The pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) (liposomal AMB) and the conventional formulation, AMB deoxycholate (AMB-DOC), were compared in a phase IV, open-label, parallel study in healthy volunteers. After a single 2-h infusion of 2 mg of liposomal AMB/kg of body weight or 0.6 mg of AMB-DOC/kg, plasma, urine, and feces were collected for 168 h. The concentrations of AMB were determined by liquid chromatography tandem mass spectrometry (plasma, urine, feces) or highperformance liquid chromatography (HPLC) (plasma). Infusion-related side effects similar to those reported in patients, including nausea and back pain, were observed in both groups. Both formulations had triphasic plasma profiles with long terminal half-lives (liposomal AMB, 152 ؎ 116 h; AMB-DOC, 127 ؎ 30 h), but plasma concentrations were higher (P < 0.01) after administration of liposomal AMB (maximum concentration of drug in serum [C max ], 22.9 ؎ 10 g/ml) than those of AMB-DOC (C max , 1.4 ؎ 0.2 g/ml). Liposomal AMB had a central compartment volume close to that of plasma (50 ؎ 19 ml/kg) and a volume of distribution at steady state (V ss ) (774 ؎ 550 ml/kg) smaller than the V ss of AMB-DOC (1,807 ؎ 239 ml/kg) (P < 0.01). Total clearances were similar (approximately 10 ml hr ؊1 kg ؊1 ), but renal and fecal clearances of liposomal AMB were 10-fold lower than those of AMB-DOC (P < 0.01). Two-thirds of the AMB-DOC was excreted unchanged in the urine (20.6%) and feces (42.5%) with >90% accounted for in mass balance calculations at 1 week, suggesting that metabolism plays at most a minor role in AMB elimination. In contrast, <10% of the liposomal AMB was excreted unchanged. No metabolites were observed by HPLC or mass spectrometry. In comparison to AMB-DOC, liposomal AMB produced higher plasma exposures and lower volumes of distribution and markedly decreased the excretion of unchanged drug in urine and feces. Thus, liposomal AMB significantly alters the excretion and mass balance of AMB. The ability of liposomes to sequester drugs in circulating liposomes and within deep tissue compartments may account for these differences.The treatment of systemic fungal infections remains challenging, especially in neutropenic patients. Recent advances in drug delivery technology have resulted in several lipid-based formulations of amphotericin B, an effective but toxic fungicidal drug (5). Liposomal amphotericin B (AmBisome) is a liposomal formulation consisting of amphotericin B in small, unilamellar vesicles. Liposomal amphotericin B is safer than conventional amphotericin B (amphotericin B deoxycholate) (6, 12, 33) and is currently indicated for the treatment of disseminated fungal infections and visceral leishmaniasis and for empirical therapy for febrile neutropenia. The unique therapeutic properties of liposomal amphotericin B may result from its ability to alter the disposition of amphotericin B in the body (5). Studies in animals and humans have shown that liposomal amphotericin B produces higher drug levels in p...

Unilamellar liposomal amphotericin B (AmBisome) (liposomal AMB) reduces the toxicity of this antifungal drug. The unique composition of liposomal AMB stabilizes the liposomes, producing higher sustained drug levels in plasma and reducing renal and hepatic excretion. When liposomes release their drug payload, unbound, protein-bound, and liposomal drug pools may exist simultaneously in the body. To determine the amounts of drug in these pools, we developed a procedure to measure unbound AMB in human plasma by ultrafiltration and then used it to characterize AMB binding in vitro and to assess the pharmacokinetics of nonliposomal pools of AMB in a phase IV study of liposomal AMB and AMB deoxycholate in healthy subjects. We confirmed that AMB is highly bound (>95%) in human plasma and showed that both human serum albumin and ␣ 1 -acid glycoprotein contribute to this binding. AMB binding exhibited an unusual concentration dependence in plasma: the percentage of bound drug increased as the AMB concentration increased. This was attributed to the low solubility of AMB in plasma, which limits the unbound drug concentration to <1 g/ml. Subjects given 2 mg of liposomal AMB/kg of body weight had lower exposures (as measured by the maximum concentration of drug in serum and the area under the concentration-time curve) to both unbound and nonliposomal drug than those receiving 0.6 mg of AMB deoxycholate/kg. Most of the AMB in plasma remained liposome associated (97% at 4 h, 55% at 168 h) after liposomal AMB administration, so that unbound drug concentrations remained at <25 ng/ml in all liposomal AMB-treated subjects. Although liposomal AMB markedly reduces the total urinary and fecal recoveries of AMB, urinary and fecal clearances based on unbound AMB were similar (94 to 121 ml h ؊1 kg ؊1 ) for both formulations. Unbound drug urinary clearances were equal to the glomerular filtration rate, and tubular transit rates were <16% of the urinary excretion rate, suggesting that net filtration of unbound drug, with little secretion or reabsorption, is the mechanism of renal clearance for both conventional and liposomal AMB in humans. Unbound drug fecal clearances were also similar for the two formulations. Thus, liposomal AMB increases total AMB concentrations while decreasing unbound AMB concentrations in plasma as a result of sequestration of the drug in long-circulating liposomes.Recent advances in drug delivery technology have resulted in the development of lipid-based formulations of amphotericin B, an effective but toxic fungicidal drug used in the treatment of invasive fungal infections (4). Liposomal amphotericin B (AmBisome), a liposomal formulation of amphotericin B in small, unilamellar vesicles, is significantly less toxic than the conventional amphotericin B deoxycholate formulation (5,11,26) and is currently indicated for the treatment of disseminated fungal infections and visceral leishmaniasis and as empirical therapy for persistent febrile neutropenia. The unique therapeutic properties of liposomal amphotericin B hav...

Purpose: GRN1005 is a peptide-drug conjugate with the ability to penetrate the blood-brain barrier (BBB) and tumor cells by targeting the low-density lipoprotein receptor-related protein-1. We conducted a first-in-human phase I trial of GRN1005 in patients with recurrent glioma.Methods: Patients received GRN1005 by intravenous infusion every 3 weeks. Doses were escalated using a modified Fibonacci scheme. Study objectives included safety, tolerability, identification of the maximum tolerated dose (MTD), pharmacokinetics, and preliminary evidence of efficacy. Tumor extracted from patients undergoing surgery following administration of GRN1005 was analyzed to determine whether therapeutic concentrations of GRN1005 were achieved.Results: Sixty-three patients received GRN1005 at doses of 30 to 700 mg/m 2 every 3 weeks. Therapy was well tolerated with neutropenia, leucopenia, and fatigue as the most frequent drug-associated grade 3/4 or higher toxicities. The MTD was 650 mg/m 2 every 3 weeks. Dose-limiting toxicities were grade 3 mucositis and grade 4 neutropenia. There was no evidence of central nervous system toxicity or antibody production. Pharmacokinetic analysis showed that exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. Eight of 27 patients dosed !420 mg/m 2 had stable disease, which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were shown in tumor tissue of surgical patients dosed with !200 mg/m 2 . Conclusion: GRN1005 delivers paclitaxel across the BBB and achieves therapeutic concentrations in tumor tissue. It has similar toxicity to paclitaxel and appears to have activity in recurrent glioma. The recommended phase II dose is 650 mg/m 2 every 3 weeks.