Published in:
01-05-2008 | Adis Drug Evaluation
Posaconazole
A Review of its Use in the Prophylaxis of Invasive Fungal Infections
Authors:
James E. Frampton, Lesley J. Scott
Published in:
Drugs
|
Issue 7/2008
Login to get access
Summary
Abstract
Posaconazole is a second-generation triazole antifungal agent with a broad pectrum of activity that includes Aspergillus spp., Candida spp. and the Zygomycetes. n the US, posaconazole oral suspension administered three times daily is indicated for prophylaxis against invasive Aspergillus and Candida infections in patients aged ≥13 years who are at high risk of developing these infections because of immunosuppression, such as haematopoietic stem cell transplant (HSCT) recipients with graft-versus-host disease (GVHD), or those with haematological malignancies with prolonged neutropenia as a result of chemotherapy. EU-approved prophylactic indications for posaconazole are similar to those in the US.
Posaconazole provided effective prophylaxis against invasive fungal infectionsand was generally well tolerated in two large, well designed trials in HSCT recipients with GVHD, or patients receiving induction-remission chemotherapy for acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS) that was expected to result in prolonged neutropenia. It offers coverage of clinically relevant pathogens and is potentially associated with fewer drug-drug interactions than other licensed triazole antifungal agents. Its usefulness in some patients may be limited by the lack of an intravenous formulation, although one is currently being developed. As with other antifungal agents, concerns remain regarding the potential emergence of resistance to broad-spectrum antifungal prophylaxis with posaconazole. Despite this, posaconazole is a valuable emerging option for use as prophylaxis against invasive fungal infections in immunocompromized patients who are at high risk of developing these infections.
Pharmacological Properties
Posaconazole blocks the biosynthesis of ergosterol, the primary sterol component of the fungal cell membrane, resulting in inhibition of fungal cell growth or fungal cell death. In vitro, posaconazole exhibits good activity against Aspergillus and Candida spp., including Candida spp. inherently less susceptible to fluconazole. It has also demonstrated activity against A. fumigatus and Candida isolates resistant to other triazoles. The in vitro activity of posaconazole against Aspergillus and Candida spp. was generally similar to that of voriconazole, but greater than that of fluconazole, itraconazole and amphotericin B. Candida spp. isolates with reduced in vitro susceptibility to posaconazole and/or other triazoles have been obtained after triazole prophylaxis.
Posaconazole demonstrates dose-proportional pharmacokinetics in healthy volunteers over the range from 50 to 400 mg twice daily. Peak plasma concentration is reached after a median of 3–5 hours; steady-state plasma concentrations (which are similar in adult and juvenile patients with invasive fungal infection) are attained by day 7–10. Plasma posaconazole exposure is increased by food (particularly high-fat meals); each dose of the drug should be administered with a full meal or, in patients who cannot eat a full meal, with a liquid nutritional supplement. Plasma concentrations of posaconazole varied considerably in prophylaxis trials that enrolled HSCT recipients with GVHD, or patients receiving induction-remission chemotherapy for AML or MDS that was expected to result in prolonged neutropenia. Posaconazole is extensively distributed into tissues and is predominantly eliminated unchanged in the faeces.
The pharmacokinetic profile of posaconazole is not influenced to a clinically significant extent by, nor is dosage adjustment necessary on the basis of, age, gender, bodyweight or ethnicity; it is similarly unaffected by hepatic or renal impairment. Posaconazole is an inhibitor of cytochrome P450 (CYP) 3A4; coadministration of posaconazole with CYP3A4 substrates that are known to prolong the corrected QT (QTc) interval (i.e. astemizole, cisapride, halofantrine, pimozide, quinidine or terfenadine) is contraindicated. Adjustment (and frequent monitoring) of ciclosporin, tacrolimus or sirolimus dosage is recommended when posaconazole is used in conjunction with these immunosuppressants (CYP3A4 ubstrates).
Clinical Efficacy
Prophylaxis with posaconazole (oral suspension) 200 mg three times daily was effective in two randomized, investigator- or double-blind, multinational studies (n = 600 and 602). This regimen was more effective than fluconazole 400 mg once daily or itraconazole 200 mg twice daily (combined results) in preventing invasive fungal infections in patients with neutropenia who were undergoing remission-induction chemotherapy for AML or MDS. It was noninferior to, but not more effective than, fluconazole 400 mg once daily in preventing invasive fungal infections in HSCT recipients with GVHD. Posaconazole prophylaxis significantly reduced the incidence of breakthrough invasive aspergillosis (vs fluconazole in patients with GVHD and fluconazole or itraconazole [combined results] in neutropenic AML/MDS patients) and all breakthrough invasive fungal infections (vs fluconazole in patients with GVHD) during the period of prophylaxis. It also significantly reduced the incidence of invasive aspergillosis (vs fluconazole in patients with GVHD) and all invasive fungal infections (vs fluconazole or itraconazole [combined results] in neutropenic AML/MDS patients) during a fixed post-randomization time period.
These studies were not powered to evaluate between-group differences in mortality. Nonetheless, during the extended observation period, posaconazole prophylaxis significantly reduced all-cause mortality in neutropenic AML/MDS patients but not in patients with GVHD, and significantly reduced invasive fungal infection-related mortality in both neutropenic AML/MDS patients and patients with GVHD.
Pharmacoeconomic Considerations
Preliminary results from decision-analytic models that incorporated data from the randomized, multinational studies, suggested that prophylaxis with posaconazole generally dominated that with fluconazole or itraconazole (combined results) in neutropenic AML/MDS patients, and was cost effective relative to that with fluconazole in patients with GVHD.
Tolerability
One or more possibly or probably treatment-related adverse events were experienced by approximately one-third of neutropenic AML/MDS patients or patients with GVHD receiving posaconazole prophylaxis. Disorders of the gastrointestinal system (e.g. nausea, vomiting and diarrhoea) and the liver/biliary system (e.g. bilirubinaemia; increased ALT, ASP and hepatic enzyme levels) were among the most common treatment-related adverse events reported by recipients of posaconazole 200 mg three times daily (n = 605) in the two multinational prophylaxis studies. QT or QTc interval prolongation was reported by 12 of 304 (4%) neutropenic AML/MDS patients, with no cases reported in patients with GVHD. Serious increases in hepatic enzymes, bilirubinaemia and hepatocellular damage were infrequent, each occurring in ≤2% of posaconzole recipients.
The adverse event profile of posaconazole appeared to be generally similar to that of fluconazole or itraconazole, although significantly more AML/MDS patients receiving posaconazole than fluconazole or itraconazole recipients (combined results) reported serious adverse events (6% vs 2%).