Pharmacokinetics of sulfobutylether- -cyclodextrin (SBECD) in subjects on hemodialysis

Abstract

Background. The disposition of sulfobutylether-β-cyclodextrin (SBECD), the solubilizing excipient in intravenous (IV) voriconazole, was assessed in seven male subjects with end-stage renal disease on hemodialysis and six subjects with normal renal function. Methods. All subjects received twice-daily IV voriconazole at the standard voriconazole dose [6 mg/kg (96 mg/kg SBECD) every 12 h (Q12h) on Day 1 followed by 3 mg/kg (48 mg/kg SBECD) Q12h on Days 2–4, with a single IV dose on the morning of Day 5]. Subjects were sampled at selected pre-dose trough times, at selected times after infusions and intensively on Day 3 (non-dialysis) and Day 4 (dialysis with high-flux membranes). Compartmental analyses were performed by NONMEM. Results. SBECD disposition was characterized by a two-compartment model. In renal failure, mean central (V₁) and peripheral compartment volumes (V₂) were 9.9 and 6.5 L, respectively. In normal subjects, V₁ and V₂ were 9.6 and 5.2 L, respectively; SBECD clearance (CL) was 130 mL/min. CL in renal failure off-dialysis was 2.6 and 48 mL/min during dialysis; mean half-life decreased from 79 to 5 h during dialysis (normal subjects: 2.1 h). Conclusion. Hemodialysis can significantly reduce levels of SBECD in subjects with end-stage renal disease.