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Infiltrative Cardiomyopathies
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Arthur Qi, Quynh Nguyen, Haran Yogasundaram, Gavin Y. Oudit
Substrate reduction therapy, specifically eliglustat tartrate (Genz-112638), is an emerging treatment for FD, and represents an alternative approach to reducing glycosphingolipid levels that has proven effective in treating Gaucher disease, another glycosphingolipidosis.34 Through inhibition of the glucosylceramide synthase enzyme that catalyzes the first step of glycosphingolipid synthesis, substrate reduction therapy reduces upstream production of glycosphingolipids.23 In FD mouse models, substrate reduction therapy has been shown to reduce Gb3 and lyso-Gb3 levels in the kidneys, heart, and liver, with maximal effect when used in conjunction with ERT.23,27 However, eliglustat was ineffective at lowering glycosphingolipid levels in the brain due to its poor ability to cross the blood-brain barrier.35 A novel oral glucosylceramide synthase inhibitor, ibiglustat (Genz-682452), was designed to cross the blood brain barrier and has shown efficacy in lowering Gb3 and lyso-Gb3 levels in the brain, especially in conjunction with ERT.34
Gaucher disease
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Another approach, called substrate reduction therapy, is possible with an inhibitor of ceramide glucosyltransferase, and the agent N-butyldeoxynojirimycin was approved in 2004 (miglustat) for adult patients with Gaucher disease for whom IV enzyme replacement is not practical [90–92]. Results are similar to those [93] with enzyme therapy [19]. Studies are underway using a more specific glucosylceramide synthase inhibitor, eliglustat tartrate [94].
Current and emerging pharmacotherapy for Gaucher disease in pediatric populations
Published in Expert Opinion on Pharmacotherapy, 2021
Richard Sam, Emory Ryan, Emily Daykin, Ellen Sidransky
Eliglustat, the most commonly used SRT, has been used as a long-term treatment for adults with GD1. Patients considering this therapy must be evaluated for their CYP2D6 status using an FDA-cleared test, to determine whether they are CYP2D6 extensive metabolizers, intermediate metabolizers, or poor metabolizers [86,91,93,94], and to assess patient eligibility and recommended dosage. Thus, assessment of drug–drug interaction with other medications can be vital, especially if considered for pediatric patients. Side effects may include general gastrointestinal upset as well as headache, back/arm/leg pain, dizziness or weakness, and eliglustat may be contraindicated in those who have hepatic impairment, cardiac arrhythmias related to prolonged PR, QTc or QRS intervals, or based on CYP2DG metabolizer status and other concurrent medications. Currently, there are clinical trials of eliglustat for pediatric patients with GD1 and GD3 to evaluate the safety and pharmacokinetics of eliglustat in pediatric patients, either alone or in combination with Cerezyme (Table 3). For this study, anticipated to be completed by March 2023, treatment will be analyzed over two 1-year treatment periods [95].
Hematological manifestations and complications of Gaucher disease
Published in Expert Review of Hematology, 2021
Shoshana Revel-Vilk, Jeff Szer, Ari Zimran
Of the two approved SRT drugs, only eliglustat is approved as first-line therapy (based on CYP2D6 metabolism status) [51]. Miglustat is approved only for patients with mild to moderate GD1, for whom ERT is not suitable or not a therapeutic option [52]. While ERT can be administered to any patient, eliglustat should not be prescribed to children, pregnant or lactating women, patients with existing cardiac disease, patients with severe hepatic impairment, and CYP2D6 ultra-rapid metabolizers [53,54]. The dose of eliglustat is not dependent on body weight but on the CYP2D6 status, once a day for poor metabolizers and twice a day for extensive and intermediate metabolizers. The use of SRT was associated with a higher prevalence of adverse effects, and therefore in our algorithm, it is offered for patients unwilling and unable to get ERT [48].
Dual enzyme therapy improves adherence to chemotherapy in a patient with gaucher disease and Ewing sarcoma
Published in Pediatric Hematology and Oncology, 2023
Brandon Lucari, Eran Tallis, Vernon Reid Sutton, Timothy Porea
Dual therapy with ERT and SRT has been implemented in refractory GD. Ha et al.17 found improvement in platelet count in a patient suffering from severe thrombocytopenia refractory to ERT with the addition of eliglustat. Similar success was observed in reducing lymphadenopathy among 4 patients with ERT resistant type 3 GD.18 Miglustat has had mixed success. Amato et al.19 shared a report of improved bone pain and thrombocytopenia with ERT and miglustat in two patients. These results were not corroborated by Elstein et al.20 who found no improvement in hematologic parameters. The lack of observed platelet increase may be secondary to the study population having been in maintenance with ERT prior to the addition of miglustat. The use of eliglustat in combination therapy for our patient was supported by results of the ENGAGE trial demonstrating a 41% improvement in platelet count over nine months in treatment naïve type 1 GD patients. There are equivocal reports of increased clearance of imiglucerase by miglustat. The authors of this study noted that the results were not conclusive due to the small number of patients studied and the variable dosing of imiglucerase included in the study. Additionally, our patient was on eliglustat with a different mechanisms of action: Eliglustat reduces the production of glucosylceramide by directly inhibiting glucosylceramide synthase, a rate-limiting enzyme in the production of glycosphingolipids.21 Treatment for GD with ERT and SRT is limited by the financial burden estimated to cost more than 200,000 US dollars annually.22 In our patient we were able to obtain insurance approval to reduce this burden but given the severity of her ES the benefit of expedient GD treatment outweighed the increased costs.