Pharmacotherapy of antifungal drugs

Pharmacotherapy of antifungal drugs
Isabel Spriet Pharmacy Dpt, UZ Leuven

The fungal ‘players’ Opportunistic fungi Normal flora Candida spp.
Ubiquitious in our environment Aspergillus spp. Cryptococcus spp. Mucor spp. Newly emerging fungi - Fusarium - Scedosporium Endemic geographically restricted - Blastomyces spp. - Coccidiodes spp. - Histoplasma spp.

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:

Candidemia – Mortality rate
Pathogen % Isolated % Mortality CNS 31.9 21 S aureus 15.7 25 Enterococci 11.1 32 Candida spp. 7.6 38 E. Coli 5.7 24 Klebsiella spp. 5.4 27 Enterobacter spp. 4.5 28 Pseudomonas spp. 4.4 33 Serratia spp. 1.4 26 S. viridans 23 Hospital acquired pathogens and their associated mortality Edmond et al. CID 1999; 29:

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

Risk factors for fungal disease
Candidiasis Aspergillosis Broad spectrum antibiotics Intravascular catheters Abdominal surgery Neoplastic diseases Chemotherapy Immunosuppressants -Granulocytopenia Decreased neutrophil number Decreased function T-cell dysfunction Hematologic malignancies Organ allograft recipients Corticosteroids AIDS

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

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

Outline Product Overview
Spectrum Therapeutic indications Recommended dosages Pharmacokinetics Pharmacokinetic difficulties and problems Tolerability and safety Therapeutic drug monitoring?

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

Polyenes

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

Amphotericin B Spectrum and Recommended dosage
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

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

Amphotericin B Tolerability 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

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++

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: Cagnoni PJ. J Clin Oncol 2000; 18: Greenberg RN. J Med Economics 2002; 2:

Azoles

The azoles Target: 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

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

Fluconazole

Fluconazole Spectrum, 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: Candidemia in non-neutropenic patients Fluco 400 mg + remove IV catheter ! C. glabrata-I: fluco 800 mg ! C. glabrata-R: caspofungin Invasive candidiasis (intra-abdominal/ postoperative) Fluco 400 mg (+ surgical drainage) Alternative caspofungin 70/50 mg IV Charlier C. JAC 2006; 57:

Fluconazole Pharmacokinetics
 Bio-availability - > 90% - not dependent of gastric pH or food: IV-PO switch possible!  Distribution extensive: Vd L/kg protein binding: 11% CSF levels: 70% of plasma levels good penetration in bone  Metabolism not metabolised  Excretion 60-75% glomerular filtration: dose adjustments in decreased renal clearance 8-10% feces halflife: hrs: OD administration, LD required removed by dialysis Charlier C. JAC 2006; 57:

Fluconazole Pharmacokinetics
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:

Fluconazole Tolerability 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:

Fluconazole Therapeutic drug monitoring?
No routine indications for measuring fluco levels Predictable fluconazole PK and serum concentrations Charlier C. JAC 2006; 57:

Voriconazole

Voriconazole Spectrum 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:

Voriconazole Recommended 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) Children (2-12 yrs) 2 x 7 mg/kg

Voriconazole Pharmacokinetics
Bio-availability 96% Steady state 5-6 days loading dose necessary! Distribution extensive (Vd: 4.6 L/kg) CSF concentration: 50% of plasma concentration: dosage increase by 50% protein binding 58% Metabolism CYP2C9, CYP2C19, CYP3A4 major metabolite (72%): N-oxide Elimination 80% via urine 20% via feces

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:

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

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

Voriconazole Safety Visual disturbances: (20%) Hepatotoxicity (13%)
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

Adverse effects of voriconazole
Voriconazole Safety 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

Voriconazole Tolerability 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

Voriconazole Therapeutic 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. FDA report - no correlation Smith. AAC 2006; 50: 28 patients, random plasma samples progressive disease in 18 patients with levels < 2.05 µg/ml Trifilio S. BMT 2007; 40:451-6. 71 patients, trough plasma levels 6 candidiasis cases in patients with levels < 2 µg/ml Denning D. CID 2002; 34: Herbrecht study liver failure or liver toxicity in 6 out of 22 patients with levels > 6 µg/ml

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 µg/ml Pascual A. CID 2008;46:

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 Epub

Posaconazole

Posaconazole Spectrum, 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

Posaconazole Pharmacokinetics
Bio-availability 52-100% Dependent on dosing frequency and intake with/without meal Saturation in absorption if daily dose > 800 mg Distribution Extensive (Vd: 2447L) Tissue penetration: limited data crosses BBB distributes into bone and eye Protein binding > 98% Metabolism Primarily unchanged excretion <30% metabolised as glucuronide conjugates (UGT 1A4) Elimination Majority via feces as unchanged drug Minimal renal elimination (14%) Halflife 20 hr - Halflife 20 uur laat toe om 1x per dag te doseren, maar betere AUC werd bekomen door de dosis in 2 te splitsen door betere absorptie Schiller D et al. Clin Ther 2007; 29:

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: Goodwin M et al. JAC Epub.

