Carglumic acid enhances rapid ammonia detoxification in classical organic acidurias with a favourable risk-benefit profile: a retrospective observational study
| Autor: | Angeles Garcia-Cazorla, Anupam Chakrapani, Francesco Papadia, Maria Bueno Delgado, Celine Plisson, David Gil-Ortega, Vassili Valayannopoulos, Patricia Rosello, Julien Baruteau, Jeannie Le Mouhaer, Samia Pichard, Nathalie Guffon, Aline Cano, Pedro Gomez-de Quero, Mireia del Toro, Floris C. Hofstede, Sema kalkan-Ucar, Agustin Molina, Mahmut Çoker, María L. Couce, Mercedes Martinez-Pardo Casanova, Maria Alice Donati, Rosa A Lama-More |
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| Přispěvatelé: | Ege Üniversitesi |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Propionic Acidemia Hyperammonaemia Clinical Trial Phase III OA decompensation episodes Gastroenterology chemistry.chemical_compound 0302 clinical medicine Glutamates Hyperammonemia Genetics(clinical) Pharmacology (medical) Ammonia Measurement Propionic acidemia Non-U.S. Gov't Genetics (clinical) Medicine(all) education.field_of_study Research Support Non-U.S. Gov't Inborn Errors General Medicine Clinical Trial Carglumic acid Multicenter Study Treatment Outcome Female congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Population Research Support 03 medical and health sciences Phase III Ammonia Internal medicine Journal Article medicine Humans Decompensation education Amino Acid Metabolism Inborn Errors Retrospective Studies business.industry Research Infant Newborn Infant nutritional and metabolic diseases Newborn medicine.disease Organic acidurias (OAs) Amino Acid Metabolism 030104 developmental biology Endocrinology chemistry Methylmalonic aciduria Concomitant business 030217 neurology & neurosurgery |
| Zdroj: | Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid Consejería de Sanidad de la Comunidad de Madrid ORPHANET JOURNAL OF RARE DISEASES r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu instname r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu Fundació Sant Joan de Déu Orphanet Journal of Rare Diseases Orphanet Journal of Rare Diseases, 11. BioMed Central |
| ISSN: | 1750-1172 |
| Popis: | WOS: 000373180700001 PubMed ID: 27030250 Background: Isovaleric aciduria (IVA), propionic aciduria (PA) and methylmalonic aciduria (MMA) are inherited organic acidurias (OAs) in which impaired organic acid metabolism induces hyperammonaemia arising partly from secondary deficiency of N-acetylglutamate (NAG) synthase. Rapid reduction in plasma ammonia is required to prevent neurological complications. This retrospective, multicentre, open-label, uncontrolled, phase IIIb study evaluated the efficacy and safety of carglumic acid, a synthetic structural analogue of NAG, for treating hyperammonaemia during OA decompensation. Methods: Eligible patients had confirmed OA and hyperammonaemia (plasma NH3 > 60 mu mol/L) in >= 1 decompensation episode treated with carglumic acid (dose discretionary, mean (SD) first dose 96.3 (73.8) mg/kg). The primary outcome was change in plasma ammonia from baseline to endpoint (last available ammonia measurement at = 1 dose of study drug and had post-baseline measurements) comprised 41 patients (MMA: 21, PA: 16, IVA: 4) with 48 decompensation episodes (MMA: 25, PA: 19, IVA: 4). Mean baseline plasma ammonia concentration was 468.3 (+/- 365.3) mu mol/ L in neonates (29 episodes) and 171.3 (+/- 75.7) mu mol/L in non-neonates (19 episodes). At endpoint the mean plasma NH3 concentration was 60.7 (+/- 36.5) mu mol/L in neonates and 55.2 (+/- 21.8) mu mol/ L in non-neonates. Median time to normalise ammonaemia was 38.4 hours in neonates vs 28.3 hours in non-neonates and was similar between OA subgroups (MMA: 37.5 hours, PA: 36.0 hours, IVA: 40.5 hours). Median time to ammonia normalisation was 1.5 and 1.6 days in patients receiving and not receiving concomitant scavenger therapy, respectively. Although patients receiving carglumic acid with scavengers had a greater reduction in plasma ammonia, the endpoint ammonia levels were similar with or without scavenger therapy. Clinical symptoms improved with therapy. Twenty-five of 57 patients in the safety population (67 episodes) experienced AEs, most of which were not drug-related. Overall, carglumic acid seems to have a good safety profile for treating hyperammonaemia during OA decompensation. Conclusion: Carglumic acid when used with or without ammonia scavengers, is an effective treatment for restoration of normal plasma ammonia concentrations in hyperammonaemic episodes in OA patients. Orphan Europe; Orphan Europe SARL This study was sponsored by Orphan Europe. The study sponsor was involved in the conception and design of the study, collection and interpretation of data, in manuscript preparation and in the decision to submit the manuscript for publication. We thank Brigitte Chabrol, Rita Fischetto, Gemma Ginovart, Elisabetta Pasquini and Carlo Dionisi-Vici for their valuable insights during data analysis. We also thank Dr Silke Geb and Dr Helene Ogier de Baulny for their contributions to the study. Medical writing assistance was provided by apothecom scopemedical ltd, funded by Orphan Europe SARL. |
| Databáze: | OpenAIRE |
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