Pharmacokinetic and imaging studies in patients receiving a formulation of liposome-associated adriamycin

Abstract

Summary Pharmacokinetic and imaging studies in 19 patients receiving liposome-entrapped adriamycin (L-ADM) were carried out within the framework of a Phase I clinical trial (Gabizon et al., 1989a). The formulation of L-ADM tested consisted of 0.2 gM-extruded multilamellar vesicles composed of egg phosphatidylcholine, egg-derived phosphatidyl-glycerol (PG), cholesterol, and ADM intercalated in the fluid lipid bilayer. Plasma clearance of total drug extracted from the plasma after L-ADM infusion followed a biexponential curve with a pattern similar to that reported for free ADM. The plasma concentration of drug circulating in liposome-associated form was also measured in a subgroup of seven patients. Liposomeassociated drug was found to be rapidly cleared from plasma. Its ratio to nonliposome-associated drug appeared to correlate with liver reserve, with highest ratios in patients with normal liver function. Liposome clearance, as measured by the plasma concentration of PG in three patients was slower than the clearance of liposome-associated ADM, suggesting that liposomes lose part of their drug payload during circulation. To learn about the liposome organ distribution, imaging studies were carried out with "'Indium-deferoxamine labelled liposomes of the same composition. Liposomes were cleared predominantly by liver and spleen and to a lesser extent by bone marrow in seven out of nine patients. In two patients with active hepatitis and severe liver dysfunction, there was minimal liver uptake and increased spleen and bone marrow uptake. Except for one hepatoma patient, intrahepatic and extrahepatic tumours were not imaged by liposomes, suggesting that liposome uptake is restricted to cells of the reticulo-endothelial system (RES). These observations indicate that a major fraction of this L-ADM formulation is rapidly cleared by the RES, and that the mechanism of drug delivery is probably the combined result of slow release from the RES depot and drug leakage from circulating liposomes.Liposome-entrapped adriamycin (L-ADM) has been shown to have reduced toxicity and preserved or improved antitumour efficacy in experimental animal models (reviewed in Perez-Soler, 1989;Gabizon, 1989). Recently we have carried out a Phase I clinical study (Gabizon et al., 1989a) with a formulation of L-ADM in which the drug is incorporated in the fluid bilayer of the vesicles (Amselem et al., 1990a). The results have been consistent with the preclinical observations, namely the maximal tolerated dose (MTD) of L-ADM was increased in relation to the MTD of free drug administered at the conventional 3-weekly schedule. However the dose limiting toxicity for L-ADM was, as for free ADM, myelotoxicity. Thus, although the toxicities of free ADM and L-ADM differ quantitatively, they are qualitatively similar.In this report we summarise pharmacokinetic and imaging studies with L-ADM and radiolabelled liposomes of the same composition in the Phase I study patients and a small group of additional patients with similar eligibility criteria. The...

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