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

• Published in: Nephrology, dialysis, transplantation Vol. 27; no. 3; pp. 1207 - 1212
• Main Authors: LUKE, David R, WOOD, Nolan D, TOMASZEWSKI, Konrad E, DAMLE, Bharat
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.03.2012
• Subjects: Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antifungal Agents - administration & dosage; Antifungal Agents - pharmacokinetics; beta-Cyclodextrins - administration & dosage; beta-Cyclodextrins - pharmacokinetics; Biological and medical sciences; Case-Control Studies; Emergency and intensive care: renal failure. Dialysis management; Excipients - administration & dosage; Excipients - pharmacokinetics; Follow-Up Studies; Humans; Intensive care medicine; Kidney Failure, Chronic - metabolism; Kidney Failure, Chronic - therapy; Male; Medical sciences; Pharmacology. Drug treatments; Prognosis; Pyrimidines - administration & dosage; Pyrimidines - pharmacokinetics; Renal Dialysis; Tissue Distribution; Triazoles - administration & dosage; Triazoles - pharmacokinetics; Voriconazole; Kidney disease; Human; Urinary system disease; Hemodialysis; Azole derivatives; Oligosaccharide; SBECD; Extrarenal dialysis; β-Cyclodextrin; Cyclodextrin; Antifungal agent; Renal failure; Voriconazole; Triazole derivatives; Pharmacokinetics
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfr472

The disposition of sulfobutylether-β-cyclodextrin (SBECD), the solubilizing excipient in intravenous (i.v.) voriconazole, was assessed in seven male subjects with end-stage renal disease on hemodialysis and six subjects with normal renal function. All subjects received twice-daily i.v. 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 i.v. 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. SBECD disposition was characterized by a two-compartment model. In renal failure, mean central (V(1)) and peripheral compartment volumes (V(2)) were 9.9 and 6.5 L, respectively. In normal subjects, V(1) and V(2) 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). Hemodialysis can significantly reduce levels of SBECD in subjects with end-stage renal disease.