title: Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment.
abstract: The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann-Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings.
authors: Nextcea Inc., 600 West Cummings Park, Suite 6375, Woburn, MA 01801, USA.
authors: Nanjun
authors: N
authors: Liu
authors: Nextcea Inc., 600 West Cummings Park, Suite 6375, Woburn, MA 01801, USA.
authors: Elizabeth A
authors: EA
authors: Tengstrand
authors: Nextcea Inc., 600 West Cummings Park, Suite 6375, Woburn, MA 01801, USA.
authors: Lisa
authors: L
authors: Chourb
authors: Nextcea Inc., 600 West Cummings Park, Suite 6375, Woburn, MA 01801, USA. Electronic address: frank.hsieh@nextcea.com.
authors: Frank Y
authors: FY
authors: Hsieh
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003404:Creatinine / Q000652:urine; D004285:Dogs; D015195:Drug Design; D064420:Drug-Related Side Effects and Adverse Reactions / Q000097:blood / Q000378:metabolism* / Q000652:urine; D005260:Female; D006801:Humans; D008064:Lipidoses / Q000097:blood / Q000139:chemically induced* / Q000378:metabolism*; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism* / Q000652:urine; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D050178:Monoglycerides / Q000097:blood / Q000378:metabolism* / Q000652:urine; D010743:Phospholipids / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D015203:Reproducibility of Results; D013045:Species Specificity
chemical_list: D015415:Biomarkers; D008246:Lysophospholipids; D050178:Monoglycerides; D010743:Phospholipids; C012786:bis(monoacylglyceryl)phosphate; D003404:Creatinine
keywords: Biomarker; Bis(monoacylglycerol)phosphate; Di-22:6-BMP; Di-docosahexaenoyl (22:6) bis(monoacylglycerol)phosphate; Drug-induced phospholipidosis; Safety assessment