All subjects signed informed consent and the study was approved by the Institutional Review Board of Hennepin County Medical Center, Minneapolis, MN, USA. This study was conducted in compliance with the ethical principles originating from the Declaration of Helsinki and with local laws and regulations relevant to the conduct of clinical studies in the USA. Before participation in the study, all subjects underwent a complete physical examination as well as an ECG, urinalysis (where possible), complete blood count with differential, platelet count and blood chemistry profile. Subjects were excluded from the study if they had a history of clinically significant drug allergies, including polysulfone and cellulose (dialysis membranes) had received hemodialysis while clinically nephrotic had received an experimental drug or device within 1 month prior to study showed evidence of alcohol or drug abuse, HIV, clinically significant hepatic, renal including nephrosis (except dialysis subjects), bronchospastic or hematologic disease had acute liver disease or had a clinically important change in baseline status within the 4 weeks prior to the start of study. There was no requirement to quantify SBECD content within the commercially available product. The study consisted of a screening visit within the 3 weeks prior to the start of the study, 4.5 days of IV voriconazole dosing containing SBECD and a follow-up visit 7–10 days following the final dose. This was an open-label parallel-group study in which eight subjects with end-stage renal disease [creatinine clearance (CrCl) 70 mL/min) were studied as the control group. Since hemodialysis is one of the most common methods of renal replacement therapy, the following study was designed to evaluate the influence of hemodialysis on the disposition of SBECD.
The influence of renal dysfunction on the disposition of IV voriconazole has been described previously but only briefly on the disposition of its solubilizing agent, SBECD. The properties of SBECD suggest that it would accumulate in the presence of renal dysfunction and that it is dialyzable. SBECD is hydrophilic, not protein bound, and is excreted almost exclusively by glomerular filtration by the kidney. The pharmacokinetics of SBECD are predictable in healthy subjects and subjects with renal impairment who do not undergo renal replacement therapy.
The clinical importance of these findings is yet to be elucidated. Although only demonstrated in animal studies, accumulation of SBECD at supraclinical concentrations has resulted in renal vacuolation and appearance of pulmonary foamy macrophages. SBECD is primarily cleared by the kidneys, yet only some accumulation of SBECD has been described in subjects with moderate to severe renal dysfunction. Whereas an early generation of cyclodextrins has been associated with hepatic and/or renal dysfunction, SBECD was designed to minimize any cyclodextrin-associated toxicity, thus creating a useful and safe excipient. Voriconazole (Vfend® Pfizer Inc.), a triazole antifungal for the treatment of systemic yeast and mould infections, incorporates a solubilizing excipient, sulfobutylether-β-cyclodextrin (SBECD), in its intravenous (IV) formulation. Cyclodextrin, hemodialysis, pharmacokinetics, SBECD, voriconazole Introduction
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