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Original research
Pharmacologic properties of high-dose ambroxol in four patients with Gaucher disease and myoclonic epilepsy
  1. Yoon-Myung Kim1,
  2. Mi-Sun Yum2,
  3. Sun Hee Heo3,
  4. Taeho Kim3,
  5. Hee Kyung Jin4,
  6. Jae-sung Bae5,
  7. Go Hun Seo2,
  8. Arum Oh2,
  9. Hee Mang Yoon6,
  10. Hyun Taek Lim7,
  11. Hyo-Won Kim8,
  12. Tae-Sung Ko2,
  13. Hyeong‐Seok Lim9,
  14. Mark J Osborn10,
  15. Jakub Tolar10,
  16. Claudia Cozma11,
  17. Arndt Rolfs11,12,
  18. Ari Zimran13,
  19. Beom Hee Lee2,14,
  20. Han-Wook Yoo2,14
  1. 1 Department of Pediatrics, Gangneung Asan Hospital, Gangneung, The Republic of Korea
  2. 2 Department of Pediatrics, Asan Medical Center Children’s Hospital, College of Medicine University of Ulsan, Seoul, The Republic of Korea
  3. 3 Asan Institute for Life Sciences, Asan Medical Center, College of Medicine University of Ulsan, Seoul, The Republic of Korea
  4. 4 Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu, The Republic of Korea
  5. 5 Department of Physiology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, The Republic of Korea
  6. 6 Department of Radiology and Research Institute of Radiology, Asan Medical Center, College of Medicine University of Ulsan, Seoul, The Republic of Korea
  7. 7 Department of Ophthalmology, Asan Medical Center, College of Medicine University of Ulsan, Seoul, The Republic of Korea
  8. 8 Department of Psychiatry, Asan Medical Center, College of Medicine University of Ulsan, Seoul, The Republic of Korea
  9. 9 Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, College of Medicine University of Ulsan, Seoul, The Republic of Korea
  10. 10 Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota Medical Center, Minneapolis, Minnesota, USA
  11. 11 Centogene AG, Rostock, Germany
  12. 12 Albrecht-Kossel-Institute for Neuroregeneration, Medical University of Rostock, Rostock, Germany
  13. 13 The Hebrew University Hadassah Medical School, Jerusalem, Israel
  14. 14 Medical Genetics Center, Asan Medical Center, College of Medicine University of Ulsan, Seoul, The Republic of Korea
  1. Correspondence to Professor Han-Wook Yoo, Seoul, Korea (the Republic of); hwyoo{at}amc.seoul.kr; Professor Beom Hee Lee; bhlee{at}amc.seoul.kr

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.

  • metabolic disorders
  • Parkinson's disease
  • neurology

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Footnotes

  • 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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