Safety, Tolerance, and Pharmacokinetics of High-Dose Liposomal Amphotericin B (AmBisome) in Patients Infected withAspergillusSpecies and Other Filamentous Fungi: Maximum Tolerated Dose Study

Abstract

We conducted a phase I-II study of the safety, tolerance, and plasma pharmacokinetics of liposomal amphotericin B (L-AMB; AmBisome) in order to determine its maximally tolerated dosage (MTD) in patients with infections due to Aspergillus spp. and other filamentous fungi. Dosage cohorts consisted of 7.5, 10.0, 12.5, and 15.0 mg/kg of body weight/day; a total of 44 patients were enrolled, of which 21 had a proven or probable infection (13 aspergillosis, 5 zygomycosis, 3 fusariosis). The MTD of L-AMB was at least 15 mg/kg/day. Infusion-related reactions of fever occurred in 8 (19%) and chills and/or rigors occurred in 5 (12%) of 43 patients. Three patients developed a syndrome of substernal chest tightness, dyspnea, and flank pain, which was relieved by diphenhydramine. Serum creatinine increased two times above baseline in 32% of the patients, but this was not dose related. Hepatotoxicity developed in one patient. Steady-state plasma pharmacokinetics were achieved by day 7. The maximum concentration of drug in plasma (C max ) of L-AMB in the dosage cohorts of 7.5, 10.0, 12.5, and 15.0 mg/kg/day changed to 76, 120, 116, and 105 g/ml, respectively, and the mean area under the concentration-time curve at 24 h (AUC 24 ) changed to 692, 1,062, 860, and 554 g ⅐ h/ml, respectively, while mean CL changed to 23, 18, 16, and 25 ml/h/kg, respectively. These data indicate that L-AMB follows dose-related changes in disposition processing (e.g., clearance) at dosages of >7.5 mg/kg/day. Because several extremely ill patients had early death, success was determined for both the modified intent-to-treat and evaluable (7 days of therapy) populations. Response rates (defined as complete response and partial response) were similar for proven and probable infections. Response and stabilization, respectively, were achieved in 36 and 16% of the patients in the modified intent-to-treat population (n ‫؍‬ 43) and in 52 and 13% of the patients in the 7-day evaluable population (n ‫؍‬ 31). These findings indicate that L-AMB at dosages as high as 15 mg/kg/day follows nonlinear saturation-like kinetics, is well tolerated, and can provide effective therapy for aspergillosis and other filamentous fungal infections.

Pseudohyperphosphatemia associated with high-dose liposomal amphotericin B therapy

“…Thus, the increase in the estimated C L-AMB from 193.3 (day 13) to 344.4 (day 16) mg/l while on 10 mg/kg/day dosage, and from 82.2 (day 18) to 215.6 (day 21) mg/l while on 7.5 mg/kg/day dosage, is consistent with the reported pharmacokinetics of the drug. In addition, on the first day of the 7.5 mg/kg/day dosage (day 18) the estimated C L-AMB is in good agreement with the reported C max (mean ± SD = 75.9 ± 58.4 mg/l) [8].…”

“…To prove that this discrepancy is due to interference of L-AMB with the LX20 analytical method, we performed spiking studies to achieve L-AMB concentrations similar to those seen in the sera of patients receiving high-dose L-AMB therapy [8,20,21]. Spiking was done with normal clear serum pool in order to mimic normal physiologic conditions, with normal saline in order to remove the possibility of alternate interfering substances, and with lipemic serum pool to verify that endogenous hyperlipidemia does not interefere with the LX20 Pi method.…”

“…Pharmacokinetic studies have demonstrated that mean area under the concentration-time curve from 0 to 24 h (AUC 24 ) and maximum concentration of drug in plasma (C max ) increased with sequentially higher daily doses of L-AMB and reached the upper limit at 10 mg/kg/day [8,20,21]. Furthermore, both AUC 24 and C max increased with the duration (days 1, 7, and up to 24 days) of drug therapy.…”

“…This lipid formulation has a favorable toxicity profile when compared to conventional amphotericin B deoxycholate [2][3][4] and has been approved for use at dosages ranging from 3 to 6 mg/kg/day for indications including empirical therapy of persistent febrile neutropenia, systemic aspergillus, candida, and cryptococcus infections, visceral leishmaniasis, and cryptococcal meningitis in HIV infected patients. The improved safety and tolerability of this formulation have allowed for the use of increasingly higher dosages for the treatment of refractory infections [5][6][7][8]. However, a single case in the pediatric literature reported severe hyperphosphatemia related to therapy with 25 mg/kg/day of L-AMB [9].…”

A prospective randomized controlled trial comparing PCR-based and empirical treatment with liposomal amphotericin B in patients after allo-SCT

“…18 Furthermore, the dosage of liposomal amphotericin B can be increased safely to dosages higher than 3 mg/kg if necessary. 19 To investigate the impact of PCR as a diagnostic tool for guiding preemptive antifungal therapy, we compared the incidence of IFIs as well as the overall and IFI-related mortality in patients after Allo-SCT randomized to PCRbased preemptive as opposed to empirical treatment with liposomal amphotericin B.…”