Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy.

Abstract

BACKGROUND:

Ambroxol (ABX) has been suggested as an augmentative pharmacological agent for neuronopathic Gaucher disease (nGD). This study assessed the long-term safety and efficacy of combined therapy with high-dose ABX and enzyme replacement therapy (ERT) in nGD.

METHODS:

ABX+ERT therapy was administered for 4.5 years in four patients with nGD. ABX was initiated at a dose of 1.5 mg/kg/day, and the dose was escalated up to 27 mg/kg/day. The target plasma level was 10 µmol/L or less. The changes in glucocerebrosidase activity, biochemical, safety and neurocognitive findings were assessed.

RESULTS:

Enhanced residual GCcase activity was observed in all patients, as evidenced in both in vitro and in vivo studies. During the first 2 years of study with ABX (up to 21 mg/kg/day), mean seizure frequencies and neurocognitive function worsened. After ABX dosage was increased up to 27 mg/kg/day of ABX, its trough plasma concentration was 3.2-8.8 µmol/L. Drug-to-drug interaction, especially with antiepileptic drug significantly affected the pharmacokinetic parameters of ABX. Importantly, at 27 mg/kg/day of ABX, the seizure frequencies markedly decreased from the baseline, and the neurocognitive function was improved. In addition, Lyso-Gb1, a biomarker for the severity and progression of GD, was normalised in all patients. High-dose ABX was well-tolerated with no severe adverse events.

CONCLUSIONS:

Long-term treatment with high-dose ABX+ERT was safe and might help to arrest the progression of the neurological manifestations in GD.

• Authors: Yoon-Myung Kim, Mi-Sun Yum, Sun Hee Heo, Taeho Kim, Hee Kyung Jin, Jae-Sung Bae, Go Hun Seo, Arum Oh, Hee Mang Yoon, Hyun Taek Lim, Hyo-Won Kim, Tae-Sung Ko, Hyeong-Seok Lim, Mark J Osborn, Jakub Tolar, Claudia Cozma, Arndt Rolfs, Ari Zimran, Beom Hee Lee, Han-Wook Yoo
• Journal: Journal of medical genetics (J Med Genet) Vol. 57 Issue 2 Pg. 124-131 (02 2020) ISSN: 1468-6244 [Electronic] England
• PMID: 31649052 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Chemical References

• Biomarkers
• Ambroxol
• Glucosylceramidase

Topics

• Adolescent
• Ambroxol (administration & dosage)
• Biomarkers (blood)
• Child
• Dose-Response Relationship, Drug
• Enzyme Replacement Therapy
• Epilepsies, Myoclonic (blood, drug therapy, pathology)
• Female
• Gaucher Disease (blood, drug therapy, pathology)
• Glucosylceramidase (blood)
• Humans
• Male