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: Goodwin M et al. JAC Epub.

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: Goodwin M et al. JAC Epub.

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: Goodwin M et al. JAC Epub.

Posaconazole Therapeutic 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 Epub.

Posaconazole Therapeutic 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 Epub.

Caspofungin

The echinocandins Target: fungal cell wall
Echinocandines inhibit 1,3-beta-glucan synthase depletion of glucan polymers: weak cell wall

Caspofungin Spectrum of activity and indications
Candida spp. (ex. C. parapsilosis) and Aspergillus spp. Not Cryptococcus as its cell wall does not contain ß-D-glucan Not Fusarium spp., Zygomycetes Empirical therapy for presumed fungal infections in febrile, neutropenic patients Candidemia, intra-abdominal abscess, peritonitis Invasive aspergillosis if refractory or intolerant to other therapies

Caspofungin Measurement of in vitro activity?
Candida spp.: minimal inhibitory concentration (MIC) Macroscopic growth inhibition Lowest concentration of the drug that results in inhibiting growth in 24 hours Aspergillus spp.: minimal effective concentration (MEC) Microscopic endpoint Lowest concentration of the drug that results in formation of aberrantly growing hyphal tips

Caspofungin Recommended dosage
Loading dose: 70 mg Maintenance dose: 50 mg Patients > 80 kg: 70 mg Child B liver cirrhosis Maintenance dose: 35 mg Mistry GC. J Clin Pharmacol 2007; 47: 951.

Caspofungin Pharmacokinetics
 Bio-availability <2%: only IV  Distribution Vd 4.5L high levels in liver, spleen, kidney equal levels in lung tissue low levels in heart, skeletal muscle, brain distribution phase determines clearance protein binding: 96%: no elimination via IHD  Metabolism - hydrolysis and N-acetylation: no active metabolites - not CYP450 dependent  Excretion via urine and faeces (only 2% unchanged)  PK linear: 3 phases distribution phase elimination phase of 8 hrs additional elimination phase with longer halflife of 27 hrs

Pharmacokinetic problems? Elimination based on tissue distribution No dose adjustments in renal insufficiency No CYP-mediated metabolism No CYP-mediated drug interactions No genetic polymorphisms Uptake via hepatic transporter: OATP OATP= organic anion transporting polypeptide Reduced uptake in patients with hepatic insufficiency Dose reduction in Child B liver cirrhosis No recommendations in Child C Drug interactions mediated by OATP? Sandhu P et al. DMD 2005; 33:

OATP = organic anion transporting polypeptide drug uptake transporter Basolateral membrane of hepatocytes Contributes to overall elimination of caspofungin Cyclosporin and rifampicin are also substrates for OATP1B1

Co-administration with cyclosporin AUC caspo + 25% Competitive inhibition at OATP? Co-administration with rifampicin Inhibition and induction effect on caspo First days: rifa blocks OATP After continued dosing: rifa induces OATP  Net effect: AUC caspo ↓: increase MD to 70mg/day Other inducers: efavirenz, nevirapine, dexamethasone, phenytoin, carbamazepin Increase MD to 70 mg/day

Caspofungin Tolerability and Safety
Excellent safety and tolerability can be explained by mode of action: human cells do not have a cell wall Adverse events = unspecific drug reactions Histamine-mediated: headache, fever, nausea Elevation of hepatic enzyme levels AST, ALT and ALP < 5-fold ULN

Caspofungin TDM in critically ill patients
Caspofungin plasma concentrations in surgical intensive care units C24hr concentrations 40 SICU patients Altered drug plasma concentrations due to altered PK? Results: Trough levels: µg/ml Literature (Stone studies): µg/ml Higher in patients with low body weight (< 75 kg) Higher in patients with albumin concentration > 23.6 g/L ! Patients’ body weight varied from 48 – 108 kg >< every patient got LD 70 mg/ MD 50 mg! Nguyen TH et al. JAC 2007; 60:

Anidulafungin - Micafungin

Anidulafungin - Micafungin Spectrum, therapeutic indications and recommended dosage
-Candida spp. -Aspergillus spp.  Indications -Invasive candidiasis -Esophageal candidiasis -Prophylaxis for Candida infections in HSCT  Dosage LD: 200 mg MD: 100 mg -prophylaxis: 50 mg OD -treatment: 150 mg OD  Dose adjustement in hepatic impairment No  Weight based dose adjustments

