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JAC Advance Access published online on October 3, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn401
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Posaconazole as salvage treatment of invasive fungal infections in patients with underlying renal impairment

R. Y. Hachem1,*, A. A. Langston2, J. R. Graybill3, J. R. Perfect4, L. D. Pedicone5, H. Patino5 and I. I. Raad1

1 Department of Infectious Diseases, Infection Control and Employee Health, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Bone Marrow Transplantation, Emory University Hospital, Atlanta, GA, USA 3 Department of Medicine, Chief, Division of Infectious Diseases, University of Texas Health Science Center, San Antonio, TX, USA 4 Department of Medicine, Division of Infectious Diseases, Duke University Mycology Research Unit, Durham, NC, USA 5 Schering-Plough Research Institute, Kenilworth, NJ, USA

* Corresponding author. Tel: +1-713-792-4389; Fax: +1-713-792-8233; E-mail: rhachem{at}mdanderson.org

Received 23 May 2008; returned 3 July 2008; revised 22 August 2008; accepted 2 September 2008


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Objectives: The aim of this study is to determine the efficacy and safety of posaconazole in patients with underlying renal impairment.

Patients and methods: We analysed the efficacy and safety of posaconazole in patients with renal impairment in a post hoc subanalysis of a Phase 3, multicentre, open-label trial in patients with invasive fungal infections (IFIs). In the Phase 3 study, 330 patients intolerant of or with IFIs refractory to standard antifungal therapy received posaconazole 800 mg daily in divided doses. In our subanalysis, 238 patients with proven/probable IFIs, including 65 patients with renal impairment (creatinine clearance < 50 mL/min or serum creatinine (sCR) level >2 mg/dL at baseline) and 173 patients with greater renal function [creatinine clearance ≥ 50 mL/min (acceptable renal function)], formed the modified intent-to-treat population. Success was defined as complete or partial response, and non-success was defined as stable disease or treatment failure.

Results: Overall response rates were similar in the renal impairment group (49%) and in the acceptable renal function (50%) group. Seventeen of the 41 patients with renal impairment and aspergillosis responded. Adverse events occurred in 32/65 (49%) patients with renal impairment and in 72/173 (42%) patients with acceptable renal function. The most common adverse events in both groups were nausea (14% patients with renal impairment versus 8% with acceptable renal function), altered/elevated levels of other medications (8% versus 2%), increased sCR levels (6% versus 0%), vomiting (6% versus 4%), abdominal pain (5% versus 5%) and dizziness (5% versus 1%).

Conclusions: These results suggest that posaconazole is effective and well tolerated in patients with refractory IFIs regardless of renal impairment.

Key Words: refractory IFIs , aspergillosis , antifungals , azoles


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Immunocompromised patients—such as recipients of haematopoietic stem cell transplants (HSCTs) and solid organ transplants, patients infected with the human immunodeficiency virus and patients with cancer who have chemotherapy-induced neutropenia—are at increased risk for invasive fungal infections (IFIs).1,2 Despite the availability of many antifungal agents, the prognosis for immunocompromised patients with IFIs is poor. Reported IFI-related mortality rates range from 33% in patients with haematological cancer or candidiasis to ~70% or higher in HSCT recipients with aspergillosis, fusariosis or zygomycosis.1,3–5 Many of these immunocompromised patients at risk for IFIs have significant underlying renal impairment that is associated with treatment or underlying disease and that can compromise the efficacy and tolerability of conventional antifungal therapy. Different formulations of amphotericin B and azoles that contain cyclodextrins, which are nephrotoxic excipients used in a number of pharmaceutical preparations, have varying degrees of nephrotoxicity that can potentiate the toxic effects of chemotherapeutic agents.6,7

Studies have shown that the triazole posaconazole exhibits in vitro, in vivo and clinical activity against a wide variety of yeasts and moulds, including Aspergillus species,8–10 and shows efficacy in several models of experimental pulmonary, cerebral and disseminated aspergillosis.11–16 In addition, a single-dose pharmacokinetics study in healthy volunteers showed that posaconazole is predominantly eliminated as an unchanged parent drug in faeces.17 Another single-dose study showed that posaconazole exposure levels are similar in healthy persons and in patients with varying degrees of renal impairment and that, consequently, dosage adjustments are not necessary for patients with chronic renal disease.18

A large Phase 3, multicentre, open-label trial showed the efficacy of oral posaconazole given in divided doses at 800 mg daily as salvage treatment of invasive aspergillosis and other IFIs in patients with cancer or underlying immunodeficiency and in recipients of HSCT who are intolerant of or who have infection refractory to other antifungal therapies.10,19 In the post hoc subanalysis of patients in this Phase 3 study described herein, we determined the efficacy and safety of posaconazole in patients with underlying renal impairment.


