Posaconazole for the prevention and treatment of invasive fungal infections

teaser

Andreas H Groll
MD
Associate Professor
Infectious Disease Research Programme
Center for Bone Marrow Transplantation and Department of Paediatric Haematology/Oncology
University Children’s Hospital
M�nster
Germany
E: [email protected]

Invasive fungal infections have evolved into important causes of morbidity and mortality in immunocompromised patients. For more than three decades, treatment has been limited to amphotericin B deoxycholate with or without flucytosine. Therapeutic options emerged only with the clinical development of fluconazole and itraconazole in the late 1980s. The past 10-15 years, however, have witnessed a major expansion in our antifungal armamentarium through the introduction of less toxic formulations of amphotericin B, the advent of echinocandin lipopeptides and the development of a second generation of antifungal triazoles.(1)

Posaconazole is a novel second-generation antifungal triazole that targets the synthesis of ergosterol, the main sterol in the cell membrane of fungi. Posaconazole has been selected for clinical development based on refined structure activity relationships that provide enhanced antifungal activity, absence of cytochrome P450 (CYP450)-mediated metabolism and limited mechanism-based adverse reactions. Posaconazole possesses potent and broad-spectrum antifungal activity in vitro and in vivo. It has favourable pharmacokinetic properties, appears to be well tolerated and has demonstrated antifungal efficacy in the treatment of oropharyngeal and oesophageal candidiasis, refractory oropharyngeal candidiasis, aspergillosis, fusariosis and zygomycosis, and as antifungal prophylaxis in high-risk patients. This paper reviews the clinical pharmacology of posaconazole and its current indications for the prevention and treatment of invasive fungal infections.

Structure and antifungal activity
Posaconazole (Noxafil(R)) is a chirally and chemically stable, lipophilic, second-generation antifungal triazole with a molecular structure similar to that of itraconazole.(2) Similar to other members of this class, posaconazole inhibits CYP450-dependent 14-alpha demethylase in the biosynthetic pathway of ergosterol. This interaction leads to an accumulation of toxic 14-alpha methylsterols and a depletion of ergosterol, resulting in a perturbation of the function of the fungal cell membrane and blockage of cell growth and replication.(3)

In vitro, posaconazole has potent and broad spectrum activity against opportunistic, endemic and dermatophytic fungi. This activity extends to organisms that are often refractory to existing triazoles, such as amphotericin B or echinocandins, such as Candida glabrata, Candida krusei, Aspergillus terreus and Fusarium spp.(4) In vivo, a large variety of animal models of invasive fungal infections have provided consistent evidence of therapeutic efficacy against these organisms in normal and in immunocompromised animals.(5) Importantly, posaconazole possesses activity against zygomycetes both in vitro and in vivo, distinguishing it from all available azoles.(3,4)

Clinical pharmacokinetics and metabolism
Posaconazole is available as oral suspension only and achieves optimal exposure when administered in two to four divided doses given with food or a nutritional supplement.

The compound has dose-proportional pharmacokinetics in the 50 mg and 800 mg dose range, with saturation of absorption occurring above 800 mg; following repeat dosing, steady state is achieved after 7-10 days with a six- to eightfold accumulation of plasma concentrations.(6)

Posaconazole has a large volume of distribution in the order of 5 l/kg and a prolonged elimination half-life of approximately 20 hours. It is not significantly metabolised through the CYP450 enzyme system but primarily excreted in unchanged form in the faeces. The drug is inhibitory against cytochrome P450 3A4 but has no effects on 1A2, 2C8, 2C9, 2D6 and 2E1 isoenzymes, and therefore a limited spectrum of drug-drug interactions can be expected.(3,7,8) Posaconazole is a substrate and inhibitor of P-glycoprotein (P-gp).

However, investigation of the relationship between MDR1 mRNA expression and posaconazole exposure showed no correlation. Thus, the moderate variability in the compound’s pharmacokinetics is unlikely to be due to interindividual differences in P-gp expression.(9)

Safety and tolerance
Posaconazole appears to be well tolerated in a manner comparable to fluconazole. The overall safety of posaconazole has been assessed in more than 400 patients with invasive fungal infections from two open-label clinical trials who received �posaconazole suspension (800 mg/day in divided doses). Treatment related adverse events occurred in 38% of patients (164/428); the most common events were nausea (8%), vomiting (6%), headache (5%), abdominal pain (4%) and diarrhoea (4%). Treatment-related abnormal liver function test results were observed in up to 3% of patients. There were no clinically significant differences in mean QTc interval change from baseline. Serious adverse events considered �possibly or probably related to posaconazole occurred in 35 (8%) patients.

