betadex and Kidney-Failure--Chronic

Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well defined. We performed a three-period randomized crossover study of 15 patients with end-stage renal failure during 6-hour treatment with Genius dialysis, standard hemodialysis, or hemodiafiltration using a high-flux polysulfone membrane. At the start of renal replacement therapy, the patients received a single 2-h infusion of voriconazole (4 mg per kg of body weight) solubilized with SBECD. SBECD, voriconazole, and voriconazole-N-oxide concentrations were quantified in plasma and dialysate samples by high-performance liquid chromatography (HPLC) and by HPLC coupled to tandem mass spectrometry (LC-MS-MS) and analyzed by noncompartmental methods. Nonparametric repeated-measures analysis of variance (ANOVA) was used to analyze differences between treatment phases. SBECD and voriconazole recoveries in dialysate samples were 67% and 10% of the administered doses. SBECD concentrations declined with a half-life ranging from 2.6 +/- 0.6 h (Genius dialysis) to 2.4 +/- 0.9 h (hemodialysis) and 2.0 +/- 0.6 h (hemodiafiltration) (P < 0.01 for Genius dialysis versus hemodiafiltration). Prediction of steady-state conditions indicated that even with daily hemodialysis, SBECD will still exceed SBECD exposure of patients with normal renal function by a factor of 6.2. SBECD was effectively eliminated during 6 h of renal replacement therapy by all methods, using high-flux polysulfone membranes, whereas elimination of voriconazole was quantitatively insignificant. The SBECD half-life during renal replacement therapy was nearly normalized, but the average SBECD exposure during repeated administration is expected to be still increased.

Topics: Adult; Aged; Antifungal Agents; beta-Cyclodextrins; Cross-Over Studies; Female; Half-Life; Hemodiafiltration; Humans; Infusions, Intravenous; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged; Pyrimidines; Renal Dialysis; Solvents; Triazoles; Voriconazole

The pharmacokinetics of intravenous itraconazole (ITC) was studied in dialysis patients. Dialysis had no effect on the half-life and clearance of ITC or OH-ITC. However, dialysis allowed the clearance of hydroxypropyl-beta-cyclodextrin (HP-beta-CD). The area under the concentration-time curve from time zero to infinity (AUC(0- infinity)) for HP-beta-CD administered before dialysis was lower than the AUC(0- infinity) when it was administered after dialysis (P < 0.01). Administration of ITC intravenously just prior to hemodialysis appears to produce adequate systemic exposures of ITC and OH-ITC while allowing dialysis clearance of HP-beta-CD. Studies of multiple administrations are warranted.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Antifungal Agents; Area Under Curve; beta-Cyclodextrins; Calibration; Cyclodextrins; Half-Life; Humans; Infusions, Intravenous; Itraconazole; Kidney Failure, Chronic; Renal Dialysis

Indoxyl sulphate (IS), a protein-bound uremic toxin that dramatically increases in the sera of patients with end-stage renal disease (ESRD), is poorly removed by conventional haemodialysis (HD). The purpose of this study was to explore whether the addition of water-soluble sorbent poly-β-cyclodextrins (PCDs) to dialysate can increase the clearance of IS in uremic rats in vivo.. Male SD rats (450-550 g, n = 18) with nephrectomy plus IS injection (10-mg/kg) were randomly divided into three groups: 1. The HD group (n = 6): conventional HD for 4 h; 2. the 2% PCD group: 2% PCD added to the dialysate, HD for 4 h; and 3. the 4% PCD group: 4% PCD added to the dialysate, HD for 4 h. The serum IS levels in model rats were similar to those of ESRD patients. A stable and safe rat HD treatment mode was established by adjusting the vascular access, blood flow rate, dialysate flow rate, dialysis pipe, dialysate configuration, temperature, treatment environment, and other aspects.. Our study found that adding 2% PCD to dialysate significantly improved the clearance of IS approximately twofold compared with conventional HD. Further increasing the PCD concentration to 4% did not increase IS clearance.. Therefore, our study showed that adding water-soluble sorbent PCDs to dialysate significantly improved the clearance of IS in uremic rats in vivo.

