Phospholipidosis

Phospholipidosis is a lysosomal storage disorder characterized by the excess accumulation of phospholipids in tissues.[1][2][3] Many cationic amphiphilic drugs, including anti-depressants, antianginal, antimalarial, and cholesterol-lowering agents, are reported to cause drug-induced phospholipidosis (DIPL) in animals and humans. The mechanisms of DIPL involve trapping or selective uptake of DIPL drugs within the lysosomes and acidic vesicles of affected cells. Drug trapping is followed by a gradual accumulation of drug-phospholipid complexes within the internal lysosomal membranes. The increase in undigested materials results in the abnormal accumulation of multi-lammellar bodies (myeloid bodies) in tissues.

It is not possible to predict which tissues will be affected by DIPL in animals and humans. The use of specific in-vitro cell lines is not recommended as a means of gate-keeping for DIPL screening, only as part of an iterative process. An in-vivo screening platform, such as biomarker, is required for preclinical and clinical DIPL assessment.

The traditional method to evaluate DIPL is visual confirmation of myeloid bodies in tissues by electron microscopy. Electron microscopy has limited utility to monitor DIPL in humans because of the invasive nature of acquiring patient tissue biopsy samples. A qualified biomarker of DIPL in the blood or urine is needed to provide a more routine, non-invasive, and cost effective means to monitor DIPL in the clinic.[4]

Phospholipidosis biomarkers

Drug-induced phospholipidosis represents a concern in risk assessment. There is the absence of information related to the prevalence and time course of the condition in humans. A readily accessible biomarker in the urine or blood is urgently needed for routine phospholipidosis assessment. Di-docosahexaenoyl (22:6)-bis(monoacylglycerol) phosphate (di-22:6-BMP) was identified and patented by Nextcea Inc (Woburn, MA) as a non-invasive biomarker to evaluate DIPL in animals and humans.[5] BMP is a phospholipid increased in the tissues of patients with DIPL. BMP is localized within the intra-vesicular vesicles of late endosomes and lysosomes where it plays a role in phospholipid and cholesterol trafficking. Di-22:6-BMP in the blood or urine may provide a non-invasive marker for routine diagnosis/screening and research on the role of phospholipidosis in the etiology of drug-induced toxicities. The FDA has formed a PL working group to address concerns related to DIPL and develop policy recommendations. FDA has published a paper to support the use of di-22:6 BMP as an effective biomarker to predict drug-induced phospholipidosis.[6] Di-22:6-BMP may be used as a biomarker of DIPL to support development of guidance for industry and regulatory reviewers on how to proceed with drug development when DIPL is observed in preclinical and clinical regulatory studies.

Regulatory considerations

DIPL has become a significant concern for drug development and safety assessment because its association with drug toxicity is unclear. For example, DIPL in animals is described in the drug labeling for azithromycin (Zithromax), telithromycin (Ketek), and fluoxetine (Prozac). The significance and prevalence of DIPL for humans remains unclear.

Drugs that cause DIPL in animals and humans are associated with unwanted clinical side effects, such as drug-induced QT prolongation, myopathy, hepatotoxicity, nephrotoxicity, or pulmonary dysfunction. For example, drugs with the potential to cause QT prolongation, including macrolide antibiotics (telithromycin, erythromycin), antiarrthymic drug (amiodarone), antidepressants (imipramine, fluoxetine) and antipsychotic drugs (haloperidol, chlorpromazine), also cause phospholipidosis in animal and human tissues. A number of anti-malarial compounds (chloroquine, hydroxychloroquine, mefloquine, quinine, quinidine) cause phospholipidosis, myopathy and neurological damage. DIPL of the kidney proximal tubules and glomerular podocytes occurs frequently with the development of the renal toxicities of aminoglycosides (gentamicin, tobramycin, netilmicin, and amikacin) and chloroquine, respectively. The similarities between DIPL and the inherited lysosomal storage disorder Niemann-Pick disease type C also present an issue for regulators.

References

  1. ↑ Anderson N, Borlak J (2006). "Drug-induced phospholipidosis". FEBS Lett. 580 (23): 5533–540. doi:10.1016/j.febslet.2006.08.061. PMID 16979167.
  2. ↑ Reasor MJ, Hastings KL, Ulrich RG (2006). "Drug-induced phospholipidosis: issues and future directions". Expert Opin Drug Saf. 5 (4): 567–83. doi:10.1517/14740338.5.4.567. PMID 16774494.
  3. ↑ Nonoyama T, Fukuda R (2008). "Drug induced phospholipidosis pathological aspects and its prediction". J Toxicol Pathol. 21: 9–24. doi:10.1293/tox.21.9.
  4. ↑ Tengstrand E, Miwa G, Hsieh F (2010). "Bis(monoacylglycerol)phosphate as a non-invasive biomarker to monitor the onset and time-course of phospholipidosis with drug-induced toxicities". Expert Opinions in Drug Metabolism and Toxicology. 6 (5): 555–570. doi:10.1517/17425251003601961. PMID 20370598.
  5. ↑ Tengstrand-Baronas E, Lee JW, Alden C, Hsieh F (2007). "Biomarkers to monitor drug-induced phospholipidosis". Toxicology and Applied Pharmacology. 218 (1): 72–78. doi:10.1016/j.taap.2006.10.015. PMID 17156806.
  6. ↑ Thompson K, Haskins K, Rosenzweig B, Stewart S, Zhang J, Peters D, Knapton A, Rouse R, Mans D, Colatsky T (2012). "Comparison of the Diagnostic Accuracy of Di-22:6-Bis(monoacylglycerol)Phosphate and Other Urinary Phospholipids for Drug-Induced Phospholipidosis or Tissue Injury in the Rat". International Journal of Toxicology. 31 (1): 14–24. doi:10.1177/1091581811430167. PMID 22267869.

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