AmBisome (NeXstarPharmaceuticals, San Dimas, CA) is a unilamellar liposomal formulation of amphotericin B that was recently approved for use as empirical treatment for presumed fungal infections in febrile neutropenic patients and for aspergillosis, candidiasis, and cryptococcosis infections refractory to amphotericin B. It is a small closed microscopic sphere (<100 nm in diameter) with an inner aqueous core (i.e., a true liposome). AmBisome remains as an intact sphere in vitro and for prolonged periods of time in vivo during the processes of systemic transport and pharmacologic action. As a consequence of its size and in vivo stability, AmBisome has physiochemical properties and a pharmacokinetic profile that are considerably different from those of currently available lipid-complexed amphotericin B formulations, with greatly increased area under the plasma concentration-time curve and much lower clearance at equivalent doses. AmBisome liposomes can be seen to accumulate at sites of fungal infection. Disruption of AmBisome liposomes occurs after attachment to the fungal cell wall and results in amphotericin B binding to fungal cell membrane ergosterol with subsequent cell lysis. AmBisome has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi.

The safety, tolerance, and pharmacokinetics of a small unilamellar liposomal formulation of amphotericin B (AmBisome) administered for empirical antifungal therapy were evaluated for 36 persistently febrile neutropenic adults receiving cancer chemotherapy and bone marrow transplantation. The protocol was an open-label, sequential-dose-escalation, multidose pharmacokinetic study which enrolled a total of 8 to 12 patients in each of the four dosage cohorts. Each cohort received daily doses of either 1.0, 2.5, 5.0, or 7.5 mg of amphotericin B in the form of AmBisome/kg of body weight. The study population consisted of patients between the ages of 13 and 80 years with neutropenia (absolute neutrophil count, <500/mm3) who were eligible to receive empirical antifungal therapy. Patients were monitored for safety and tolerance by frequent laboratory examinations and the monitoring of infusion-related reactions. Efficacy was assessed by monitoring for the development of invasive fungal infection. The pharmacokinetic parameters of AmBisome were measured as those of amphotericin B by high-performance liquid chromatography. Noncompartmental methods were used to calculate pharmacokinetic parameters. AmBisome administered as a 1-h infusion in this population was well tolerated and was seldom associated with infusion-related toxicity. Infusion-related side effects occurred in 15 (5%) of all 331 infusions, and only two patients (5%) required premedication. Serum creatinine, potassium, and magnesium levels were not significantly changed from baseline in any of the dosage cohorts, and there was no net increase in serum transaminase levels. AmBisome followed a nonlinear dosage relationship that was consistent with reticuloendothelial uptake and redistribution. There were no breakthrough fungal infections during empirical therapy with AmBisome. AmBisome administered to febrile neutropenic patients in this study was well tolerated, was seldom associated with infusion-related toxicity, was characterized by nonlinear saturation kinetics, and was effective in preventing breakthrough fungal infections.

AmBisome (ABLP) is a unilamellar liposomal preparation of amphotericin B that has demonstrated an improved safety profile compared to conventional amphotericin B. Single- and multiple-dose pharmacokinetics were determined by using noncompartmental methods for rats administered ABLP at 1, 3, 9, and 20 mg/kg/day. The toxicological profile was evaluated following 30 consecutive days of intravenous ABLP administration. Mean plasma amphotericin B concentrations reached 500 and 380 μg/ml (males and females, respectively) following 30 days of ABLP administration at 20 mg/kg. The overall apparent half-life was 11.2 ± 4.5 h (males) or 8.7 ± 2.2 h (females), and the overall clearance (CL) was 9.4 ± 5.5 ml/h/kg (males) or 10.2 ± 4.1 ml/h/kg (females). ABLP appears to undergo saturable disposition, resulting in a non-dose-proportional amphotericin B area under the curve and a lower CL at higher doses. Histopathological examination revealed dose-related transitional-cell hyperplasia in the transitional epithelium of the urinary tract (kidney, ureters, and urinary bladder) and moderate hepatocellular necrosis at the 20-mg/kg/day dose. Administration of ABLP in doses of up to 20 mg/kg/day resulted in 100-fold higher plasma amphotericin B concentrations, with significantly lower toxicity than that reported with conventional amphotericin B therapy.

Summary:The pharmacokinetics of tacrolimus following its administration as monotherapy or in combination with corticosteroids or methotrexate to 31 BMT patients are presented. All patients received i. Tacrolimus is an immunosuppressive agent more recently studied in allogeneic liver transplantation and kidney transplantation, 2 either alone or in combination with corticosteroids, that has also been proven effective in the treatment of GVHD after BMT.3-5 Tacrolimus may thus represent an alternative therapy for this indication.The pharmacokinetics of tacrolimus in normal volunteers and in liver and kidney transplant patients have been pre- 2,6-8 Recent reports have described in detail the safety and efficacy of tacrolimus used alone or in combination with methylprednisolone or methotrexate in the prevention of GVHD and included selected pharmacokinetic data.9,10 The present report presents a detailed evaluation of the p.o. and i.v. pharmacokinetics of tacrolimus in patients from these studies. In transplant patients, tacrolimus may be administered concomitantly with agents that can alter tacrolimus disposition.2 In this context, tacrolimus has demonstrated a synergistic effect on human lymphocytes in vitro when combined with methylprednisolone, 11 suggesting a possible interaction upon concomitant administration of these agents. Since the immunosuppressive regimen in BMT patients involved the concomitant administration of methylprednisolone or methotrexate, the effects of these drugs on the pharmacokinetics of tacrolimus were evaluated. Materials and methods PatientsParticipants in this study were patients with hematologic malignancies who received HLA-identical sibling donor bone marrow transplants and were on tacrolimus-based therapy. Each study patient was informed of the nature and risks of the study and gave written informed consent which was approved by an institutional review board. Pre-screening evaluation of potential study patients included vital signs, history and physical examination, height, weight, standard hematologic and biochemistry tests, and pregnancy tests for females. Eligible patients had negative pregnancy test and negative HIV tests. In addition, patients in the nonrandomized study (see below) had AST and ALT values р1.5 times upper limit of normal (ULN), total bilirubin within normal limits, and an estimated creatinine clearance у60 ml/min. Patients in the randomized study had AST, ALT and total bilirubin values р2 times ULN and a glomerular filtration rate у60 ml/min. Patients were excluded if they were recipient of T cell-depleted donor marrow. Study designThis study obtained pharmacokinetic data from randomly selected subsets of patients in two phase II trials of tacrol-

The tolerance and pharmacokinetics (PK) of tacrolimus (T) by the addition of mycophenolate mofetil (MMF) in stable kidney transplant patients (6/group) on long-term tacrolimus-based therapy were investigated. Patients received combination T and MMF therapy at three MMF doses: 1, 1.5, and 2 g/day administered twice daily. A 12-hour blood PK profile for T was obtained prior to MMF dosing; concomitant 12-hour profiles for T, mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were obtained after 2 weeks of administration. Tolerance was monitored through 3 months. The intra- and intergroup PK of T were variable. The mean AUC0-12 of T for each group was increased after 2 weeks of concomitant MMF administration, but the increase was not statistically significant. Both drugs were well tolerated. Gastrointestinal events were of interest as such have been attributed to both T and MMF. Events reported were diarrhea, nausea, dyspepsia, and vomiting. Other common adverse events were headache, hypomagnesemia, and tremors. Most were mild, although a few were considered to be moderate. There was no apparent relationship between the incidence of any adverse event and MMF treatment group. In the present study, the coadministration of T and MMF did not significantly alter T pharmacokinetics.