Eliglustat tartrate has the ability to inhibit target enzymes and has good potency, with an IC50 of 24 nM [1]. The addition of Genz-112638 (0.6-1000 nM) to K562 or B16/F10 cells over a period of 72 hours led in a delayed suppression of GM1 and GM3 cell surfaces, with an average IC50 of 24 nM (range 14-1000 nM) in K562 cells. 34 nM), with an average IC50 value for GM3 inhibition in B16/F10 cells of 29 nM (range 12-34 nM). 48 nanometers)[1].

In comparison to age-matched control animals, mice with a significant accumulation of substrate prior to therapy had lower levels of step ceramide and fewer Gaucher cells in their spleen, lung, and heart [1].

Absorption, Distribution and Excretion
Following twice-daily administration of 84 mg of elegilinestat, the peak plasma concentration (Cmax) for CYP2D6 rapid metabolizers (EM) ranged from 12.1 to 25.0 ng/mL, for intermediate metabolizers (IM) it was 44.6 ng/mL, and for slow metabolizers (PM) it ranged from 113 to 137 ng/mL. The median time to peak concentration (Tmax) was 1.5–2 hours for rapid metabolizers, 2 hours for intermediate metabolizers, and 3 hours for slow metabolizers. In CYP2D6 rapid metabolizers (EM), the AUCtau was 76.3–143 ng∙hr/mL; in CYP2D6 intermediate metabolizers (IM), it was 306 ng∙hr/mL; and in CYP2D6 slow metabolizers (PM), it was 922–1057 ng∙hr/mL. In CYP2D6 rapid metabolizers, the pharmacokinetics of ilireglustat were time-dependent, with exposure increasing more than proportionally in the dose range of 42–294 mg. In CYP2D6 slow metabolizers, the pharmacokinetics of ilireglustat were linear and time-independent. At steady state, the systemic exposure of CYP2D6 slow metabolizers taking 84 mg of ilireglustat twice daily was 7–9 times higher than that of rapid metabolizers. Following a single oral dose of 84 mg of ilireglustat, the bioavailability in CYP2D6 rapid metabolizers was less than 5%. Iligorastat has low oral bioavailability, suggesting that transporter proteins and/or extensive first-pass metabolism may play a role. Iligorastat can be taken with or without food. In CYP2D6 rapid metabolizers, severe renal impairment has no effect on the pharmacokinetics of ligorastat. The effect of renal impairment on the pharmacokinetics of ligorastat was not assessed in CYP2D6 intermediate metabolizers, CYP2D6 slow metabolizers, or CYP2D6 rapid metabolizers with end-stage renal failure. Compared with CYP2D6 rapid metabolizers with normal hepatic function, CYP2D6 rapid metabolizers with mild hepatic impairment had 1.2-fold increased Cmax and AUC, respectively, while CYP2D6 rapid metabolizers with moderate hepatic impairment had 2.8-fold and 5.2-fold increased Cmax and AUC, respectively. The effects of mild and moderate hepatic impairment on CYP2D6 intermediate metabolizers (IM) and slow metabolizers (PM) were not assessed, nor were the effects of severe hepatic impairment assessed.
After oral administration, eligrastat is primarily excreted as metabolites in urine (42%) and feces (51%).
In patients with CYP2D6 rapid metabolizer (EM), the volume of distribution of intravenously administered eligrastat is 835 L.
In healthy CYP2D6 rapid metabolizer (EM) patients, the clearance rate after intravenous administration of 42 mg eligrastat (0.5 times the recommended oral dose) is 88 L/h (80–105 L/h).
Metabolism/Metabolites

Eligrastat is primarily metabolized by CYP2D6, with a small amount metabolized by CYP3A4. In patients with impaired CYP2D6 metabolizer (PM), eligrastat is primarily metabolized by CYP3A4. The main metabolic pathway of eligrastat involves the sequential oxidation of the octanoyl group and the 2,3-dihydro-1,4-benzodioxane moiety. These two pathways work together to produce a variety of oxidative metabolites. Evaluation of the activity of eliglinostat metabolites revealed that none of them were active. Genz-399240 (M24) was identified as the major metabolite of eliglinostat, with the exposure to the remaining metabolites accounting for less than 10% of the total drug exposure. Genz-399240 (M24) did not show any significant off-target effects. Therefore, no transporter substrate-specific characterization was performed.