Anidulafungin - Micafungin Pharmacokinetics
 Bio-availability Low, only IV administration  Distribution Rapid distribution halflife Vd: 0.57 L/kg Protein binding: 99% No specific tissue distribution studies done Vd: 0.39 L/kg - Protein binding: 99% poor CNS penetration  Metabolism No hepatic metabolism No CYP involvement Metabolism by slow non-enzymatic, chemical degradation Breakdown by arylsulfatase and COMT  Elimination Halflife : 24hrs Via feces - Halflife: 13 hrs - Via feces, > 90% unchanged  PK linear

Anidulafungin- Micafungin Pharmacokinetics
 Dose adjustments in hepatic insufficiency? No Studied in Child A,B,C: no increase in plasma levels Not studied in Child C Dose adjustments in renal insufficiency/dialysis? Drug interactions? Small increase in anidula levels if combined with cyclosporine Possibly mild inhibition of CYP3A with small increase in cyclosporin, sirolimus and nifedipin levels

Anidulafungin-Micafungin Tolerability and Safety
Adverse reactions = mild Infusion (histamine-mediated) related reactions (especially at high infusion rates): flushing, pruritis, rash, urticaria Coagulopathy Diarrhoea, vomiting, nausea Hepatic enzyme elevation: ALT, ALP, bilirubin In 5-10% of patients Usually < 3-fold ULN

Micafungin Warning EMEA – risk hepatocellular tumour formation
discontinuation if persistent elevation ALT/AST consider alternative in patients with severe liver function impairment or chronic liver diseases or concomitant hepatotoxic therapy

Case report

CASE I Man, 49 yrs old, 65 kg Medical history: Admitted because of
diabetes, insuline dependent abuse: nicotine, ethyl (10 U/day) weight loss: - 25 kg/2 months Admitted because of hyperglycemia fever, hypotension, leucopenia, thrombopenia Rx thorax: bilateral infiltrates Diagnosis: CAP: start Cefuroxim – amikacin Elevated liver function tests (bili: 3.38 mg/dL): cirrhosis? On day 8: high fever: switch AB into meropenem – fluconazol Transfer UZ Leuven

CASE I Man, 49 yrs old, 65 kg Admitted upon ICU
high fever, severe hypotension, respiratory distress: Intubation + mechanical ventilation Fluid resuscitation, noradrenalin, antibiotics New cultures Day 10 and 11: BA Aspergillus + Day 12: BAL Aspergillus +/ galactoBAL: 8.3 Serum galactomannan day 11: 3.2 Diagnosis: Invasive aspergillosis start Vfend IV LD 400 mg on day 11 Stop Diflucan

CASE I Man, 49 yrs old, 65 kg At the same day:
Decrease of renal function: start CVVH ! Vfend IV: accumulation of SBECD: switch PO? Auramin stain: + : tuberculosis! Start TB therapy: ethambutol, pyrazinamid, moxifloxacin and rifampicin ! Vfend + Rifampicin = contra-indicated! Switch Cancidas Interaction with rifampicin! Dosage: LD 70 mg – MD 70 mg

CASE II Female, 49 yrs old, 80 kg
Medical history: Henoch-Schönlein vasculitis R/ Medrol 64 mg during 1 month Hospital admission because of anorexia, chills, sputa, respiratory insufficiency Suspicion of pneumonia: Augmentin CRP ↑: switch to Tazocin BAL: A. fumigatus/ serum GM 4.8: R/ Vfend tablets 2x400mg LD, 200 mg PO IHD - terminal renal insufficiency

Day 6: Transfer to UZ Leuven - MICU Serum GM: 0.7/BA: fungi CT brain: cerebral aspergillosis – multiple lesions Ocular Aspergillus invasion Diagnosis: Pulmonary, cerebral, ocular IA Switch Vfend PO → IV + increase dose based on body weight: 2 x 320 mg Vfend intravitreal injection Switch Tazocin into Meronem (follow up GM)

Day 12: switch Vfend IV → PO (suspension) Association of L-AmB high dose: 5 mg/kg Day 14: serum GM: 0.1 CT brain: worsening cerebral lesions

Discussion CNS aspergillosis Voriconazole = first line – standard dose or higher dose (penetration 50%)? Combination with L-AmB? Initial Vfend dose: too low? Tablets vs. oral suspension (weight based dosing)? Vfend IV vs. PO? PO ↔ critically ill patient, enteral feeding: absorption? IV ↔ accumulation of SBECD in patient with IHD Encephalopathy due to brain accumulation of SBECD? Encephalopathy due to high vorico levels?

Final Remarks

How to choose? Spectrum Site of infection Patient-specific factors
Likely or documented pathogen Site of infection Patient-specific factors Concomitant diseases Hepatic/renal function Toxicities Drug interactions with concomitant therapy IV/PO Cost/ Reimbursement criteria

Conclusion Despite development of new antifungals during last decade
 mortality of IFI remains very high optimalisation of diagnostics improvement of knowledge on pharmacokinetics – role of TDM?  avoid toxicity  warrant effective drug concentrations

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