Efficacy and Safety of Posaconazole (POS) in the Treatment of Refractory Invasive Fungal Infections (rIFIs) in Patients with Underlying Renal Impairment. (2005)

Abstract Background: Patients with IFIs often have underlying renal impairment. POS, an extended-spectrum triazole antifungal, is in development for the treatment of rIFIs. We studied the activity and safety of POS in rIFI subjects with underlying renal impairment, some of whom had undergone hematopoietic stem cell transplantation (HSCT). Methods: This was a 12-month, multicenter, open-label study of POS (800 mg/day in divided doses) in subjects with IFIs who were refractory to or intolerant of prior antifungal therapy. Success was defined as complete or partial response; nonsuccess was defined as stable disease, failure, or undetermined outcome. For this analysis, patients were stratified by baseline estimated creatinine clearance (CrCl) or serum creatinine (SCr). Results: Of the 330 subjects enrolled who were refractory to or intolerant of prior antifungal therapy and received ≥1 dose of POS, 39 subjects with CrCl &amp;lt;40 mL/min and 20 subjects with CrCl of 40-&amp;lt;50 mL/min were included in this analysis. An additional 6 subjects with baseline SCr &amp;gt;2 mg/dL for whom CrCl could not be determined were also included. In the &amp;lt;40 mL/min group, 31% (12/39) had undergone HSCT, 38% (15/39) had underlying hematologic malignancy (HM), and 33% (13/39) had undergone solid organ transplantation (SOT). In the 40-&amp;lt;50 mL/min group, 60% had undergone HSCT (12/20), 80% (16/20) had HM, and 20% (4/20) were SOT recipients. In patients with SCr &amp;gt;2 mg/dL, 67% (4/6) had undergone HSCT and 83% (5/6) had HM. As shown in the table, POS therapy resulted in similar response rates for most IFIs regardless of degree of renal impairment. These results are comparable to the total study population (Raad et al. 44th ICAAC 2004 abs M-669). POS was generally well tolerated. The safety profile in subjects with baseline renal dysfunction was similar to that reported for the total study population (Raad et al. 44th ICAAC 2004 abs M-669). The most common treatment-related treatment-emergent adverse events were nausea (6/39 in &amp;lt;40 mL/min group; 3/20 in 40-&amp;lt;50 mL/min group), vomiting (4/39 in &amp;lt;40 mL/min group), increased SCr (4/39 in &amp;lt;40 mL/min group), dizziness (3/39 in &amp;lt;40 mL/min group), increased phosphatase alkaline levels (3/39 in &amp;lt;40 mL/min group), and altered drug level (3/39 in &amp;lt;40 mL/min group). Conclusion: As in the overall study population, POS demonstrated good activity against refractory IFIs and was well tolerated in these subjects with underlying renal impairment, regardless of the level of renal impairment. POS may offer a clinically important alternative for treatment of refractory IFI in subjects with underlying renal impairment. CrCl (mL/min) Successful Response by Organism Moderate to Severe Renal Impairment (&amp;lt;40) Mild Renal Impairment (40-&amp;lt;50) SCr &amp;gt;2 mg/dL *Subjects could have &amp;gt;1 pathogen; †Histoplasma and other; ‡Histoplasma, Phaeohyphomycetes, Pseudallescheria, and other. All* 19/39 (49%) 9/20 (45%) 4/6 (67%) Aspergillus 11/24 (46%) 4/13 (31%) 1/2 (50%) Candida 1/3 (33%) 0/2 (0%) – Fusarium 1/1 (100%) 2/2 (100%) – Cryptococcus 3/5 (60%) 1/1 (100%) – Coccidioides 0/1 (0%) 0/1 (0%) – Zygomycetes 1/3 (33%) – – Miscellaneous 2/3 (66%)† 2/4 (50%)‡ 3/4 (75%)†