betadex and Renal-Insufficiency

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-beta-cyclodextrin (SBECD), respectively.. 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.. 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 (r2 = 0.857). Although two subjects had >30% increase in serum creatinine from baseline, these changes did not correlate with SBECD trough levels (r2 = 0.053). The majority of subjects with moderate renal insufficiency were able to tolerate 7 days of intravenous voriconazole solubilized with SBECD.. 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).

Topics: Administration, Oral; Adult; Aged; Antifungal Agents; beta-Cyclodextrins; Creatinine; Humans; Injections, Intravenous; Male; Middle Aged; Prospective Studies; Pyrimidines; Renal Insufficiency; Severity of Illness Index; Solubility; Triazoles; Voriconazole

Intravenous voriconazole (VRC) is formulated by the incorporation of sulfobutylether-β-cyclodextrin (SBECD), which may accumulate to adversely affect renal function. However, the effect of long-term use of intravenous VRC on renal function is unclear. Our retrospective analysis of data confirmed that worsening of renal function was significantly associated with a cumulative dose of intravenous VRC (≥400 mg/kg), suggesting that a higher cumulative dose of intravenous VRC is a risk factor for renal dysfunction.

Topics: Administration, Intravenous; Adolescent; Adult; Aged; Antifungal Agents; beta-Cyclodextrins; Female; Humans; Kidney; Male; Middle Aged; Renal Insufficiency; Retrospective Studies; Voriconazole; Young Adult

Because of concerns about accumulation of cyclodextrin, oral voriconazole is recommended for patients with renal impairment. However, intravenous voriconazole may occasionally be imperative in critically ill patients with life-threatening invasive aspergillosis. We investigated the clinical effects of intravenous voriconazole formulated with sulfobutylether β-cyclodextrin (SBECD) in patients with renal impairment. A prospective observational study was conducted on 25 adult patients with haematological malignancies who were treated with intravenous voriconazole for invasive aspergillosis. Among them, seven patients had a baseline creatinine clearance (CrCl) <50 ml min(-1) (case). Although voriconazole trough concentrations were significantly higher in cases (5.84 mg l(-1) ) than controls (2.28 mg l(-1) ), the proportion of concentrations within the target range did not differ between two groups (4/7 and 12/18, respectively; P = 0.658). The frequency of severe adverse events in cases (3/7) was comparable to that of controls (4/18; P = 0.355). No patients showed significant deterioration in renal function after the voriconazole therapy even in patients with renal impairment. Although CrCl <50 ml min(-1) was associated with higher voriconazole concentrations, its clinical impact remains unclear. SBECD-formulated intravenous voriconazole did not lead to a higher incidence of severe adverse events including nephrotoxicity in haematological patients with CrCl <50 ml min(-1) .

Topics: Administration, Intravenous; Adolescent; Adult; Antifungal Agents; Aspergillosis; beta-Cyclodextrins; Creatinine; Cytochrome P-450 CYP2C19; Drug Compounding; Drug Monitoring; Female; Hematologic Neoplasms; Humans; Invasive Fungal Infections; Male; Middle Aged; Prospective Studies; Renal Insufficiency; Voriconazole; Young Adult

Topics: Aged; Animals; Antifungal Agents; beta-Cyclodextrins; Critical Illness; Female; Humans; Male; Middle Aged; Mycoses; Pyrimidines; Renal Dialysis; Renal Insufficiency; Triazoles; Voriconazole

Voriconazole was introduced for the treatment of life-threatening fungal infections. The intravenous form includes the solvent vehicle sulphobutylether beta cyclodextrin sodium which shows an impaired clearance under intermittent dialysis therapy. This investigation aimed to determine first clinical data on sulphobutylether beta cyclodextrin sodium blood levels to verify the risk for accumulation.. In four patients suffering from renal insufficiency and intermittent dialysis therapy who needed a treatment with intravenous voriconazole as a reserve antifungal at the intensive care unit of the Mainz University Hospital the trough levels of voriconazole and sulphobutylether beta cyclodextrin sodium were measured.. A 75-year-old woman showed a maximal sulphobutylether beta cyclodextrin sodium plasma level of 145 microg/ml in the initial phase. After a few days renal function recovered and the plasma levels came down to less than 20 microg/ml. In contrast to this patient with a recovery of renal function the remaining three patients showed renal failure during the complete period of intravenous treatment with voriconazole. In these patients an accumulation of sulphobutylether beta cyclodextrin sodium plasma levels was determined with a maximum of 523 mug/ml in a 18-year-old man, 409 microg/ml in a 57-year-old man, and 581 microg/ml in a 47-year-old man.. The present data indicate an accumulation of sulphobutylether beta cyclodextrin sodium in patients treated with intravenous voriconazole and dialysis therapy. Fortunately, no toxic effects were observed, although the accumulated dose values were lower but comparable with those used in previous toxicity studies with animals.

Topics: Aged; Antifungal Agents; beta-Cyclodextrins; Critical Illness; Female; Humans; Pyrimidines; Renal Insufficiency; Renal Replacement Therapy; Solvents; Triazoles; Voriconazole