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Toxicol Appl Pharmacol. 2014 Sep 15;279(3):467-476. doi: 10.1016/j.taap.2014.06.014. Epub 2014 Jun 23.

Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment.

Author information

1
Nextcea Inc., 600 West Cummings Park, Suite 6375, Woburn, MA 01801, USA.
2
Nextcea Inc., 600 West Cummings Park, Suite 6375, Woburn, MA 01801, USA. Electronic address: frank.hsieh@nextcea.com.

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.

KEYWORDS:

Biomarker; Bis(monoacylglycerol)phosphate; Di-22:6-BMP; Di-docosahexaenoyl (22:6) bis(monoacylglycerol)phosphate; Drug-induced phospholipidosis; Safety assessment

PMID:
24967688
DOI:
10.1016/j.taap.2014.06.014
[Indexed for MEDLINE]

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