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.
- metabolic disorders
- Parkinson's disease
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Y-MK and M-SY contributed equally.
BHL and H-WY contributed equally.
Contributors BHL, HKJ, J-SB, AR, AZ and H-WY contributed to designing the study. Y-MK, M-SY, GHS, AO, HMY, HTL, H-WK, T-SK, BHL and HMY were the clinicians who conducted all clinical and radiological examinations. S-HH, T-SK, H-SL, CC and AR did the laboratory experiments. BHL, Y-MK, M-SY, HKJ, J-SB, H-WY, HTL, MJO, JT, AR, AZ and HMY analysed the data. Y-MK, M-SY, S-HH and BHL drafted the manuscript and HKJ, MJO, JT, CC, AR, AZ revised the manuscript. All authors were involved in analysing and interpreting the data. All authors read and approved the final manuscript.
Funding This research was supported in part by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (NRF-2015K1A4A3046807, NRF-2016M3A9B4915706 and NRF-2018M3A9H1078335) and by ISU ABXIS, Gyeonggi-do, Korea.
Competing interests None declared.
Patient consent for publication Parental/guardian consent obtained.
Ethics approval The study was approved by Institutional Review Board, Asan Medical Center, Seoul, Korea and the Ministry of Food and Drug Safety, Korea.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.
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