The most common severe adverse events were altered drug level, increased hepatic enzymes, �usea, rash and vomiting (1% each). No significant trends related to age, sex or race were observed, and no unique treatment-related adverse events were identified in patients during long-term exposure (more than six months) compared with those identified during shorter-duration therapy.(10,11) Of note, in two large, prospective, randomised comparative clinical trials investigating posaconazole for prevention of invasive fungal infections in high-risk patients with leukaemia or haematopoietic stem cell transplantation, posaconazole was well tolerated and the rate of study drug discontinuations in posaconazole-treated subjects was not different from that in subjects in the control cohort receiving fluconazole or itraconazole.(12,13)

Drug interactions
Posaconazole is not significantly metabolised through the CYP450 enzyme system, and CYP450-mediated drug-drug interactions will have limited potential to impact posaconazole pharmacokinetics.(7) Posaconazole is inhibitory against cytochrome P450 3A4 but has no effects on 1A2, 2C8, 2C9, 2D6 and 2E1 isoenzymes.(8) The drug-drug interaction potential of posaconazole has been investigated in seven open-label, crossover drug interaction studies. No dose adjustments are needed when posaconazole is co-administered with glipizide, zidovudine and lamivudine, whereas dosages of ritonavir and indinavir may need to be lowered. Monitoring of ciclosporin and tacrolimus blood concentrations is mandatory, and dose adjustments should be made accordingly. Due to a relevant decrease in posaconazole concentrations, concomitant use with rifabutin, phenytoin or cimetidine should be avoided. As with other azoles, caution is advised when posaconazole is coadministered with CYP3A4 substrates that have the potential to prolong the QTc interval.(14,15)

Clinical efficacy
Posaconazole has been targeted for prevention and treatment of serious infections caused by opportunistic and endemic fungal organisms.

Posaconazole has demonstrated strong antifungal efficacy in phase II clinical trials in immunocompromised patients with primary or refractory oropharyngeal and oesophageal candidiasis.(16,17) In a randomised, comparative phase III trial, posaconazole 100mg daily (day 1: 200 mg) was as effective as fluconazole 100 mg daily (day 1: 200 mg)  in the primary treatment of HIV-associated oropharyngeal candidiasis: 155/169 (91.7%) of patients receiving posaconazole vs 148/160 (92.5%) of patients receiving fluconazole achieved a complete clinical response (cure). The relapse rate at day 42 was greater in fluconazole recipients than in posaconazole treated subjects (38.2 vs 31.5%; p = 0.038).(18)

Posaconazole (800 mg in divided doses) was also investigated as salvage therapy in a large phase II study including 330 patients with invasive fungal infections intolerant to or refractory to standard therapies and a contemporaneous external control of 279 patients.(19) Most patients (86%) were refractory to previous therapy. Successful outcomes at the end of treatment in the posaconazole and in the contemporaneous external control cohorts were 42% vs 26% in aspergillosis (107 and 86 patients, respectively(20), 39% vs 50% in fusariosis (18 vs four patients), 56% vs 50% in zygomycoses (11 vs eight patients), 69% vs 43% (16 vs seven patients) in
coccidioidomycosis, 52% vs 53% in candidiasis (23 vs 30 patients), 48% vs 58% in cryptococcosis (31 vs 64 patients), 81% vs 0% in chromoblastomycosis (11 vs two patients) and 64% vs 60% in other invasive fungal infections (30 vs 20 patients). In a subset analysis of 39 patients with mostly refractory proven or probable central nervous system infections, �posaconazole was efficacious against cryptococcal meningitis (success rate in 29 patients: 48%) and against infections caused by opportunistic or endemic moulds (five of 10 patients: 50%).(21) These data are in agreement with the compound’s extended spectrum of activity in vitro and demonstrate efficacy for the treatment of refractory invasive opportunistic and endemic mycoses. Of note, in a retrospective analysis of the manufacturer’s compassionate use programme, including 91 patients with proven or probable zygomycosis refractory or intolerant to prior antifungal therapy, a 60% success rate (complete and partial responses) at 12 weeks was observed after initiation of therapy, providing the first evidence for the clinical utility of posaconazole as second line or consolidation therapy of zygomycosis.(22)

