Therapeutic drug monitoring and safety of intravenous voriconazole formulated with sulfobutylether β‐cyclodextrin in haematological patients with renal impairment

Abstract

SummaryBecause 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 b-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 À1 (case). Although voriconazole trough concentrations were significantly higher in cases (5.84 mg l À1 ) than controls (2.28 mg l À1 ), 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 À1 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 À1 .

Effect of Cumulative Intravenous Voriconazole Dose on Renal Function in Hematological Patients

“…Three months after intravenous VRC treatment, the median serum creatinine level was 0.80 mg/dl (range, 0.36 to 1.50 mg/dl) in 81 evaluable patients, and no patient required renal replacement therapy. Previous studies showed that use of intravenous VRC was not associated with renal dysfunction in patients with baseline moderate to severe renal impairment in several different clinical contexts (3)(4)(5)(6)(7)(8). However, the median duration of intravenous VRC treatment in the previous studies was much shorter than that in our study (3)(4)(5)(6)(7).…”

“…Previous studies showed that use of intravenous VRC was not associated with renal dysfunction in patients with baseline moderate to severe renal impairment in several different clinical contexts (3)(4)(5)(6)(7)(8). However, the median duration of intravenous VRC treatment in the previous studies was much shorter than that in our study (3)(4)(5)(6)(7). Indeed, intravenous SEBCD administered at Ն160 mg/kg causes dose-dependent changes in renal tubular vacuolation in animal models treated for 1 to 6 months (1), but there are no data evaluating the effect of cumulative doses of SBECD on renal function in humans.…”

“…Meanwhile, long-term use of intravenous VRC is common in hematological patients due to treatment-related gastrointestinal toxicities and prolonged immunosuppression. Several studies demonstrated that the use of intravenous VRC in patients with baseline moderate to severe renal impairment did not lead to acute renal toxicity (3)(4)(5)(6)(7)(8). However, the effect of long-term use of intravenous VRC on renal function in patients without baseline severe renal impairment is unclear.…”

Pharmacokinetics and Pharmacodynamics of Posaconazole

“…However, from the experience with voriconazole, also containing sulfobutylether-β-cyclodextrin, we have learned that the benefits of efficacious treatment may outweigh the risk associated with accumulation of sulfobutylether-βcyclodextrin. In addition, sulfobutylether-β-cyclodextrin appeared to accumulate by about sixfold in the kidney, but was not nephrotoxic itself [123][124][125]. Data on pharmacokinetics, efficacy, and safety upon long-term posaconazole use are lacking in this special population, for which future studies are expected to fill the gap.…”

Azoles de antes y ahora: una revisión

“…La característica lipofílica de los azoles, hace que sea necesario combinarlos con moléculas como la ciclodextrina, que se convierte en el vehículo de transporte del fármaco; se ha demostrado que este compuesto en pacientes con enfermedad renal y tasa de filtración glomerular menor a 50 ml/min/1,73 m 2 , se acumula, precipitando la ocurrencia de más efectos adversos relacionados con la nefrotoxicidad; sin embargo, su impacto clínico sigue sin estar claro. Es así como en pacientes adultos con enfermedad renal crónica y neoplasias hematológicas, a quienes se administró voriconazol endovenoso para el tratamiento de AI, no se encontró deterioro de la función renal ni efectos adversos graves 27 .…”