 mg/kg

  30. VoriconazolePharmacokinetics

  31. VoriconazolePharmacokinetics Voriconazole serum levels: high interindividual variability! !Difficult pharmacokinetics! • Non-linear kinetics: saturable metabolism! • Disproportional increase in plasma levels if dosage increased • Half-life = dose dependent • In children: linear pharmacokinetics: higher metabolising capacity • Dosage 7 mg/kg bid • Genetic polymorphism CYP2C19 • 3 genotypes: extensive metabolizers, heterozygous extensive metabolizers, poor metabolizers • PM especially in Asian population: 18-23% • PM in Caucasion population: 3-5% • Plasma levels up to 2-fold (HEM) or 4- fold (PM) higher! Purkins L et al. AAC 2002; 46:2546-53.

  32. VoriconazolePharmacokinetics • Extensive CYP-metabolism: drug interactions! • Other drugs affecting voriconazole plasma levels • Contra-indicated with potent inducers • Rifampicin, ritonavir, carbamazepine, phenobarbital • Dose adjustments needed if combined with phenytoin (5 mg/kg bid) • Voriconazole affecting plasma levels of others (inhibition) • Contra-indicated with sirolimus, terfenadines, astemizole, cisapride, … • Dose adjustments needed if combined with • Cyclosporin (- 50% ): if not, risk of nephrotoxicity • Tacrolimus (- 66%): if not, risk of nephrotoxicity

  33. VoriconazolePharmacokinetics • Oral bio-availability affected if taken with food • reduction oral bio-availability with > 20%! • no studies if administered with enteral feeding on ICU • Stop enteral feeding 1hr before up to 2 hrs after administration • Administration 2x daily: 6 hrs without calory intake! Purkins L et al. Br J Clin Pharmacol 2003; 56 (S1): 17-23

  34. VoriconazoleSafety • Visual disturbances: (20%) • Altered perception of light, photophobia, blurred vision, color vision changes: mechanism unknown • transient, infusion related • more in patients with higher levels - how to assess in sedated patients? • Hepatotoxicity (13%) • AST, ALT, alkaline phosphatase, bilirubin elevations • AST, ALP and BILI abnormalities correlating with higher vorico plasma levels • Phototoxicity (6%): erythema, Steven-Johnson syndrome, toxic epidermal necrolysis • Neurological changes: confusion and hallucinations

  35. VoriconazoleSafety • Adverse effects of voriconazole • French pharmacovigilance database • 4 year registration period • detailed registration of cases • causality assessment • Results • LFT abnormalities in 23% patients • Visual disturbances in 18% of patients • Skin rashes in 17% of patients • Cardiovascular events (10%), hematologic disorders (8%) renal disturbances (4%) Eiden C. Ann Pharmacother 2007; 41:755-63

  36. VoriconazoleTolerability and Safety • Nephrotoxicity of SBECD • IV vials contain SBECD, a solubilizer • in patients with moderate to severe renal failure (CrCl < 50 ml/min): accumulation of SBECD with potential nephrotoxicity (vacuolization of urinary epithelium) • frequent problem in ICU patients: switch to oral formulation? Or other product? Von Mach MA et al. BMC Clin Pharamacol 2006; 6:6

  37. VoriconazoleTherapeutic drug monitoring? • Complex pharmacokinetics High inter and intra- individual variability!! • Serum levels correlated with efficacy/safety? • Optimal serum levels: 2-6 µg/ml • Well above MIC of Aspergillus/Candida spp.

  38. VoriconazoleTherapeutic drug monitoring? • TDM voriconazole • 52 adult patients: 181 samples • 25%: levels < 1mg/L • Correlated with oral therapy • Lack of response more frequent in this group • 31%: levels > 5.5 mg/L • Correlated with omeprazole comedication • 5 patients with neurotoxicity • 4 of 5 treated intravenously • TDM improves efficacy and safety • Proposed therapeutic interval 1-5.5 µg/ml • Pascual A. CID 2008;46:201-211.

