Impact of hepatic and renal impairment on the pharmacokinetics and tolerability of eliglustat therapy for Gaucher disease type 1

Publication date: Available online 14 November 2019Source: Molecular Genetics and MetabolismAuthor(s): Jing Li, Jun Chen, Vanaja Kanamaluru, Sebastiaan J.M. Gaemers, M. Judith Peterschmitt, Audrey W. Hou, Yong Xue, Sandrine Turpault, Dan RudinAbstractEliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) who have extensive (EM), intermediate (IM), or poor (PM) CYP2D6 metabolizer phenotypes. It was initially not recommended in GD1 patients with hepatic or renal impairment due to insufficient data. Two Phase 1 studies (NCT02536937/NCT02536911) evaluated the effects of hepatic and renal impairment on pharmacokinetics and tolerability following a single 84-mg dose of eliglustat. Compared to matched healthy EM subjects (n = 7 for both studies), geometric means for eliglustat maximum concentration (Cmax) and area under the plasma concentration versus time curve extrapolated to infinity (AUC) were not substantially different in EMs with mild hepatic impairment (n = 6), higher in EMs with moderate hepatic impairment (n = 7), and similar in EMs with severe renal impairment (n = 7). Higher exposures of eliglustat at steady-state were predicted using a physiologically-based pharmacokinetic (PBPK) model in EMs with mild or moderate hepatic impairment compared with normal hepatic function after repeated 84-mg eliglustat doses. Higher exposures of eliglustat were also predicted in EMs with mild hepatic impairment after coadministration with a C...
Source: Molecular Genetics and Metabolism - Category: Genetics & Stem Cells Source Type: research

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Discussion Gaucher disease (GD) was first described by Philippe Gaucher in 1882. It was the first lysosomal storage disease (LSD) described and is the comparison prototype for many variations and their treatment. There are about 50 LSD and more well-known ones include Fabry, Niemann-Pick and Pompe diseases. LSDs currently have more than 300 different enzymes or membrane proteins affected which cause central nervous system and visceral disease. Overall the frequency of LSDs in aggregate is 1:3000 – 7000 live births. GD has an estimated prevalence of 1:57,000 – 111,000. It is higher within the Ashkenazi Jewish po...
Source: PediatricEducation.org - Category: Pediatrics Authors: Tags: Uncategorized Source Type: news
Gaucher disease (GD) is one of the most prevalent lysosomal storage diseases and is associated with hormonal and metabolic abnormalities, including nutritional status disorders, hypermetabolic state with high ...
Source: Orphanet Journal of Rare Diseases - Category: Internal Medicine Authors: Tags: Review Source Type: research
Bi-allelic mutations in the gene for glucocerebrosidase (GBA) cause Gaucher disease, an autosomal recessive lysosomal storage disorder. Gaucher disease causing GBA mutations in the heterozygous state are also high risk factors for Parkinson's disease (PD). GBA analysis is challenging due to a related pseudogene and structural variations (SVs) that can occur at this locus. We have applied and refined a recently developed nanopore DNA sequencing method to analyze GBA variants in a clinically assessed New Zealand longitudinal cohort of PD.
Source: Parkinsonism and Related Disorders - Category: Neurology Authors: Source Type: research
Abstract Glycosphingolipids are important building blocks of the outer leaflet of the cell membrane. They are continuously recycled, involving fragmentation inside lysosomes by glycosidases. Inherited defects in degradation cause lysosomal glycosphingolipid storage disorders. The relatively common glycosphingolipidosis Gaucher disease is highlighted here to discuss new insights in the molecular basis and pathophysiology of glycosphingolipidoses reached by fundamental research increasingly using chemical biology tools. We discuss improvements in the detection of glycosphingolipid metabolites by mass spectrometry an...
Source: Current Opinion in Chemical Biology - Category: Biochemistry Authors: Tags: Curr Opin Chem Biol Source Type: research
ConclusionsThis is the first family with GD and this combination of variants which causes a phenotype remarkable for severe bone disease with no or mild hematological manifestations.
Source: Molecular Genetics and Metabolism Reports - Category: Genetics & Stem Cells Source Type: research
AbstractGaucher disease (GD) is the most common inherited lysosomal storage disorder. It is a multi-system disease secondary a deficient activity of glucocerebrosidase- β-acid by variants in theGBA gene. The wide variability in the severity of clinical manifestations causes it to be diagnosed at any age. Only about 30% of patients are identified to have it in their childhood. Leaving aside the most serious forms of the diseases that are observed in the first weeks of life, most of the manifestations focus on the increase of visceral size, cytopenias, growth retardation, and bone pain crisis. The introduction of enzyma...
Source: Clinical Reviews in Bone and Mineral Metabolism - Category: Internal Medicine Source Type: research
The differentiation between Gaucher disease type 3 (GD3) and type 1 is challenging because pathognomonic neurologic symptoms may be subtle and develop at late stages. The ophthalmologist plays a crucial role i...
Source: Orphanet Journal of Rare Diseases - Category: Internal Medicine Authors: Tags: Research Source Type: research
We describe a case of a 33-year-old man with a previous diagnosis of type 3 GD who displayed a progressive weakening of the limbs followed by upper motor neuron involvement. A diagnosis of definite Amyotrophic Lateral Sclerosis was made. This is the first reported case of concurrent Gaucher disease and the ALS phenotype in the same patient.
Source: Molecular Genetics and Metabolism Reports - Category: Genetics & Stem Cells Source Type: research
Abstract Gaucher disease (GD) results from inherited mutations in the lysosomal enzyme β-glucocerobrosidase (GCase). Currently available treatment options for Type 1 GD are not efficacious for treating neuronopathic Type 2 and 3 GD due to their inability to cross the blood-brain barrier. In an effort to identify small molecules which could be optimized for CNS penetration we identified tamoxifen from a high throughput phenotypic screen on Type 2 GD patient-derived fibroblasts which reversed the disease phenotype. Structure activity studies around this scaffold led to novel molecules that displayed improved po...
Source: Bioorganic and Medicinal Chemistry Letters - Category: Chemistry Authors: Tags: Bioorg Med Chem Lett Source Type: research
Haploinsufficiency in the Gaucher disease GBA gene, which encodes the lysosomal glucocerebrosidase GBA, and ageing represent major risk factors for developing Parkinson ’s disease (PD). Recently, more than fifty o...
Source: Molecular Neurodegeneration - Category: Neurology Authors: Tags: Research article Source Type: research
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