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Design

This report presents the findings of a subanalysis of a Phase 3, multicentre, open-label study that evaluated the efficacy and safety of posaconazole in patients with proven or probable IFIs, who were intolerant of or whose infection was refractory to standard antifungal therapies [subanalysis of population in NCT00034658 [ClinicalTrials.gov] (www.clinicaltrials.gov)]. An independent, blinded data review committee assessed patients' eligibility, diagnosis and treatment outcomes.

Patient selection

Patients or their legally authorized representative gave signed, written, informed consent, or the informed consent was obtained by means approved by the study investigator's Institutional Review Board or Ethics Committee. Consent must have been given before the first dose of study medication was administered and before any study-related invasive or diagnostic procedure or test was performed.

In the Phase 3 study, 330 patients with proven or probable IFIs according to the European Organization for Research and Treatment of Cancer-Mycoses Study Group criteria20 received at least one dose of posaconazole orally. Inclusion criteria included proven or probable IFI that was refractory or resistant to standard antifungal therapies [in the case of candidiasis caused by isolates resistant to both fluconazole and amphotericin B as described in the CLSI (formerly the NCCLS) antifungal susceptibility testing document M27-A21] or must have been intolerant of conventional antifungal therapy, or both, to be included in the modified intent-to-treat population in our subanalysis. Intolerance was defined by the presence of renal impairment [serum creatinine (sCR) level greater than twice the upper limit of normal], severe infusion-related toxic effects (or other organ dysfunction) or high risk of toxic effects based on an underlying disease or the use of concomitant nephrotoxic medications, which precluded the use of standard antifungal therapies. Abnormal renal function was defined as a baseline-estimated creatinine clearance (CLCR) level < 50 mL/min or, if the CLCR was unknown, a baseline sCR level > 2 mg/dL. CLCR was calculated on the basis of the patient's sCR level, age and sex using the Cockcroft–Gault formula of (140–age) x (weight)/(sCR x 72) for male patients and (140–age) x weight x 0.85/(sCRx72) for female patients.22 Adults or children aged ≥13 of either gender and any race were eligible for enrolment. Patients were required to have the ability to take study medication orally by swallowing or via a nasogastric tube. Female subjects had to be non-lactating, and, if of childbearing potential, using effective contraception and have a negative pregnancy test within 72 h of the start of the study drug. Patients were excluded if they had serious or severe hypersensitivities to azole antifungal drugs; were taking concomitant medications known to interact with azole antifungals; were taking (or were expected to take) systemic antifungal treatment or vinca alkaloids; had a QTc interval ≥20% above normal; had hepatic function tests >10x the upper limit of normal; were previously enrolled in the study; had a life expectancy of <72 h; were artificially ventilated and unlikely to be extubated within 24 h of entry into the study; had a clinical or laboratory condition that, in the opinion of the investigator, could make the evaluation of the safety and efficacy of posaconazole difficult; or had a concurrent progressive neurological disease (except if due to IFI) apart from multiple sclerosis, transient ischaemic attacks, previous cardiovascular accidents or subarachnoid haemorrhages, stable epilepsy, HIV-associated dementia and cytomegalovirus retinitis.

Treatment

Patients received posaconazole oral suspension (40 mg/mL) for a total daily dose of 800 mg in divided doses (200 mg four times daily while in the hospital and 400 mg twice daily as outpatients). Whenever possible, doses were administered with food or a liquid nutritional supplement to enhance bioavailability.23 Subjects with Candida infections of the bloodstream; disseminated, metastatic (deep organ) or hepatosplenic candidiasis; or candidal endocarditis were to receive posaconazole for a minimum of 14 days. Patients with other IFIs were to receive posaconazole for a minimum of 28 days. All subjects were to receive posaconazole for at least 7 days after symptom resolution. The maximum treatment duration was to be 12 months.

