Letter to the Editor

The Society of Toxicologic Pathology (STP) Scientific and Regulatory Policy Committee (SRPC) recently formed a working group of interested STP members to “prepare a document that reviews current scientific practices, regulations and relevant literature and provides recommendations for the recognition, confirmation, and risk assessment of phospholipidosis in nonclinical toxicity studies.” Our 8-member group met and discussed this charge in the context of related efforts outside of the STP and, the current literature. Here we relate the salient points of our discussion and our conclusions to the general membership.

Drug-induced phospholipidosis is recognized by both the pharmaceutical industry and the Food and Drug Administration (FDA) as a significant challenge for drug development. Dr. Lawrence Sancilio of the FDA Division of Pulmonary and Allergy Products outlined the form and function of the “FDA Phospholipidosis Working Group” at the March 2006 meeting of the Predictive Toxicology Discussion Group at the New York Academy of Sciences Meeting in New York City. He described a group composed of pharmacology/toxicology reviewers, medical officer reviewers, and a research scientist with the ultimate objective of developing “guidance on phospholipidosis.” The FDA’s interests in this subject are broad and include determining the incidence/prevalence of phospholipidosis (clinical and preclinical), understanding the toxic implications of the phenomenon, and identifying biomarker strategies. A Pharma DruSafe Subcommittee, with 11 members representing 10 pharmaceutical companies, is supporting the FDA’s effort by working with the agency to build a database of phospholipidosis-inducing pharmaceutical compounds.

Our group also reviewed and discussed a number of recent publications addressing various facets of drug-induced phospholipidosis. Most germane to our charge was a recent review by Reasor et al. (Expert Opin Drug Saf 5(4): 567–583, 2006). In this manuscript, the authors discussed the principal morphologic and biochemical features, diagnostic criteria, mechanisms, toxicological implications, and relevant regulatory issues pertaining to phospholipidosis. The review also included a table of representative compounds (marketed and experimental) reported to induce phospholipidosis, and a robust bibliography.

Complementary to this review were three additional papers of interest. Sawada, et al. (Toxicol Sci 83: 282–292, 2005) used large-scale gene expression analysis in Hep G2 cells to “examine the molecular mechanisms that contribute to the development of phospholipidosis and to identify specific markers that might form the basis of an in vitro screening test.” Sawada identified a few putative mechanisms and a set of 12 gene markers in the work. Monteith, et al. (Expert Opin Drug Metab Toxicol 2(5): 687–696, 2006) reviewed the status of several in silico, in vitro, and in vivo screening and biomarker strategies. Anderson and Borlak (FEBS Lett 580: 5533–5540, 2006) reviewed the ultrastructural features of the “morphological hallmark” lamellar bodies, explored molecular mechanisms, and compared drug-induced phospholipidosis with naturally occurring heritable lysosomal storage diseases.

Ultimately, our working group concluded that ongoing efforts by the FDA Working Group in collaboration with the DruSafe Subcommittee and the papers recently published by Reasor, Sawada, Monteith, and Anderson et al. have or are accomplishing the original charge outlined by the STP SRPC. However, the group did recognize continuing unmet needs. Although Reasor and Anderson et al. restated a number of implicated mechanisms and Sawada et al. added a few related proposals suggested by results from toxicogenomic studies, there remain gaps in our understanding of the mechanism(s) of drug-induced phospholipidosis. Descriptions of phospholipidosis without definitive evidence of associated cellular injury or dysfunction continue to challenge our risk assessment. We are likely to continue to discharge potentially beneficial compounds from development until we have a better mechanistic understanding of the causes and implications of phospholipid accumulation and use this understanding to develop clinically useful biomarkers and informed risk assessments. Our working group believes that this will require novel experimental efforts outside our charge and capabilities as a group.

We encourage STP to stay abreast of the challenges of drug-induced phospholipidosis through continuing education, encouragement of mechanistic research, and support of the ongoing efforts by the FDA and DruSafe to guide and influence an eventual product that can facilitate safe and effective drug development.

We respectively submit these observations and conclusions for consideration by the SRPC and general membership.