Letter to the Editor

Berridge, Brian R.; Chatman, Linda A.; Odin, Marielle; Schultze, A. Eric; Losco, Patricia E.; Meehan, James T; Peters, Terry; Vonderfecht, Steven

doi:10.1080/01926230701196414

Cited by 25 publications

(9 citation statements)

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“…There has been an increased interest in the validation of a noninvasive biomarker to monitor the time-course and functional impact of DIPL in nonclinical/clinical studies (Berridge et al, 2007;Chatman et al, 2009;Sadrieh, 2010;Willard, 2008). Several studies have shown the usefulness of di-22:6-BMP in the plasma/serum and urine to monitor tissue DIPL in animals (Baronas et al, 2007;Mesens et al, 2012;Papov et al, 2009;Phillips et al, 2009;Thompson et al, 2012a,b).…”

Section: Discussionmentioning

confidence: 98%

“…There is currently an inability to monitor DIPL routinely in the clinic. The FDA has formed a Phospholipidosis Working Group (PLWG) to address these concerns and develop policy recommendations for the pharmaceutical industry (Berridge et al, 2007). The goals of the PLWG are to assess whether there should be a clinical concern when DIPL is observed in animals and to develop tools to better predict/monitor DIPL.…”

Section: Introductionmentioning

confidence: 99%

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

Liu¹,

Tengstrand²,

Chourb³

et al. 2014

Toxicology and Applied Pharmacology

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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

Liu¹,

Tengstrand²,

Chourb³

et al. 2014

Toxicology and Applied Pharmacology

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“…In 2006, the USA FDA outlined the form and function of the "FDA phospholipidosis Working Group" at a meeting of the Predictive Toxicology Discussion Group. The ultimate objective of the Working Group is development of a "Guidance on PLDsis", and the FDA's interests in this subject are in determining the incidence/prevalence of PLDsis (clinical and preclinical), understanding the toxicity implications of the phenomenon and identifying biomarker strategies 19 . This review focuses on the recent advances in drug (CAD)-induced PLDsis, in particular, on possible biomarkers for PLDsis and methods of its prediction in drug development, including results obtained in our laboratories.…”

Section: Introductionmentioning

confidence: 99%

Drug-induced Phospholipidosis -Pathological Aspects and Its Prediction

Nonoyama

Fukuda

2008

J Toxicol Pathol

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Drug-induced phospholipidosis (PLDsis) is an excessive accumulation of polar phospholipids in cells or tissues/organs caused by xenobiotics. Numerous drugs and chemicals are capable of inducing the storage disorder in animals and humans; however, despite their diverse pharmacological activities, each of these drugs shares common physicochemical properties: a hydrophobic aromatic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group and therefore are in the group of cationic amphiphilic drugs. In affected cells the appearance of membrane-bound inclusions, primarily lysosomal in origin, with a lamellar structure (lamellar bodies) is a definitive morphologic hallmark. Massive accumulations can occur in animal tissues such as the lung with little effect on organ function. The inducing drug also accumulates in association with the excess phospholipid. Although these alterations are generally reversible after cessation of drug treatment, PLDsis is of regulatory concern and an issue for drug safety for pharmaceutical companies. Thus, the assessment of potential target organ dysfunction and the identification of clinical biomarkers are important objectives for new drug development. Recent advances in biotechnology such as metabonomics and toxicogenomics have been providing novel tools to elucidate the mechanisms of PLDsis and to establish biomarkers for screening tests in the preclinical stages and for monitoring in the clinical phases in addition to conventional approaches such as morphology (lamellar bodies) and biochemical methods including assays of specific metabolites and phospholipase inhibition. (J Toxicol Pathol 2008; 21: 9-24)

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“…This database will facilitate the building of quantitative structure-activity relationship models for identification of characteristics associated with PL (Willard 2008). The overall plans of the FDA working group are to develop a general guidance document for use in future interpretation of PL (Berridge et al 2007). Food and Drug Administration interests also include determining the incidence/prevalence of PL in clinical and preclinical settings, assessing any potential toxic implications of PL, and identifying biomarkers of PL (Berridge et al 2007).…”

Section: Regulatory Considerations In Risk Management Of Plmentioning

confidence: 99%

“…The overall plans of the FDA working group are to develop a general guidance document for use in future interpretation of PL (Berridge et al 2007). Food and Drug Administration interests also include determining the incidence/prevalence of PL in clinical and preclinical settings, assessing any potential toxic implications of PL, and identifying biomarkers of PL (Berridge et al 2007). Of recent interest to the FDA PL Working Group is a potential relationship between PL and QT prolongation, since it has been noted that the physiochemical properties of some marketed drugs that cause PL may also cause QT prolongation (Willard 2008).…”

Section: Regulatory Considerations In Risk Management Of Plmentioning

confidence: 99%

A Strategy for Risk Management of Drug-Induced Phospholipidosis

et al. 2009

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Drug-induced phospholipidosis (PL) is an excessive accumulation of phospholipids and drug in lysosomes. Phospholipidosis signals a change in cell membrane integrity and accumulation of intracellular drug or metabolite in tissues. The sensitivity and susceptibility of preclinical models to detect PL vary with therapeutic agents, and PL is expected to be reversible after discontinuation of drug treatment. The prevailing scientific opinion is that PL by itself is not adverse; however, some regulatory authorities consider PL to be adverse because a small number of chemicals are able to cause PL and concurrent organ toxicity. Until a greater understanding of PL emerges, a well-thought-out risk management strategy for PL will increase confidence in safety and improve selection and development of new drugs. This paper provides a tiered approach to risk management of drug-induced PL. It begins with use of in silico and in vitro tools to design and select compounds with reduced potential to produce PL. Early in vivo studies in two species are used to better characterize potential for toxicity and PL. Finally, routine risk management tools (i.e., translational biomarkers, assessment of reversibility) are used to support confidence in safety of compounds that induce PL in animals.

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Letter to the Editor

Cited by 25 publications

References 0 publications

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

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

Drug-induced Phospholipidosis -Pathological Aspects and Its Prediction

A Strategy for Risk Management of Drug-Induced Phospholipidosis

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