Evaluation of Sulfobutylether-β-Cyclodextrin Exposure in a Critically Ill Patient Receiving Intravenous Posaconazole While Undergoing Continuous Venovenous Hemofiltration

Abstract

We present a 31-year-old female who had undergone an allogeneic bone marrow transplantation and who was started on intravenous posaconazole for pulmonary mycosis while undergoing continuous venovenous hemofiltration (CVVH). We performed steady-state pharmacokinetic evaluations for both posaconazole and sulfobutylether-β-cyclodextrin (SBECD). SBECD was effectively removed by CVVH, with observed exposure similar to that for patients with moderate renal impairment. Intravenous posaconazole at standard doses may be utilized in critically ill patients undergoing CVVH without significant risk of SBECD accumulation.

TEXT

Posaconazole is a broad-spectrum triazole antifungal with activity against yeast, molds, and endemic fungi. It is FDA approved for prophylaxis against invasive Aspergillus and Candida infections in severely immunocompromised patients and is recommended by treatment guidelines for Mucorales and as salvage therapy for cryptococcosis, aspergillosis, and coccidioidomycosis (1–5). Initially, posaconazole was only available as an oral suspension, but given its variable pharmacokinetics and reliance on ingestion with a high-fat meal for optimal absorption, alternative formulations have been developed. The intravenous (i.v.) posaconazole formulation provides an alternative administration strategy when enteral absorption is impaired. Intravenous posaconazole contains 6,680 mg of the solubilizing agent sulfobutylether-β-cyclodextrin (SBECD) for every 300 mg of posaconazole. It is recommended that i.v. posaconazole be avoided in patients with a creatinine clearance (CL_CR) of less than 50 ml/min/1.73 m² to prevent accumulation of SBECD, which may be associated with hepatotoxicity and nephrotoxicity (1, 6).

Previous reports have described SBECD exposure associated with voriconazole administration in critically ill patients undergoing renal replacement therapy; however, less is known regarding intravenous posaconazole administration in this patient population (7). We report a case of an allogeneic stem cell transplant patient on continuous renal replacement therapy who received treatment with intravenous posaconazole as empirical therapy for a probable invasive pulmonary mold infection. In addition, we describe the pharmacokinetics and clearance of the excipient SBECD during continuous venovenous hemofiltration (CVVH).

We present a 31-year-old female who underwent an allogeneic bone marrow transplant for severe aplastic anemia and was admitted to the University of Colorado Hospital with a diagnosis of neutropenic fever and sepsis. Voriconazole therapy was empirically started at hospital admission based on computed tomography (CT) imaging results demonstrating bilateral upper lobe pulmonary nodules. Due to severe mucositis and graft-versus-host disease, the patient required intravenous rather than enteral voriconazole therapy.

Ten days after admission, the patient was transferred to the medical intensive care unit with acute hypoxic respiratory failure requiring mechanical ventilation and oliguric renal failure with initiation of CVVH. The patient underwent CVVH utilizing the NxStage System One dialysis machine (NxStage Medical Inc., Lawrence, MA) with NxStage Cartridge Express and filter (high-flux polyethersulfone membrane with 1.5-m² membrane surface area). The blood flow rate was 300 ml/min, and the predilution replacement therapy fluid flow rate was 2,000 ml/h. The ultrafiltration rate was adjusted hourly to keep the patient's volume status net even. Given her clinical deterioration despite therapeutic voriconazole levels and complaints of visual changes attributed to the voriconazole therapy, her antifungal regimen was changed to intravenous posaconazole (300 mg twice a day [BID] on day 1, then 300 mg daily) on hospital day 24. Steady-state posaconazole and SBECD plasma and effluent concentrations were obtained on day 10 of intravenous posaconazole therapy. Despite broad-spectrum antimicrobial therapy, the patient's multiorgan failure worsened, and she expired from septic shock on hospital day 38. All cultures remained negative, and a definitive pathogen for the pulmonary nodules could not be identified.

Posaconazole plasma concentrations were measured and analyzed by Advanced Diagnostic Laboratories at National Jewish Health (National Jewish Health Pharmacokinetics Laboratory, Denver, CO). Plasma and effluent samples were collected for measurement of SBECD concentrations at 0, 2, 3, 4, 6, 8, 12, and 24 h after administration. SBECD concentrations were determined utilizing a previously described liquid chromatography-tandem mass spectrometry (LC-MS/MS) method at the University of Colorado Medicinal Chemistry Core Laboratory (University of Colorado Anschutz Medical Campus, Aurora, CO) (7).

Posaconazole and SBECD concentrations were analyzed by standard noncompartmental pharmacokinetics. Data from a recent pharmacokinetic study of SBECD during intravenous voriconazole therapy were utilized to determine SBECD pharmacokinetic parameters for various CVVH ultrafiltration levels (2,000, 3,000, and 6,000 ml/h) (7). The clearance parameters from this study were coupled with the pharmacokinetics determined for this subject to simulate SBECD concentrations during intravenous posaconazole administration using ADAPT 5 (Biomedical Simulations Resource, Los Angeles, CA), using the individual simulation with output error option. The simulated dose represented SBECD administered to this patient (6,680 mg i.v. every 12 h for 2 doses, followed by 6,680 mg i.v. every 24 h). Data from these simulations were then plotted using GraphPad Prism software (version 5.04; La Jolla, CA) (Fig. 1).

FIG 1.