Recently, two pivotal preventative randomised phase III studies in high-risk patients with haematopoietic stem cell transplantation (HSCT) and graft-vs-host disease (GVHD)(12) and acute leukaemias(13) have been completed. In the first study, patients received either posaconazole 200 mg TID or fluconazole 400 mg QD, respectively, with the start of immunosuppression for a total of 16 weeks. Treatment with posaconazole led to a decreased incidence of invasive fungal infections at 16 weeks (5% vs 9%; p = 0.07), with a statistically significant decrease in invasive Aspergillus infections (2% vs 7%; p = 0.006). Seven days after the end of treatment, fewer patients had invasive fungal disease (2% vs 8%; p = 0.004) and fewer patients had invasive aspergillosis (1% vs 6%; p = 0.001). There were no differences in overall mortality at 12 weeks.(12) In the second study, patients received either posaconazole 200 mg TID and either fluconazole 400 mg QD or itraconazole 200 mg BID, respectively. Treatment was started with each cycle following drop of the absolute neutrophil count (ANC) to ≤500 ml for up to 12 weeks. Significantly fewer patients enrolled in the posaconazole arm developed an invasive fungal infection at day 7 after the end of treatment than in the comparator arm (2% vs 8%; p < 0.01); most importantly, treatment with posaconazole resulted in a significant decrease in the rate of invasive aspergillosis (1% vs 7%; p < 0.001). At day +100 postrandomisation, the rate of invasive fungal infections was 5% and 11% (p < 0.01) and patients treated with posaconazole had a significantly improved survival probability (p = 0.035).(13) These two landmark studies demonstrate the preventative efficacy of posaconazole, in particular against invasive Aspergillus infections in high-risk patients, and a statistically significant survival benefit in patients with acute myeloblastic leukaemia/myelodysplastic syndrome undergoing remission induction chemotherapy.

Approval status and dosing
Posaconazole has been approved in the EU for the treatment of aspergillosis, fusariosis, chromoblastomycosis and coccidioidomycosis refractory to or intolerant of standard therapies. In both the EU and the USA, posaconazole is approved for the treatment of oropharyngeal candidiasis, including disease refractory to itraconazole and/or fluconazole, and for prophylaxis of invasive Candida and Aspergillus infections in high-risk patients ≥13 years with HSCT and GVHD or those with haematological malignancies and prolonged neutropenia.

The recommended daily dosage for salvage treatment is 400 mg BID given with food; for patients not tolerating solid food, a dosage of 200 mg QID is recommended, preferentially together with a nutritional supplement. The dosage for primary treatment of OPC is 100 mg QD (day 1: 100 mg BID) and 400 mg BID for refractory disease; for prophylaxis of invasive Candida and Aspergillus infections, the recommended dosage is 200 mg TID.

Current data indicate no need for dosage adjustments based on differences in age, sex, race,(23) renal or hepatic function.(24,25) The pharmacokinetics of  posaconazole in paediatric patients (under 18 years of age) have not been studied yet. Very limited data obtained in 12 paediatric subjects (8 years of age or more) appear to indicate no fundamental differences in trough plasma concentrations as compared with adults.(26) Salvage treatment with posaconazole resulted in successful outcomes in five of 11 paediatric subjects (8-17 years of age), which appears similar to the outcome in the adult population.(27)

Conclusions
Invasive fungal infections will remain an important cause of morbidity and mortality in immunocompromised paediatric patients. Therefore, the availability of new and versatile therapeutics is an important advance. Current data indicate a potentially major future role for posaconazole in the prevention and treatment of fungal infections. This triazole possesses potent and broad-spectrum antifungal activity in vitro and has demonstrated excellent efficacy in a large array of animal models of human fungal infections. Overall, the compound has favourable pharmacokinetics and does not undergo relevant oxidative metabolism, and inhibition of CYP450 is restricted to the 3A4 isoform. Posaconazole appears to be well tolerated in a manner comparable to fluconazole and has demonstrated clinical efficacy against oropharyngeal and oesophageal candidiasis, refractory aspergillosis, fusariosis and zygomycosis, and as antifungal prophylaxis in high-risk patients. With the ongoing clinical development of an IV formulation, further indications are expected to evolve in first-line treatment of invasive opportunistic and endemic fungal infections in both adult and paediatric patients.

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