Drug-Induced Phospholipidosis

Organizers: Mike Thibodeau and Supriya Jayadev, Boehringer-Ingelheim

The aim of the Predictive Toxicology Discussion Group is to bring experts from basic research together with toxicologists, traditionally based in development, to accelerate the adoption of new techniques that may increase the predictive power of toxicology studies.

4:30pm-5:00: Coffee and snacks

5:00pm-5:30:

Mark Reasor, West Virginia University, "Drug-Induced Phospholipidosis: Characteristics And Consequences."

5:30pm-6:00:

David Monteith, Eli Lilly and Company, "In Vitro Surrogates and Biomarkers for Drug-Induced Phospholipidosis ."

6:00pm-6:30:

Steve Vonderfecht, Amgen, "Phospholipidosis in Drug Development: Management of the Issue in Two Drug Development Programs."

6:30pm-7:00:

Lawrence Sancilio, Division of Pulmonary and Allergy Products, FDA, "Phospholipidosis Working Group."

7:00pm-7:20: Discussion/questions with all the speakers.

Mark Reasor, "Drug-Induced Phospholipidosis: Characteristics And Consequences."
Numerous drugs containing a cationic lipophilic structure are capable of inducing a phospholipidosis in cells under conditions of in vivo administration or ex vivo incubation. The principal characteristics of this condition include the reversible accumulation of polar phospholipids in association with the development of unicentric or multicentric lamellated bodies within cells. While the mechanisms for the development of phospholipidosis are reasonably well understood, the functional consequences of the presence of this condition on cellular or tissue function are not. The general consensus is that the condition is an adaptive response rather than a toxicological manifestation; however, studies supporting this conclusion are sparse. This presentation will review the characteristics and consequences of drug-induced phospholipidosis and describe areas in which additional research is needed.

David Monteith, "In Vitro Surrogates and Biomarkers for Drug-Induced Phospholipidosis."
Drug-induced Phospholipidosis is the lysosomal accumulation of phospholipids. This condition is characterized by the presence of intralysosomal lamellar inclusions, appearing as electron-dense whorls in electron micrographs, and can occur in concert with organ toxicity. The disorder has not been causally linked to aberrant cell function, however its occurrence is of concern in drug development. Molecules that possess a polar motif comprised of a lipophilic region and a charged region are aptly named cationic amphiphilic drugs (CAD), and have been shown to induce PL in a variety of tissues. In silico systems, in vitro assays and in vivo biomarkers have been developed to screen and detect induction of phospholipidosis. These screens and use of NMR, flow cytometry and expression arrays for assessing phospholipidosis will be discussed.

Steve Vonderfecht, "Phospholipidosis in Drug Development: Management of the Issue in Two Drug Development Programs."
Tissue accumulation of phospholipids (phospholipidosis) is sometimes observed in preclinical toxicity studies done to support drug development. The clinical implications of this finding are not well understood; however, it does present an issue for continued development of a compound. This presentation will describe approaches taken to move forward two programs in which phospholipidosis occurred in different organ systems. In one program, phospholipidosis was found only in the gallbladder and was associated with epithelial necrosis and ulceration. Additional in vitro and in vivo studies were used to advance this program. In the second program, phospholipidosis occurred in multiple organs in both rats and dogs, but was associated with cellula