With IC50 and Ki values of 0.04 μM, migalastat inhibits human lysosomal a-Gal A [1].

α-galactosidase A activity defects are the cause of Fabry disease, an X-linked recessive genetic illness [2]. In transgenic mice expressing human mutant α-Gal A (TgM), migalastat (oral gavage, 3 mg/kg daily for 4 weeks) enhances α-Gal A activity in the heart, kidney, spleen, and liver and demonstrates dose- and time-dependent effects. )[2]. During the first two weeks of treatment, Migasalstat demonstrated half-lives of less than one day for all key issues in TgM [2]. In transgenic mice, migastat (oral gavage, 100 mg/kg daily for 28 days) decreased the levels of lyso-Gb3 in the kidney, heart, and skin by as much as 64%, 59%, and 81%, in that order [3].

Cell Viability Assay [4]
Cell Types: EHK Cell Mutated α-Gal A
Tested Concentrations: 10 μM
Incubation Duration: 9 days
Experimental Results: Gb3 accumulation and lysosomal volume reduction.

Animal/Disease Models: Male non-transgenic (Non-Tg) C57BL/6 mice; transgenic mice expressing human mutant R301Q α-Gal A (TgM), α-Gal A knockout mice (KO), in null background Mice expressing human R301Q α-Gal A (TgM/KO) [2]
Doses: 3 mg/kg
Route of Administration: po (oral gavage); one time/day for 4 weeks
Experimental Results: Triacylceramide (Gb3) in mouse kidneys Storage is Dramatically diminished.

Absorption, Distribution and Excretion
With absorption occurring largely in the gut, the absolute bioavailability (AUC) for a single oral 150 mg migalastat hydrochloride dose or a single 2-hour 150 mg intravenous infusion was approximately 75% and Tmax was approximately 3 hours. Plasma migalastat exposure (AUC0-∞) and Cmax demonstrated dose-proportional increases at migalastat hydrochloride oral doses from 50 mg to 1,250 mg (doses from 0.5 to 8.3-fold of the approved recommended dosage). Migalastat administered with a high-fat meal (850 calories; 56% from fat), or 1 hour before a high-fat or light meal (507 calories; 30% from fat), or 1 hour after a light meal, resulted in significant reductions of 37% to 42% in mean total migalastat exposure (AUC0-∞) and reductions of 15% to 39% in mean peak migalastat exposure (Cmax) compared with the fasting state.
In a mass balance study in healthy male subjects, following oral administration of 123 mg [14C]-migalastat, approximately 77% of the total radiolabeled dose was recovered in urine and 20% of the total radiolabeled dose was recovered in feces with an overall total recovery of 98% within 96 hours post-dose. In urine, unchanged migalastat accounted for 80% of the radioactivity, which equates to 62% of the administered dose. In feces, unchanged migalastat was the only drug-related component. In plasma, unchanged migalastat accounted for approximately 77% of the plasma radioactivity, and three dehydrogenated O-glucuronide conjugated metabolites, M1 to M3, together accounted for approximately 13% of the plasma radioactivity, none of which comprised more than 6% of the radiolabeled dose. Approximately 9% of the total radioactivity in plasma was unassigned.
In healthy volunteers, the volume of distribution (Vz/F) of migalastat following ascending single oral doses (25-675 mg migalastat HCl) ranged from 77 to 133 L, indicating it is well distributed into tissues and greater than total body water (42 liters).
Following ascending single oral doses (25-675 mg migalastat hydrochloride), no trends were found for clearance (CL/F). At the 150 mg dose, CL/F was approximately 11 to 14 L/hr, while at 123 mg, the apparent clearance was calculated to be 12.5 L/hr.

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Metabolism / Metabolites
Based upon in vivo data, migalastat is a substrate for uridine diphosphate glucuronosyltransferase (otherwise known as UGT or UDPGT), being a minor elimination pathway.

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Biological Half-Life
The mean elimination half-life (t1/2) of migalastat ranges from approximately 3 to 5 hours for a single oral dose of 150 mg. For the dose of 123 mg, the mean elimination half-life was estimated to be 4 hours.

Hepatotoxicity
In placebo-controlled trials, liver test abnormalities were rare and no more common with migalastat than with placebo treatment. What abnormalities occurred were mild and resolved spontaneously without need for dose interruption. During these premarketing clinical trials and since its more widespread clinical availability, no instances of acute liver injury with jaundice have been reported attributable to migalastat. However, the total clinical experience with its use has been limited.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of migalastat during breastfeeding. Because no information is available on the use of migalastat during breastfeeding caution should be used, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
There was no detectable plasma protein binding following administration of [14C]-migalastat hydrochloride in the concentration range between 1 and 100 µM.

[1]. Asano N, et al. In vitro inhibition and intracellular enhancement of lysosomal alpha-galactosidase A activity in Fabry lymphoblasts by 1-deoxygalactonojirimycin and its derivatives. Eur J Biochem. 2000 Jul;267(13):4179-86.
[2]. Ishii S, et al. Preclinical efficacy and safety of 1-deoxygalactonojirimycin in mice for Fabry disease. J Pharmacol Exp Ther. 2009 Mar;328(3):723-31.
[3]. Young-Gqamana B, et al. Migalastat HCl reduces globotriaosylsphingosine (lyso-Gb3) in Fabry transgenic mice and in the plasma of Fabry patients. PLoS One. 2013;8(3):e57631.
[4]. Welford RWD, et al. Glucosylceramide synthase inhibition with lucerastat lowers globotriaosylceramide and lysosome staining in cultured fibroblasts from Fabry patients with different mutation types. Hum Mol Genet. 2018 Oct. 27(19):3392-3403.

