Migalastat
Migalastat Uses, Dosage, Side Effects, Food Interaction and all others data.
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 own 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 .
| Trade Name | Migalastat |
| Availability | Prescription only |
| Generic | Migalastat |
| Migalastat Other Names | 1-Deoxygalactonojirimycin, 1-Deoxygalactostatin, Migalastat |
| Related Drugs | agalsidase beta, Galafold, Fabrazyme |
| Weight | 123mg |
| Type | Oral capsule |
| Formula | C6H13NO4 |
| Weight | Average: 163.1717 Monoisotopic: 163.084457909 |
| Protein binding | There was no detectable plasma protein binding following administration of [14C]-migalastat hydrochloride in the concentration range between 1 and 100 uM . |
| Groups | Approved, Investigational |
| Therapeutic Class | |
| Manufacturer | |
| Available Country | United States |
| Last Updated: | September 19, 2023 at 7:00 am |
Uses
Migalastat is an alpha-galactosidase A chaperone used for the treatment of Fabry disease in patients with an amenable galactosidase alpha gene (GLA) variant.
Migalastat is an alpha-galactosidase A (alpha-Gal A) pharmacological chaperone indicated for the long-term treatment of adults and adolescents aged 16 years and older with a confirmed diagnosis of Fabry disease (alpha-galactosidase A deficiency) and an amenable galactosidase alpha gene (GLA) mutation/variant based upon in vitro assay data .
This indication is approved by the US FDA under accelerated approval based on reduction in kidney interstitial capillary cell globotriaosylceramide (KIC GL-3) substrate . Continued approval by the US FDA for this indication may be contingent upon verification and description of clinical benefit in ongoing confirmatory trials .
Migalastat is also used to associated treatment for these conditions: Fabry's Disease
How Migalastat works
Fabry disease is a progressive X-linked lysosomal storage disorder which 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 .
Certain GLA mutations can result in the production of abnormally folded and unstable mutant forms of alpha-Gal A . Migalastat is subsequently a pharmacological chaperone that is designed to selectively and reversibly bind with high affinity to the active sites of certain mutant forms of alpha-Gal A, the genotypes of which are referred to as amenable mutations . Such migalastat binding stabilizes these mutant forms of alpha-Gal A in the endoplasmic reticulum and facilitates their proper trafficking to lysosomes . Once in the lysosomes and surrounded by an environment defined by lower pH and higher concentrations of relevant glycosphingolipid substrates, migalastat dissociates from alpha-Gal A, thereby restoring the alpha-Gal A activity, leading to the catabolism of glycosphingolipids like globotriaosylceramide (GL-3) and globotriaosylsphingosine (lyso-Gb3) since the alpha-Gal A variants still retain enzymatic 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 .
Toxicity
The most common adverse reactions reported with migalastat (≥ 10%) during the 6-month placebo-controlled, double-blind phase of its Study 1 clinical studies were headache, nasopharyngitis, urinary tract infection, nausea, and pyrexia .
In case of overdose, general medical care is recommended . Headache and dizziness were the most common adverse reactions reported at doses of migalastat of up to 1250 mg and 2000 mg, respectively .
Food Interaction
- Take at the same time every day.
- Take on an empty stomach. Avoid eating for at least two hours before and after taking migalastat.
[Moderate] ADJUST DOSING INTERVAL: Food may reduce the oral bioavailability of migalastat.
When migalastat was administered one hour before a high-fat (850 calories; 56% from fat) or light meal (507 calories; 30% from fat), or one hour after a light meal, mean migalastat peak plasma concentration (Cmax) decreased by 15% to 39% and systemic exposure (AUC) decreased by 37% to 42% compared to administration in the fasting state.
MANAGEMENT: Migalastat should be taken on an empty stomach.
Patients should avoid eating for at least 2 hours before and 2 hours after taking migalastat to give a minimum 4 hours fast.
Clear liquids can be consumed during this 4-hour period.
Migalastat Disease Interaction
Volume of Distribution
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) .
Elimination Route
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% . Following a single oral dose of 150 mg migalastat hydrochloride solution, the time to peak plasma concentration 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 .
Migalastat administered with a high-fat meal, or 1 hour before a high-fat or light meal, 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 40% in mean peak migalastat exposure (Cmax) compared with the fasting state .
Half Life
The mean elimination half-life (t1/2) of migalastat ranges from approximately 3 to 5 hours .
Clearance
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 .
Elimination Route
A pharmacokinetic trial in healthy male volunteers with 150 mg [14C]-migalastat hydrochloride revealed that approximately 77% and 20% of the radiolabeled dose was recovered in urine and excreted in the feces, respectively .
Innovators Monograph
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