Efficacy and safety assessments

The primary efficacy endpoint was patient global response status at the end of treatment, as assessed by the data review committee. The study protocol defined a successful outcome as complete response [resolution of all attributable signs and symptoms of IFIs and all radiological, mycologic or bronchoscopic abnormalities (if present at baseline)] or partial response (partial resolution or observable improvement in any attributable clinical signs and symptoms of IFIs and any radiological, mycologic or bronchoscopic abnormalities). The protocol defined an unsuccessful outcome as stable disease (no improvement in any attributable signs or symptoms of IFIs and radiological, mycologic or bronchoscopic abnormalities) or treatment failure (deterioration in attributable clinical or radiological abnormalities that necessitated alternative antifungal therapy or resulted in death). Data were analysed using descriptive statistics only. The emphasis of the safety assessment was monitoring of adverse events.


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Patient characteristics

We identified 65 patients with proven or probable IFIs and renal impairment at baseline for this subanalysis; 59 had a CLCR <50 mL/min and 6 had an unknown CLCR but a sCR level >2 mg/dL. We compared these patients with 173 patients in the Phase 3 study who also had IFIs but who had greater renal function [i.e. CLCR ≥50 mL/min (hereafter referred to as acceptable renal function)]. Demographic and baseline characteristics of these patients are shown in Table 1. In the group with renal impairment, a large number (28) of patients were intolerant of and also had infections refractory to standard antifungal therapy. Table 1 shows that there were no substantial differences between the two groups with regard to underlying conditions of the patients.


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  		Table 1. Demographic and baseline characteristics of the modified intent-to-treat population

 
Aspergillus was the causative pathogen for IFIs in 41 of the patients with renal impairment (Table 2). Less common causative pathogens were Candida (n = 5), Fusarium (n = 3), Cryptococcus (n = 6), Coccidioides (n = 2) and the Zygomycetes (n = 3) species. Four patients had infections caused by more than one pathogen.


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  		Table 2. Global response at the end of treatment in the modified intent-to-treat population

 
Most of the patients with impaired renal function (n = 57) received amphotericin B-based preparations before study enrolment. In addition, 23 patients received itraconazole, 3 fluconazole, 3 voriconazole and 1 received an echinocandin before enrolment. Before baseline, 13 patients in this group received tacrolimus, 13 mycophenolate mofetil, 5 foscarnet and 3 cyclosporine. During or within 30 days of the end of treatment with posaconazole, 17 of the patients in the renal impairment group received tacrolimus, 13 mycophenolate mofetil, 8 foscarnet, 4 cyclosporine and 1 rapamycin. The duration of posaconazole-based therapy ranged from 2 to 365 days in the total population.

Efficacy

Overall, patients with renal impairment had a global response rate similar to that of patients with acceptable renal function after treatment of their IFIs with posaconazole (Table 2). When examined by reason for enrolment, response was similar to the overall rate in both groups. We also observed comparable response rates in the two groups in patients with invasive aspergillosis and those with infections caused by miscellaneous pathogens (e.g. Histoplasma and Pseudallescheria). Relatively few patients with other mycoses had co-existing abnormalities of renal function. Responses in these patients did not seem to be substantially different from those in patients with normal renal function, but the numbers are too small for analysis by pathogen.

Safety

Posaconazole was well tolerated in our population of seriously ill patients with IFIs and underlying renal impairment. Specifically, we observed that 32 of these 65 patients and 72 of 173 patients with acceptable renal function had at least one adverse event that was possibly or probably related to posaconazole-based treatment. The most common treatment-related adverse events are listed in Table 3.


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  		Table 3. Treatment-related adverse events with an incidence >5%

 
Fourteen patients with renal impairment reported serious adverse events (widely distributed across body systems) that were possibly or probably treatment-related. Seven patients in this group experienced treatment-related adverse events that led to the discontinuation of treatment with posaconazole, discontinuation from the study or death. Treatment with posaconazole was discontinued in one patient because of elevated pancreatic and liver enzyme levels.

We found no apparent temporal relationship between the duration of posaconazole-based therapy and the possible or probable occurrence of a clinically significant drug–drug interaction with a calcineurin inhibitor. Elevated cyclosporine or tacrolimus levels were reported in five patients and were possibly or probably related to treatment with posaconazole. One of the five patients experienced a toxic effect of cyclosporine on day 24 of treatment and subsequently died on day 30; the death was considered unrelated to treatment.

Thirty-three of the patients with renal impairment died. The most common causes of death were considered unrelated to the study treatment. Most of the deaths were caused by complications of the patient's underlying disease or progression of the IFI.


