Eliglustat

Eliglustat is a potent and specific inhibitor of glucosylceramide synthase, and acts as a substrate reduction therapy (SRT) for GD1. SRT aims to reduce the rate of synthesis of the major substrate glucosylceramide (GL-1) to match its impaired rate of catabolism in patients with GD1, thereby preventing glucosylceramide accumulation and alleviating clinical manifestations.

Pharmacodynamic effects

In clinical trials in treatment-naïve GD1 patients, plasma GL-1 levels were elevated in the majority of these patients and decreased upon eliglustat treatment. Additionally, in a clinical trial in GD1 patients stabilised on enzyme replacement therapy (ERT) (i.e. having already achieved therapeutic goals on ERT prior to initiating eliglustat treatment), plasma GL-1 levels were normal in most patients and decreased upon eliglustat treatment.

Absorption

Median time to reach maximum plasma concentrations occurs between 1.5 to 6 hours after dosing, with low oral bioavailability (<5%) due to significant first-pass metabolism. Eliglustat is a substrate of the efflux transporter P-gp. Food does not have a clinically relevant effect on eliglustat pharmacokinetics. Following repeated dosing of eliglustat 84 mg twice daily in non-PMs and once daily in PMs, steady state was reached by 4 days, with an accumulation ratio of 3-fold or less.

Distribution

Eliglustat is moderately bound to human plasma proteins (76 to 83%) and is mainly distributed in plasma. After intravenous administration, the volume of distribution was 816 L, suggesting wide distribution to tissues in humans. Nonclinical studies demonstrated a wide distribution of eliglustat to tissues, including bone marrow.

Biotransformation

Eliglustat is extensively metabolized with high clearance, mainly by CYP2D6 and to a lesser extent CYP3A4. Primary metabolic pathways of eliglustat involve sequential oxidation of the octanoyl moiety followed by oxidation of the 2,3-dihydro-1,4-benzodioxane moiety, or a combination of the two pathways, resulting in multiple oxidative metabolites.

Elimination

After oral administration, the majority of the administered dose is excreted in urine (41.8%) and faeces (51.4%), mainly as metabolites. After intravenous administration, eliglustat total body clearance was 86 L/h. After repeated oral doses of 84 mg eliglustat twice daily, eliglustat elimination half-life is approximately 4-7 hours in non-PMs and 9 hours in PMs.

Characteristics in specific groups

CYP2D6 phenotype

Population pharmacokinetic analysis shows that the CYP2D6 predicted phenotype based on genotype is the most important factor affecting pharmacokinetic variability. Individuals with a CYP2D6 poor metaboliser predicted phenotype (approximately 5 to 10% of the population) exhibit higher eliglustat concentrations than intermediate or extensive CYP2D6 metabolisers.

Gender, body weight, age, and race

Based on the population pharmacokinetic analysis, gender, body weight, age, and race had limited or no impact on the pharmacokinetics of eliglustat.

Hepatic impairment

Effects of mild and moderate hepatic impairment were evaluated in a single dose phase 1 study. After a single 84 mg dose, eliglustat C_max and AUC were 1.2- and 1.2-fold higher in CYP2D6 extensive metabolisers (EMs) with mild hepatic impairment, and 2.8- and 5.2-fold higher in CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment compared to healthy CYP2D6 extensive metabolisers (EMs).

After repeated 84 mg twice daily doses of eliglustat, C_max and AUC_0-12 are predicted to be 2.4- and 2.9-fold higher in CYP2D6 extensive metabolisers (EMs) with mild hepatic impairment and 6.4- and 8.9-fold higher in CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment compared to healthy CYP2D6 extensive metabolisers (EMs).

After repeated 84 mg once daily doses of eliglustat, C_max and AUC_0-24 are predicted to be 3.1- and 3.2-fold higher in CYP2D6 extensive metabolisers (EMs) with moderate hepatic impairment compared to healthy CYP2D6 extensive metabolisers (EMs) receiving eliglustat 84 mg twice daily. Steady state PK exposure could not be predicted in CYP2D6 intermediate metabolisers (IMs) and poor metabolisers (PMs) with mild and moderate hepatic impairment due to limited or no single-dose data. The effect of severe hepatic impairment was not studied in subjects with any CYP2D6 phenotype.

Renal impairment

Effect of severe renal impairment was evaluated in a single dose phase 1 study. After a single 84 mg dose, eliglustat C_max and AUC were similar in CYP2D6 extensive metabolisers (EMs) with severe renal impairment and healthy CYP2D6 extensive metabolisers (EMs).

Limited or no data were available in patients with ESRD and in CYP2D6 intermediate metabolisers (IMs) or poor metabolisers(PMs) with severe renal impairment.

The principal target organs for eliglustat in toxicology studies are the GI tract, lymphoid organs, the liver in rat only and, in the male rat only, the reproductive system. Effects of eliglustat in toxicology studies were reversible and exhibited no evidence of delayed or recurring toxicity. Safety margins for the chronic rat and dog studies ranged between 8-fold and 15-fold using total plasma exposure and 1- to 2-fold using unbound (free fraction) plasma exposures.

Eliglustat did not have effects on CNS or respiratory functions. Concentration-dependent cardiac effects were observed in nonclinical studies: inhibition of human cardiac ion channels, including potassium, sodium, and calcium, at concentrations ≥7-fold of predicted human C_max; sodium ion channel-mediated effects in an ex-vivo electrophysiology study in dog Purkinje fibres (2-fold of predicted human unbound plasma C_max); and increases in QRS and PR intervals in dog telemetry and cardiac conduction studies in anaesthesised dogs, with effects seen at concentrations 14-fold of predicted human total plasma C_max, or 2-fold of predicted human unbound plasma C_max.

Eliglustat was not mutagenic in a standard battery of genotoxicity tests and did not show any carcinogenic potential in standard lifetime bioassays in mice and rats. Exposures in the carcinogenicity studies were approximately 4-fold and 3-fold greater in mice and rats, respectively, than the mean predicted human eliglustat total plasma exposure, or less than 1-fold using unbound plasma exposure.

In mature male rats, no effects on sperm parameters were observed at systemically non-toxic doses. Reversible inhibition of spermatogenesis was observed in the rat at 10-fold of predicted human exposure based on AUC, a systemically toxic dose. In rat repeated dose toxicity studies, seminiferous epithelial degeneration and segmental hypoplasia of the testes was seen at 10-fold of predicted human exposure based on AUC.

Placental transfer of eliglustat and its metabolites was shown in the rat. At 2 and 24 hours post-dose, 0.034% and 0.013% of labelled dose was detected in foetal tissue, respectively.

At maternal toxic doses in rats, foetuses showed a higher incidence of dilated cerebral ventricles, abnormal number of ribs or lumbar vertebrae, and many bones showed poor ossification.

Embryofoetal development in rats and rabbits was not affected up to clinically relevant exposure (based on AUC).

A lactation study in the rat showed that 0.23% of labelled dose was transferred to pups during 24 hours post-dose, indicating milk excretion of eliglustat and/or its related materials.