Topics: Animals; beta-Cyclodextrins; Dialysis Solutions; Indican; Kidney Failure, Chronic; Male; Rats; Rats, Sprague-Dawley; Renal Dialysis; Water

Oxidative stress is known to be involved in the pathogenesis of chronic renal failure (CRF). In this study, the effect of cyclodextrins (CDs) on oxidative stress and CRF was investigated using 5/6 nephrectomized rats as model animals.. CRF model rats were divided into five groups and treated for 8 weeks as follows: control, α-CD, β-CD, γ-CD and 2-hydroxypropyl-β-CD (HP-β-CD). Blood was collected from the rats after 4 and 8 weeks for an analysis of renal function and oxidative stress tests were carried out.. An oral administration of HP-β-CD over an 8-week period resulted in a significant decrease in serum indoxyl sulphate, creatinine and urea nitrogen levels, compared with the other CDs. The ingestion of HP-β-CD also resulted in an increase in antioxidant potential, compared with the other CDs. In in vitro studies, the interaction of HP-β-CD with a uremic toxin, indole molecule, was much higher than that for the other CDs, as evidenced by Proton nuclear magnetic resonance ((1) H NMR) measurements.. These results suggest that the ingestion of HP-β-CD might result in a significant reduction in the levels of pro-oxidants in the gastrointestinal tract, such as uremic toxins, thereby inhibiting the subsequent development of oxidative stress in the systemic circulation.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Animals; Antioxidants; beta-Cyclodextrins; Biomarkers; Blood Urea Nitrogen; Creatinine; Cytoprotection; Disease Models, Animal; Indican; Indoles; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Oxidation-Reduction; Oxidative Stress; Proton Magnetic Resonance Spectroscopy; Rats; Serum Albumin; Time Factors

Intravenous (IV) voriconazole is not recommended in patients with creatinine clearance <50 ml/min to avoid potentially toxic accumulation of sulfobutylether-β-cyclodextrin (SBECD). The purpose of this study was to evaluate the pharmacokinetics of SBECD, voriconazole, and voriconazole N-oxide in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to determine if CRRT removes SBECD sufficiently to allow for the use of IV voriconazole without significant risk of SBECD accumulation.. This prospective, open-label pharmacokinetic study enrolled patients >18 years old receiving IV voriconazole for a known or suspected invasive fungal infection while undergoing CRRT. Serial blood and effluent samples were collected on days 1, 3, 5, 7, and every 3 to 5 days thereafter. SBECD, voriconazole, and voriconazole N-oxide plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic, pharmacodynamic, and pharmacogenetic analyses were conducted.. Ten patients (mean ± standard deviation (SD)) 53 ± 11 years old, 50% male, 81 ± 14 kg, with Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores of 31.5 ± 3.8 were evaluated. All patients underwent continuous venovenous hemofiltration (CVVH) with a median predilution replacement fluid rate of 36 (interquartile range (IQR) 32 to 37) ml/kg/hr and total ultrafiltration rate of 38 (IQR 34 to 39) ml/kg/hr. Mean ± SD voriconazole and SBECD dosages administered were 8.1 ± 2.1 mg/kg/day and 129 ± 33 mg/kg/day, respectively. Voriconazole plasma trough concentrations were >1 mg/L in all patients with CVVH accounting for only 15% of the total body clearance. CVVH accounted for 86% of the total body clearance of SBECD with the majority of the dose being recovered in the effluent. Minimal increases in dose normalized SBECD area under the concentration-time curve from 0 to 12 hours (AUC0-12) (4,484 ± 4,368 to 4,553 ± 2,880 mg*hr/L; P = 0.97) were observed after study day 1.. CVVH effectively removed SBECD at a rate similar to the ultrafiltration rate. Voriconazole clearance by CVVH was not clinically significant. Standard dosages of IV voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation.. ClinicalTrials.gov NCT01101386 . Registered 6 April 2010.

Topics: Adult; Antifungal Agents; beta-Cyclodextrins; Critical Illness; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Replacement Therapy; Therapeutics; Voriconazole

Topics: Antifungal Agents; beta-Cyclodextrins; Humans; Kidney Failure, Chronic; Male; Renal Replacement Therapy; Therapeutics; Voriconazole

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.

Topics: Adult; Antifungal Agents; beta-Cyclodextrins; Case-Control Studies; Excipients; Follow-Up Studies; Humans; Kidney Failure, Chronic; Male; Prognosis; Pyrimidines; Renal Dialysis; Tissue Distribution; Triazoles; Voriconazole