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

From Schering-Plough Research Institute, Kenilworth, New Jersey (Dr Courtney, Dr Sansone, Dr Statkevich, Ms Martinho, Dr Laughlin); New Orleans Center for Clinical Research, New Orleans, Louisiana (Dr Smith); Orlando Clinical Research Center, Orlando, Florida (Dr Marbury); and Hennepin County Medical Center and DaVita Clinical Research, Minneapolis, Minnesota (Dr Swan).

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 t_1/2 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 3%, supporting that posaconazole was not removed by hemodialysis. Protein binding was similar in all groups (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.

Key Words: Posaconazole • fungal infections • drug safety • pharmacokinetics • drug tolerability

Address for reprints: Angela Sansone, PharmD, Schering-Plough Research Institute, K-15-4-4465, 2015 Galloping Hill Road, Kenilworth, NJ 07033.

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