Pharmacokinetics, Safety and Tolerance of Voriconazole in Renally Impaired Subjects Two Prospective, Multicentre, Open- Label, Parallel-Group Volunteer Studies

• Published in: Clinical drug investigation Vol. 28; no. 7; pp. 409 - 420
• Main Authors: Abel, Samantha, Allan, Richard, Gandelman, Kuan, Tomaszewski, Konrad, Webb, David J., Wood, Nolan D.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.01.2008; Wolters Kluwer Health, Inc; Springer Nature B.V
• Subjects: Administration, Oral; Adult; Aged; Antifungal Agents - administration & dosage; Antifungal Agents - adverse effects; Antifungal Agents - pharmacokinetics; beta-Cyclodextrins - chemistry; Creatinine - blood; Creatinine - urine; Humans; Injections, Intravenous; Internal Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Prospective Studies; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Pyrimidines - pharmacokinetics; Renal Insufficiency; Severity of Illness Index; Solubility; Triazoles - administration & dosage; Triazoles - adverse effects; Triazoles - pharmacokinetics; Voriconazole; Moderate Renal Impairment; Normal Renal Function; Severe Renal Impairment; Renal Impairment; Voriconazole
• ISSN: 1173-2563; 1179-1918
• DOI: 10.2165/00044011-200828070-00002

Background and objectives: Since little is known regarding the pharmacokinetics of voriconazole in renally impaired patients, two prospective, open-label, parallel-group volunteer studies were conducted to estimate the effect of renal impairment on the pharmacokinetics of oral voriconazole and intravenous voriconazole solubilized with sulphobutylether-β-cyclodextrin (SBECD), respectively. Methods: In study A, male subjects with no (n = 6), mild (n = 6), moderate (n = 6) or severe (n = 6) renal impairment received one 200 mg dose of oral voriconazole. Voriconazole plasma levels were periodically assessed until 48 hours post-dose. In study B, male subjects with no (n = 6) or moderate (n = 7) renal impairment received multiple doses of intravenous voriconazole solubilized with SBECD (6 mg/kg twice daily [day 1] then 3 mg/kg twice daily [days 2–6] followed by a final dose of 3 mg/kg on the morning of day 7) at an infusion rate of 3 mg/kg/h. Voriconazole plasma levels were periodically assessed until 36 hours following the final dose. Pharmacokinetics were determined by non-compartmental methods. Results: The pharmacokinetics of voriconazole were unaffected in subjects with any degree of renal impairment in both studies. In study B, clearance of SBECD was proportional to creatinine clearance (r 2 = 0.857). Although two subjects had >30% increase in serum creatinine from baseline, these changes did not correlate with SBECD trough levels (r 2 = 0.053). The majority of subjects with moderate renal insufficiency were able to tolerate 7 days of intravenous voriconazole solubilized with SBECD. Conclusion: These data suggest that renal impairment does not affect the pharmacokinetics of voriconazole. Furthermore, in subjects with moderate renal impairment, there is a strong linear correlation between SBECD clearance and creatinine clearance, and elevated SBECD levels do not necessarily correlate with increased serum creatinine levels (an indicator of worsening renal function).