Posaconazole Pharmacokinetics, Safety, and Tolerability in Subjects With Varying Degrees of Chronic Renal Disease

Abstract

Posaconazole is a triazole antifungal in development for the treatment of invasive fungal infections. The authors evaluated the pharmacokinetics and safety of posaconazole in healthy subjects and in those with mild (CL(CR) = 50-80 mL/min), moderate (CL(CR) = 20-49 mL/min), and severe chronic renal disease (CL(CR) <20 mL/min; receiving outpatient hemodialysis) (n = 6/group). Subjects received one 400-mg dose of posaconazole oral suspension with a standardized high-fat breakfast. For hemodialysis-dependent subjects, this dose was given on a nonhemodialysis day, and a second 400-mg dose was given 6 hours before hemodialysis. Blood samples were collected before dose and up to 120 hours postdose. For hemodialysis-dependent subjects following the second dose, additional samples (predialyzed and postdialyzed) were collected before, during, and after dialysis. There was no correlation between posaconazole pharmacokinetics and mild to moderate renal disease; the slopes of the linear regressions for creatinine clearance versus posaconazole AUC, C(max), CL/F, and t1/2 values were not significantly different from zero (P > .130). Mean CL/F values before and during hemodialysis were comparable. Furthermore, the difference in the predialyzed and postdialyzed posaconazole concentrations was only approximately 3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (approximately 98%) and was unaffected by hemodialysis. Posaconazole was generally well tolerated. One patient had elevated liver function test results that were not present at baseline and were thought to be possibly related to posaconazole. Results of this single-dose study indicate that dosage adjustments for patients with varying degrees of renal disease are not required.

Role of posaconazole in the treatment of oropharyngeal candidiasis

“…There is no dose adjustment recommended for renal or liver failure. 8,18 The structural formula is shown in Figure 1. Following multiple dose administration, steady-state plasma concentrations are attained at 7-10 days.…”

“…Only 13%-14% of posaconazole is excreted in the urine. 18 Mean total body clearance is 32 L/hour. The elimination half-life of the parent compound is 35 hours, with a range of 20-66 hours.…”

Farmacología de los azoles

“…Una característica que puede tener gran interés es la necesidad de circular en el plasma fijado a proteínas en elevada proporción que, en los casos de posaconazol [9] e itraconazol superan el 90% del fármaco circulante, mientras que para voriconazol este porcentaje se sitúa en el 58%. Considerando la reducida entidad de las concentraciones plasmáticas y el dato señalado de la fijación a proteínas, es destacable que la concentración plasmática libre resulte muy baja, especialmente en el caso de posaconazol [8,14,31] e itraconazol que, por otra parte, son los fármacos que presentan menor biodisponibilidad.…”

“…Es decir, la excreción renal, si se excluye a fluconazol, no interviene en la eliminación de los azoles, lo que supone la ausencia de acumulación de estos fármacos cuando se administran a pacientes con disfunción renal [9]. En los casos de las formulaciones intravenosas de voriconazol e itraconazol, existe riesgo de acumulación de uno de los excipientes utilizado en la solubilización; una ciclodextrina.…”

“…Voriconazol no es dializado por lo que no se precisa ajustar la dosis cuando se administra por vía oral [23], característica que comparte con posaconazol [9] e itraconazol [20], habiéndose descrito que la hemodiálisis es eficaz para eliminar del organismo la ciclodextrina utilizada como excipiente de la formulación intravenosa de este fár-maco [20].…”