Pharmacokinetics and Buccal Mucosal Concentrations of a 15 Milligram per Kilogram of Body Weight Total Dose of Liposomal Amphotericin B Administered as a Single Dose (15 mg/kg), Weekly Dose (7.5 mg/kg), or Daily Dose (1 mg/kg) in Peripheral Stem Cell Transplant Patients

Abstract

The pharmacokinetics and safety of extended-interval dosing of prophylactic liposomal amphotericin B (L-AMB) in peripheral stem cell transplant recipients were evaluated. The patients received L-AMB daily at 1 mg/kg of body weight or weekly at 7.5 mg/kg or received L-AMB as a single dose (15 mg/kg). The buccal mucosal tissue concentrations of L-AMB were measured. Of the 24 patients enrolled, 5 withdrew after the initial dose due to an infusion-related reaction (n ‫؍‬ 2) or significant increases in the serum creatinine (Scr) levels (n ‫؍‬ 3). Weekly L-AMB dosing (7.5 mg/kg) produced mean plasma concentrations of >0.300 g/ml for the first 7 days and >0.220 g/ml for 7 days after the second dose. A single L-AMB dose (15 mg/kg) produced mean plasma concentrations of >0.491 g/ml for at least 7 seven days. Amphotericin B (AMB) exhibits concentration-dependent fungicidal activity against many common opportunistic fungal pathogens (19,20). A dose-fractionation study with a murine disseminated candidiasis model demonstrated that maximization of the maximum drug concentration in plasma (C max )/ MIC ratio optimizes the efficacy of AMB (2). Theoretically, this should enable the intermittent administration of large amounts of AMB, which could make its use by ambulatory patients more practical. However, in practice, maximization of the concentration-dependent activity of AMB deoxycholate is difficult due to its dose-related nephrotoxicity. However, lipid AMB formulations are safer and demonstrate subtle pharmacokinetic differences in disposition from that of AMB deoxycholate, which allows the administration of higher doses. Lipid AMB formulations such as liposomal amphotericin B (L-AMB) should enable clinicians to optimize the pharmacodynamic properties of AMB and facilitate their use by ambulatory patients.Data from studies with neutropenic animals suggest that the administration of a single dose or intermittent doses of L-AMB up to 20 mg/kg of body weight can be employed to prevent or manage infections due to yeasts or molds (1,22). Higher L-AMB doses produce increased intravascular concentrations, which may facilitate its penetration into certain tissues and which may produce reductions in the fungal burdens in those tissues more marked than those achieved with other AMB formulations (17,28). In mice, L-AMB administered at 15 mg/kg thrice weekly produced sufficiently high and sustained kidney and spleen concentrations to provide prophylactic efficacy against systemic challenge with a Candida sp. 3 and 6 weeks posttreatment (30). In a murine model, the administration of a single prophylactic L-AMB dose (1, 5, 10, or 20 mg/kg) 7 to 9 days prior to challenge with Candida albicans or Histoplasma capsulatum produced increased L-AMB kidney and spleen concentrations which correlated with dose-dependent increases in efficacy (14).

Tissue Penetration of Antifungal Agents

“…Buccal mucosal concentrations of amphotericin B increase in a dose-dependent manner in humans after L-AMB administration and attain concentrations approximately 7 to 43 times those in plasma (166). A wide range of amphotericin B concentrations were also detectable in esophageal autopsy samples from seven patients after AmBd administration (54).…”

Prospective Phase II Single-Center Study of the Safety of a Single Very High Dose of Liposomal Amphotericin B for Antifungal Prophylaxis in Patients with Acute Myeloid Leukemia

“…Higher L-AmB doses produce increased intravascular concentrations, which may facilitate its penetration into tissues with sustained concentrations sufficiently high to provide prophylactic efficacy against fungi for several weeks posttreatment (36). In a study on pharmacokinetics and safety of extended-interval dosing of prophylactic L-AmB in stem cell transplant recipients, different schedules of L-AmB administration were evaluated (28). A single L-AmB dose of 15 mg/kg produced mean plasma concentrations of Ͼ0.491 mg/liter for at least 7 days.…”

“…The aim of the present study was to investigate the safety and feasibility of a single very high dose of L-AmB administered as Single center, prospective, pharmacokinetic (25) Pediatric patients receiving allogeneic SCT (14) 10 mg/kg weekly for 4 wk No significant change in serum creatinine level; none of the patients developed hypokalemia, hypomagnesemia, or increased alkaline phosphatase or transaminase levels; only 1 infusion toxicity requiring withholding of the wk 4 dose Only 1 patient developed evidence of IFD Single center, prospective, uncontrolled (26) Adult neutropenic patients receiving allogeneic SCT and with GVHD (21) 7.5 mg/kg once weekly during treatment of GVHD L-AmB was discontinued in 33% of patients, 19% due to nephrotoxicity and 9.5% due to infusion-related adverse events Only one IFD; no death attributed to IFD Multicenter, prospective, pilot, phase II (27) Adult patients receiving chemotherapy for AL or allogeneic SCT (29) 10 mg/kg weekly for 4 wk in AL patients and for 8 wk in SCT patients Grade 3-4 AEs, 2/21 AL patients and 6/8 SCT patients; enrollment of SCT patients was stopped Proven/probable IFDs, 4/29 (13.8%); 1 death attributed to IFD Single center, prospective, pharmacokinetic (28) Adult patients receiving allogeneic or autologous SCT (21) 1 mg/kg/day for 15 days (7 patients), 7.5 mg/ kg/wk for 2 wk (7 patients), single 15-mg/kg dose (7 patients) For the daily dosing (1-mg/kg) group, 1 patient withdrew on day 1 due to sternal pain, and 1 patient developed CTC grade 3 hypokalemia; for the weekly dosing (7.5-mg/kg) group, 1 patient was withdrawn due bronchospam after the first dose, and 1 patient developed CTC grade 3 hypokalemia; for the single-dose (15-mg/ kg) group, 2 patients developed CTC grade 3 and 1 patient developed CTC grade 4 hypokalemia Not reported a HM, hematologic malignancies; AL, acute leukemia; GVHD, graft-versus-host disease.…”

“…Some preclinical and pharmacokinetic studies suggested the relevance of a highdose regimen of L-AmB (7.5 to 15 mg/kg of body weight) administered as long-interval infusions (once weekly) or as a single administration in the prophylaxis of IFDs (25)(26)(27)(28). All these experiences demonstrated variable safety and clinical attractiveness of long intervals or single, high-dose, prophylactic schedules of L-AmB in certain high-risk populations, but this has not been adequately investigated for AML patients.…”

“…The liposomal form of AmB (L-AmB) has been investigated in order to evaluate the feasibility of its use in primary prophylaxis of IFDs in patients with hematological malignancies receiving chemotherapy or stem cell transplant (SCT) (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28). Some preclinical and pharmacokinetic studies suggested the relevance of a highdose regimen of L-AmB (7.5 to 15 mg/kg of body weight) administered as long-interval infusions (once weekly) or as a single administration in the prophylaxis of IFDs (25)(26)(27)(28).…”