Simulated plasma SBECD pharmacokinetic profiles in subjects undergoing CVVH based on ultrafiltration rate. Data represent 1,000 patient simulations for SBECD exposure with administration of the standard posaconazole dose of 300 mg i.v. every 12 h for two doses followed by 300 mg i.v. every 24 h from time zero to day 7. Data are presented for overall SBECD exposure at CVVH ultrafiltration rates varying from 2,000 to 6,000 ml/h (with the assumption that up to 90% of the time ultrafiltration rates will be in the 2,000 to 3,000 ml/h range) (top left) and individual ultrafiltration rates of 2,000 ml/h (top right), 3,000 ml/h (bottom left), and 6,000 ml/h (bottom right). Data are presented as mean concentration (solid line) and standard deviation (dashed line).

The posaconazole maximum concentration (C_max), minimum concentration (C_min), half-life, area under the concentration-time curve from 0 to 24 h (AUC_0–24), clearance (CL), and volume of distribution (V) were 2.78 mg/liter, 1.68 mg/liter, 31 h, 53 mg · h/liter, 9.5 liters/h, and 427 liters, respectively. These pharmacokinetic parameters for SBECD were 211 mg/liter, 52 mg/liter, 12.9 h, 2,608 mg · h/liter, 2.6 liters/h, and 47.8 liters, respectively.

In our patient, SBECD did not accumulate and was readily removed with CVVH. The cyclodextrin exposure with intravenous posaconazole was less than that previously observed with intravenous voriconazole, with C_max values of 211 mg/liter versus 687 mg/liter and C_min values of 52 mg/liter versus 215 mg/liter, respectively (7). This likely reflects the reduced dose of SBECD administered with once-daily posaconazole compared to that administered with twice-daily voriconazole (approximately 84 mg/kg of body weight per day for an 80-kg patient versus 128 mg/kg/day, respectively). The half-life of SBECD was still prolonged, at 12.9 h, compared to the half-life of 1.6 to 2 h observed in healthy volunteers with normal renal function (6). This is consistent with our knowledge that SBECD is highly correlated with CL_CR (r² = 0.857) (8). A reduction in total clearance for our patient was anticipated because the prescribed ultrafiltration rate of 2,000 ml/h approximates the renal function of a patient with moderate renal impairment (∼CL_CR of 30 ml/min/1.73 m²). Although the overall SBECD exposure in our patient was 2.5 times higher than that previously reported for healthy volunteers with a CL_CR of 120 ml/min/1.73 m² (AUC values of 2,608 and 919 mg · h/liter, respectively), the AUC is significantly lower than that predicted for anuric patients (12-fold higher AUC) and patients undergoing intermittent hemodialysis every 48 h (7-fold higher AUC) (9).

We simulated a model of SBECD clearance relative to CVVH ultrafiltration rates at 2,000, 3,000, and 6,000 ml/h (Fig. 1). In all simulations, steady-state SBECD concentrations were achieved within 48 to 72 h of intravenous posaconazole initiation, and further drug accumulation was not observed. Our analyses indicate that while SBECD clearance is strongly related to the ultrafiltration rate, SBECD is unlikely to accumulate to toxic concentrations even at low ultrafiltration rates. The use of higher ultrafiltration rates (e.g., 6,000 ml/h) would result in SBECD exposure similar to that for a patient with normal renal function. These findings suggest that i.v. posaconazole may be safely administered to a patient that is undergoing CVVH, despite package labeling to avoid use for CL_CR of less than 50 ml/min/1.73 m² due to potential for accumulation of SBECD.

We did not examine the impact of CVVH on posaconazole clearance given that its large molecular weight and high degree of protein binding make it unlikely to be dialyzable. A study investigating the pharmacokinetics of oral posaconazole in healthy subjects with various degrees of renal impairment and intermittent hemodialysis demonstrated that chronic renal disease did not have a clinically significant impact on posaconazole pharmacokinetics (10). Predialyzed and postdialyzed posaconazole plasma AUC values differed by only 3%, indicating that posaconzole was not removed by hemodialysis. In our patient case, intravenous posaconazole at the usual recommended dose of 300 mg i.v. every 12 h followed by 300 mg i.v. daily was effective at achieving steady-state trough concentrations of >1.5 mg/liter while the patient was receiving continuous renal replacement therapy. Although there are no established guidelines for therapeutic drug monitoring of posaconazole, clinical studies have demonstrated a relationship between posaconazole concentrations and efficacy. Such studies have suggested that lower average exposure may be associated with increased treatment failures; therefore, we target a steady-state trough concentration of ≥0.7 mg/liter for prophylaxis and ≥1 to 2 mg/liter for treatment (11, 12). Despite CVVH, posaconazole serum concentrations were similar to those for healthy volunteers with normal renal function, including a C_max of 2.78 mg/liter (2-h level) versus a C_max of 3.28 mg/liter (1.5-h level) and a C_min of 1.68 mg/liter versus a C_min of 1.09 mg/liter (13). The half-life of i.v. posaconazole was comparable to that for patients with normal renal function, at 31 h versus 27 h, respectively. Our results further indicate that using standard doses of i.v. posaconazole with CVVH will achieve therapeutic trough levels.

In conclusion, intravenous posaconazole therapy was effective at achieving therapeutic trough concentrations in a patient undergoing CVVH. SBECD was effectively removed by CVVH at a range of ultrafiltration rates without evidence of accumulation. Intravenous posaconazole at standard doses may be utilized in critically ill patients undergoing CVVH without significant risk of SBECD accumulation. However, given the small sample size in our analysis, additional data are warranted to further establish dosing recommendations in this patient population.