Migalastat is a member of piperidines.
Fabry disease is a rare, progressive genetic disorder characterized by a defective GLA gene that causes a deficiency in the enzyme alpha-Galactosidase A (alpha-Gal A). This enzyme is responsible for breaking down glycosphingolipid substrate that, when deficient in patients with Fabry disease, builds up in the blood vessels, the kidneys, the nerves, the heart, and other organs. In the U.S., it is estimated that more than 3,000 people are living with Fabry disease, and an estimated more than 50 percent of these diagnosed patients are currently untreated. Migalastat (approved and sold under Amicus Therapeutics' brand name Galafold) is subsequently an oral pharmacological chaperone of alpha-Gal A for the treatment of Fabry disease in adults who have amenable GLA variants. In these patients, migalastat works by stabilizing the body’s dysfunctional alpha-Gal A enzyme so that it can clear the accumulation of glycosphingolipid disease substrate. Globally, it is estimated that approximately 35 to 50 percent of Fabry patients may have amenable GLA variants that are treatable with migalastat. Given the rarity of Fabry disease and the proportion of Fabry disease patients that could benefit from migalastat therapy, Amicus Therapeutics' brand name Galafold was approved using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is an unmet medical need and where a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. A further study is required to verify and describe the clinical benefits of Galafold, and the sponsor will be conducting a confirmatory clinical trial of Galafold in adults with Fabry disease. Additionally, Galafold was also granted Priority Review designation, under which the FDA’s goal is to take action on an application within six months of application filing where the agency determines that the drug if approved, would provide a significant improvement in treating, diagnosing or preventing a serious condition over available therapies. Galafold also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases. As of August 2018, migalastat under Amicus Therapeutics' brand name Galafold is currently approved in Australia, Canada, European Union, Israel, Japan, South Korea, Switzerland, and the United States.
Migalastat is pharmacologic chaperone of alpha-galactosidase the intrahepatic enzyme that is deficient in Fabry disease. Clinical experience with migalastat is limited, but it not been linked to serum enzyme elevations during therapy or to instances of clinically apparent acute liver injury.
See also: Migalastat Hydrochloride (has salt form); Larazotide Acetate (annotation moved to).

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Drug Indication
Migalastat is approved by the FDA for the treatment of adults with a confirmed diagnosis of Fabry disease and an amenable galactosidase alpha gene (GLA) variant based on in vitro assay data. This indication is approved under accelerated approval based on a reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Migalastat is also approved by the EMA and Health Canada to treat the same disease, although it is approved for both adults and adolescents aged 16 years and older in Europe.
FDA Label
Galafold is indicated for long-term treatment of adults and adolescents aged 16 years and older with a confirmed diagnosis of Fabry disease (α-galactosidase A deficiency) and who have an amenable mutation.

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Mechanism of Action
Fabry disease is a progressive X-linked lysosomal storage disorder that affects males and females. Fabry disease-causing mutations occur in the galactosidase alpha (GLA) gene and result in a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A) that is required for glycosphingolipid substrate (GL-3 and lyso-Gb3) metabolism. Reduced alpha-Gal A activity is, therefore, associated with the progressive accumulation of glycosphingolipid substrate in vulnerable organs and tissues, which ultimately leads to the morbidity and mortality associated with Fabry disease. Migalastat is a pharmacological chaperone that reversibly binds to the active site of the alpha-galactosidase A (alpha-Gal A) protein (encoded by the galactosidase alpha gene, GLA), which is deficient in Fabry disease. This binding stabilizes alpha-Gal A allowing its trafficking from the endoplasmic reticulum into the lysosome where it exerts its action. In the lysosome, at a lower pH and at a higher concentration of relevant substrates, migalastat dissociates from alpha-Gal A allowing it to break down the glycosphingolipids globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3). Certain GLA variants (mutations) causing Fabry disease result in the production of abnormally folded and less stable forms of the alpha-Gal A protein which, however, retain enzymatic activity. Those GLA variants, referred to as amenable variants, produce alpha-Gal A proteins that may be stabilized by migalastat thereby restoring their trafficking to lysosomes and their intralysosomal activity. The GLA mutations that are amenable and not amenable to treatment with migalastat are regularly maintained and updated on online sites that are readily accessible by healthcare providers.

C6H13NO4

199.63266

163.084

108147-54-2

Migalastat hydrochloride;75172-81-5

176077

Typically exists as solid at room temperature

1.456g/cm3

361.1ºC at 760 mmHg

197.3ºC

1.13E-06mmHg at 25°C

1.582

-2.3

5

5

1

11

132

4

C1[C@@H]([C@H]([C@H]([C@@H](CO)N1)O)O)O

LXBIFEVIBLOUGU-DPYQTVNSSA-N

1S/C6H13NO4/c8-2-3-5(10)6(11)4(9)1-7-3/h3-11H,1-2H2/t3-,4+,5+,6-/m1/s1

D-Galactitol, 1,5-dideoxy-1,5-imino-

Amigal, DDIG, Migalastat 1-Deoxygalactonojirimycin 1-Deoxygalactostatin AT1001 AT 1001 AT-1001 GR181413A GR 181413A GR-181413A Galafold

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)