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This subanalysis of 65 patients in a large multicentre study suggests that posaconazole is a clinically important alternative to current conventional therapy for the treatment of refractory IFIs in subjects with underlying renal impairment. In this population of severely ill patients, the overall response rate in patients with renal impairment who had aspergillosis was consistent with the response rate in patients with aspergillosis in the overall study population (42%).10

Our study also shows that posaconazole is safe and well tolerated in patients with IFIs and varying degrees of underlying renal impairment. A recently published assessment of the safety of long-term posaconazole-based treatment24 provided a valuable context for evaluating these findings. Compared with all patients in the overall long-term safety population [38% (164/428)], a higher percentage of patients in the renal impairment subgroup in our study [49% (32/65)] reported adverse events that were possibly or probably related to treatment with posaconazole. In both populations, the most frequently reported treatment-related adverse events were primarily gastrointestinal. In addition, most patient deaths were caused by adverse events attributable to complications of the patient's underlying disease or to progression of the IFI under evaluation.

Overall, posaconazole was well tolerated in this study, even by patients with the most severe renal impairment. In contrast, intravenous formulations of azole antifungals that contain cyclodextrin (such as itraconazole or voriconazole) are not recommended for patients with CLCR <30 mL/min (itraconazole) or <50 mL/min (voriconazole).7 The calcineurin inhibitors cyclosporine and tacrolimus are extensively metabolized by cytochrome P450 enzyme 3A4 (CYP3A4) in the liver and small intestine25 and are substrates for P glycoprotein.26 Although posaconazole does not significantly affect CYP1A2, CYP2C8/9, CYP2D6 or CYP2E1 activity, it is an inhibitor of hepatic CYP3A4 activity.27 Therefore, elevated cyclosporine and tacrolimus plasma levels are expected with posaconazole co-administration, as with other azoles that are CYP3A4 inhibitors.28–33 Pharmacokinetics studies have shown that the co-administration of posaconazole increases the levels of cyclosporine and tacrolimus.34 Therefore, blood levels of tacrolimus and cyclosporine should be carefully monitored during co-administration with posaconazole and after discontinuation of treatment with posaconazole.35

This subanalysis of patients with underlying renal impairment is limited by its post hoc nature and the lack of actual (rather than estimated) CLCR data for all patients. Nevertheless, the results suggest that the efficacy and safety of posaconazole are similar in patients with renal impairment and in those with normal renal function.

In conclusion, we found that posaconazole was active against aspergillosis and other IFIs in a population of patients with renal impairment, and that it was safe and well tolerated in this population. Posaconazole may be a clinically important alternative to current antifungal agents for the treatment of refractory IFIs in patients with underlying renal disease who have limited therapeutic options.


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This study was supported by Schering-Plough, and editorial assistance was funded by Schering-Plough.


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R. Y. H. is a speaker for and has received a study grant from Schering-Plough. A. A. L. has served on advisory boards for Schering-Plough. J. R. G. has received honoraria or consulting income and research support from and has served on advisory boards for Schering-Plough and Merck. J. R. P. has received research grants, honoraria and consulting fees from Enzon, Astellas, Schering-Plough, Merck and Pfizer. L. D. P. is an employee and stockholder of Schering-Plough Research Institute, Kenilworth, NJ, USA. H. P. is an employee of Schering-Plough Research Institute, Kenilworth, NJ, USA. I. I. R. is on the speakers bureaus for and has received honoraria and financial support from Schering-Plough Research Institute, Merck and Pfizer.

The role of Schering-Plough in data collection and analysis included: (i) random assignment of unique identifier numbers to patients; (ii) technical support of the data review committee in its data review process; (iii) verification and entry of data into a database after the data committee review; and (iv) post hoc analysis of data and preparation of data summaries.

Meryl Mandle of ApotheCom Associates (Yardley, PA, USA) provided assistance in preparing and editing the manuscript.


   Acknowledgements
 
We thank Meryl Mandle for editorial assistance.


   References
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2 . Richardson MD. Changing patterns and trends in systemic fungal infections. J Antimicrob Chemother (2005) 56(Suppl_1):i5–11.[Abstract]

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4 . Boutati EI, Anaissie EJ. Fusarium, a significant emerging pathogen in patients with hematologic malignancy: ten years’ experience at a cancer center and implications for management. Blood (1997) 90:999–1008.[Abstract/Free Full Text]

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33 . Romero AJ, Pogamp PL, Nilsson LG, et al. Effect of voriconazole on the pharmacokinetics of cyclosporine in renal transplant patients. Clin Pharmacol Ther (2002) 71:226–34.[CrossRef][Web of Science][Medline]

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35 . Schering Corporation. 2006. NOXAFIL® (posaconazole) oral suspension.


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