  39. VoriconazoleTherapeutic drug monitoring? • TDM … • in all patients? • in patients with progressive disease? • in patients exhibiting significant visual or hepatic toxicity? • in patients at risk of fluctuating plasma levels? • drug interactions? • changing hepatic and renal function? • treated by mouth? • ICU? • daily (cost-effectiveness)? • method? • dose adjustments? • non-lineair kinetics! Goodwin M et al. JAC 2007. Epub

  40. Posaconazole

  41. PosaconazoleSpectrum, therapeutic indication and dosage • Spectrum: Candida spp. (less active C. glabrata), Aspergillus spp., C. neoformans, H. capsulatum, Zygomycetes • Indications: • Prophylaxis of invasive fungal infections in high-risk patients (SCTx – GvHD, AML-MDS) • Treatment of IA, fusariosis, chromoblastosis, mycetoma, coccidiomycosis refractory to ampho B or itra • Dosage: 200 mg 3 - 4x/day • Only available as oral suspension

  42. PosaconazolePharmacokinetics Schiller D et al. Clin Ther 2007; 29: 1862-1886

  43. PosaconazolePharmacokinetics Posaconazole levels: high interindividual variability! !Difficult pharmacokinetics! • Absorption • 2.6-4-fold higher if taken with a meal • High-fat meals enhance absorption • Cimetidine: gastric pH: 40% decrease in posaconazole AUC and Cmax • Avoid concomitant use of histamine 2-blockers or PPIs! • Mucositis? Schiller D et al. Clin Ther 2007; 29: 1862-1886 Goodwin M et al. JAC 2007. Epub.

  44. PosaconazolePharmacokinetics • Drug interactions • Posaconazole inhibits CYP3A4 (not a substrate of CYP3A4) • Tacrolimus: dose reduction with 66% • Cyclosporine: dose reduction with 25% • Increase in serum concentrations of benzodiazepines, calcium channel blockers, statines, TCA, nevirapine… • Posaconazole is substrate of UGT 1A4 • Induction by phenytoin: contra-indicated! • Induction by rifabutin: contra-indicated! Schiller D et al. Clin Ther 2007; 29: 1862-1886 Goodwin M et al. JAC 2007. Epub.

  45. PosaconazolePharmacokinetics • Dosing in patients with hepatic impairment? • posaconazole should be used with caution • not studied using Child score • Dosing in patients with renal impairment? • Dose adjustment not necessary • Use with caution in severe renal failure Schiller D et al. Clin Ther 2007; 29: 1862-1886 Goodwin M et al. JAC 2007. Epub.

  46. Posaconazole Tolerability and Safety • Gastro-intestinal side effects • Abdominal pain, diarrhea, vomiting: 3-7% • Elevated liver function tests • Rash - Not correlated with elevated posa serum levels Schiller D et al. Clin Ther 2007; 29: 1862-1886 Goodwin M et al. JAC 2007. Epub.

  47. PosaconazoleTherapeutic drug monitoring? • Limited data available • FDA approved product information: • association between posa levels and efficacy • Proven (6%) or probable (3.8%) IFI if levels < 0.7 µg/ml • Proven (1.8%) or probable (0%) IFI if levels > 0.7 µg/ml  lower concentrations correlate with treatment failure • recommendations: • ensurance of adequate plasma levels: • Administration of posaconazole with a meal • Avoidance of drug inducing agents • Monitoring for breakthrough infections Goodwin M et al. JAC 2007. Epub.

  48. PosaconazoleTherapeutic drug monitoring? • TDM in patients with: • Progressive disease • Suspected poor oral absorption (nausea, vomiting, mucositis, compliance) • Levels > 1.25 mg/L Goodwin M et al. JAC 2007. Epub.

  49. Caspofungin

  50. The echinocandinsTarget: fungal cell wall • Echinocandines inhibit 1,3-beta-glucan synthase • depletion of glucan polymers: weak cell wall