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Biological Half-Life
Eliglustat has a terminal elimination half-life of 6.5 hours in CYP2D6 rapid metabolizers (EM) and 8.9 hours in CYP2D6 slow metabolizers (PM).

Hepatotoxicity
In placebo-controlled trials, the incidence of liver function abnormalities in the eliglustat group was not higher than in the placebo group, and the abnormalities were milder and usually resolved spontaneously without discontinuation of treatment. No cases of acute liver injury with jaundice caused by eliglustat have been reported during these premarketing Khellinical trials and after its wider Khellinical use. However, overall Khellinical experience with eliglustat is limited. Likelihood Score: E (Unlikely to cause Khellinically significant liver injury, but experience with its use is limited). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation Since no studies have been published on the use of eliglustat during lactation, alternative medications are recommended, especially for breastfed newborns or preterm infants. ◉ Effects on Breastfed Infants As of the revision date, no relevant published information was found.
◉ Effects on lactation and breast milk
As of the revision date, no relevant published information was found.

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Protein binding rate
The protein binding rate of elegiline in plasma is 76% to 83%.

[1]. A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy ofGaucher disease. Mol Genet Metab. 2007 Jul;91(3):259-68.

Pharmacodynamics
Eliglucose is a specific glucosylceramide synthase inhibitor (IC50 = 10 ng/mL). In vitro studies have shown that eliglucose has very low or no off-target activity against other glycosidases, such as α-glucosidases I and II, as well as lysosomal and non-lysosomal glucosylceramides. At 8 times the recommended dose (800 mg) and a mean peak concentration of 237 ng/mL, eliglucose has no Khellinically significant effect on QTc interval prolongation. However, pharmacokinetic/pharmacodynamic (PK/PD) data models predict that at a plasma concentration of 500 ng/mL, the PR interval, QRS interval, and QTcF interval will be prolonged by 22 ms, 7 ms, and 13 ms, respectively. Because high plasma concentrations of iligranovitol may increase the risk of arrhythmias, there are corresponding warnings and precautions for patients taking CYP2D6 or CYP3A4 inhibitors, patients with specific CYP2D6 metabolic statuses, and patients with varying degrees of hepatic impairment. Depending on the specific circumstances, the use of this drug may be contraindicated, should be avoided, or require dose adjustment. Patients with a history of heart disease (congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, ventricular arrhythmias), long QT syndrome, or currently taking class IA or II antiarrhythmic drugs should avoid using iligranovitol.

404.267

491833-29-5

Eliglustat hemitartrate;928659-70-5;Eliglustat-d15 tartrate;1884556-84-6;Eliglustat-d4

23652731

White to off-white solid powder

1.1±0.1 g/cm3

615.5±55.0 °C at 760 mmHg

326.1±31.5 °C

0.0±1.9 mmHg at 25°C

1.543

3.61

2

5

11

29

484

2

CCCCCCCC(N[C@H](CN1CCCC1)[C@@H](C2=CC=C(OCCO3)C3=C2)O)=O

N-((1R,2R)-1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-hydroxy-3-(pyrrolidin-1-yl)propan-2-yl)octanamide

FJZZPCZKBUKGGU-AUSIDOKSSA-N

Genz-99067 GENZ-112638Cerdelga Genz99067 UNIIN0493335P3GENZ 112638Genz 99067 GENZ112638 Eliglustat tartrate eliglustat hemitartrate Eliglustat trade name Cerdelga.

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)

DMSO : ~100 mg/mL (~247.19 mM)

Solubility in Formulation 1: 2.5 mg/mL (6.18 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (6.18 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (6.18 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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