Drug-induced phospholipidosis (DIPL) is a phospholipid storage disorder that results in the excessive accumulation of drugs and multilamellar (myeloid) bodies in tissues. Many factors contribute to the development of DIPL, including a drug’s structure, dose level, duration of dosing (exposure), and mechanism of action on phospholipid metabolism¹⁾. DIPL can be induced in many tissues of the body. It generally occurs in a dose (concentration) and time-dependent manner. Its occurrence in vivo cannot be predicted based only on drug structure. For a given drug, the sites of induction can vary among and within species²⁾.

　The functional implications of DIPL remain undefined. In nonclinical safety studies, compounds that cause DIPL are typically associated with higher incidences of pathological findings than non-phospholipidosis inducing compounds³⁾. The labels of many marketed drugs describe findings of DIPL during nonclinical studies, but indicate that the significance for humans is unknown. However, phospholipidosis occurs concurrently with clinically relevant toxicities (e.g., QT prolongation, myopathy, kidney toxicity, liver injury, respiratory dysfunction) caused by a number of commonly prescribed drugs⁴⁾.

　Some forms of DIPL have been considered as“ adaptive” or“ compensatory” in that they are not associated with evidence of cellular/tissue impairment. Even so, DIPL is a mechanism that promotes cellular/tissue drug accumulation. Once a drug, stored in large amounts, reaches a threshold level, drug overload can lead to cellular/tissue dysfunction and toxic off-target effects. Since DIPL may be linked to unwanted toxicities, it is important for pharmaceutical researchers and physicians to better understand, track, and manage this drug side effect.

　Several fundamental questions about DIPL remain unanswered: (1) what is the relationship between DIPL and drug toxicity, (2) what are the human consequences when DIPL is observed in animal studies, (3) are some patients more susceptible to DIPL, and (4) what are the best strategies to assess/manage DIPL in the clinic? These concerns have slowed drug development (e.g., fluoxetine) and contributed to the non-approval (e.g., tecastemizole), limited use (e.g., amiodarone), and withdrawal (e.g., perhexiline, coralgil) of marketed drugs^5,6). From a regulatory perspective, DIPL is considered an adverse finding whether justified or not⁷⁾. Any assumption about the safety and manageability of DIPL in humans should be supported by clinical evidence. Monitoring for DIPL should be performed when prescribing drugs that cause phospholipidosis in nonclinical/clinical safety studies. This review addresses the need for a non-invasive biomarker to evaluate the onset, time course, and functional impacts of DIPL. The use of di-docosahexaenoyl (22:6)-BMP (di-22:6-BMP) is highlighted as a reliable biomarker of DIPL in animals and humans. A drug risk management strategy is presented for decision making in nonclinical/clinical studies to reduce uncertainty in DIPL risk assessment.

　The translation of non-clinical findings with potential safety impact on patients into the environment of clinical trials is often difficult. The availability of markers for toxicity recorded in animal studies is key for monitoring translation, onset and progression in the clinical context. Many more or less pronounced aspects of organ or tissue damage are hardly associated with any such reliable markers of toxicity. In this context, FDA’s Critical Path Initiative has reinforced the need for additional biomarkers to predict drug toxicity in preclinical studies, specifically biomarkers that can act as surrogate endpoints and/or aid in making efficacious and cost-saving decisions or terminating drug development more quickly¹⁾. In response to the Critical Path Initiative, in October 2006, a biomarker consortium including the FDA, the Foundation for the National Institutes of Health, and the Pharmaceutical Research and Manufacturers of America was launched, which focuses on developing biomarkers for use in regulatory decision making, as well as biomarker discovery²⁾. Such biomarkers are important for translational efficacy and safety and, in terms of safety, should ideally judge early an effect of organ function or constitution before severe damage sets in to facilitate treatment discontinuation in the clinical setting and to judge reversibility. Thus, safety biomarkers add profoundly on the risk-benefit evaluation of pharmaceuticals in clinical trials, for their approval for marketing and in later stages of a pharmaceutical in real world treatment conditions. In some cases, non-clinical efficacy or safety aspects are amenable to modern imaging techniques and thus their impact on the clinical development of a drug can be judged “online” with such techniques facilitating early readout of efficacy and safety. Among various imaging modalities, the imaging of lymph nodes in particular in the gastrointestinal (GI) tract of cancer patients has become an important clinical tool³⁾. Positron emission tomography (PET) nowadays has a high resolution and offers the possibility to derive even staging information for lymph node enlargement.