Phospholipidosis
Encyclopedia
Phospholipidosis is a lysosomal storage disorder characterized by the excess accumulation of phospholipids in tissues. 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.
as a non-invasive biomarker to evaluate DIPL in animals and humans. 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. 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.
(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.
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.
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 by Nextceaas a non-invasive biomarker to evaluate DIPL in animals and humans. 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
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
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. 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 azithromycinAzithromycin
Azithromycin is an azalide, a subclass of macrolide antibiotics. Azithromycin is one of the world's best-selling antibiotics...
(Zithromax), telithromycin
Telithromycin
Telithromycin is the first ketolide antibiotic to enter clinical use. It is used to treat mild to moderate respiratory infections. Telithromycin is sold under the brand name of Ketek....
(Ketek), and fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
(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
Myopathy
In medicine, a myopathy is a muscular disease in which the muscle fibers do not function for any one of many reasons, resulting in muscular weakness. "Myopathy" simply means muscle disease...
, hepatotoxicity
Hepatotoxicity
Hepatotoxicity implies chemical-driven liver damage.The liver plays a central role in transforming and clearing chemicals and is susceptible to the toxicity from these agents. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure...
, nephrotoxicity
Nephrotoxicity
Nephrotoxicity is a poisonous effect of some substances, both toxic chemicals and medication, on the kidneys. There are various forms of toxicity. Nephrotoxicity should not be confused with the fact that some medications have a predominantly renal excretion and need their dose adjusted for the...
, or pulmonary dysfunction. For example, drugs with the potential to cause QT prolongation, including macrolide antibiotics (telithromycin
Telithromycin
Telithromycin is the first ketolide antibiotic to enter clinical use. It is used to treat mild to moderate respiratory infections. Telithromycin is sold under the brand name of Ketek....
, erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
), antiarrthymic drug (amiodarone
Amiodarone
Amiodarone is an antiarrhythmic agent used for various types of tachyarrhythmias , both ventricular and supraventricular arrhythmias. Discovered in 1961, it was not approved for use in the United States until 1985...
), antidepressants (imipramine
Imipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
, fluoxetine
Fluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
) and antipsychotic drugs (haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
, chlorpromazine
Chlorpromazine
Chlorpromazine is a typical antipsychotic...
), also cause phospholipidosis in animal and human tissues. A number of anti-malarial compounds (chloroquine
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
, hydroxychloroquine
Hydroxychloroquine
Hydroxychloroquine is an antimalarial drug, sold under the trade names Plaquenil,Axemal, Dolquine, and Quensyl, also used to reduce inflammation in the treatment of rheumatoid arthritis and lupus...
, mefloquine
Mefloquine
Mefloquine hydrochloride is an orally administered medication used in the prevention and treatment of malaria. Mefloquine was developed in the 1970s at the United States Department of Defense's Walter Reed Army Institute of Research as a synthetic analogue of quinine...
, quinine
Quinine
Quinine is a natural white crystalline alkaloid having antipyretic , antimalarial, analgesic , anti-inflammatory properties and a bitter taste. It is a stereoisomer of quinidine which, unlike quinine, is an anti-arrhythmic...
, quinidine
Quinidine
Quinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:...
) 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
Gentamicin
Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...
, tobramycin, netilmicin
Netilmicin
Netilmicin is a member of the aminoglycoside family of antibiotics. These antibiotics have the ability to kill a wide variety of bacteria. Netilmicin is not absorbed from the gut and is therefore only given by injection or infusion...
, and amikacin
Amikacin
Amikacin is an aminoglycoside antibiotic used to treat different types of bacterial infections. Amikacin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth.-Administration:Amikacin may be...
) and chloroquine
Chloroquine
Chloroquine is a 4-aminoquinoline drug used in the treatment or prevention of malaria.-History:Chloroquine , N'--N,N-diethyl-pentane-1,4-diamine, was discovered in 1934 by Hans Andersag and co-workers at the Bayer laboratories who named it "Resochin". It was ignored for a decade because it was...
, respectively. The similarities between DIPL and the inherited lysosomal storage disorder Niemann-Pick disease
Niemann-Pick disease
Niemann–Pick disease refers to a group of fatal inherited metabolic disorders that are included in the larger family of lysosomal storage diseases .-Signs and symptoms:Symptoms are related to the organs in which they accumulate...
type C also present an issue for regulators.