2-1　Drug-Induced Phospholipidosis Assessment from Nonclinical to Clinical Studies

抄録

　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.