Impact of Food on the Oral Absorption of N-Acetyl-D-Mannosamine in Healthy Men and Women.
N‐acetylneuraminic acid
N‐acetyl‐D‐mannosamine
food effect
oral absorption
Journal
Clinical pharmacology in drug development
ISSN: 2160-7648
Titre abrégé: Clin Pharmacol Drug Dev
Pays: United States
ID NLM: 101572899
Informations de publication
Date de publication:
20 Jun 2024
20 Jun 2024
Historique:
received:
08
01
2024
accepted:
14
05
2024
medline:
20
6
2024
pubmed:
20
6
2024
entrez:
20
6
2024
Statut:
aheadofprint
Résumé
N-Acetyl-D-mannosamine (ManNAc) is an endogenous monosaccharide and precursor of N-acetylneuraminic acid (Neu5Ac), a critical sialic acid. ManNAc is currently under clinical development to treat GNE myopathy, a rare muscle-wasting disease. In this randomized, open-label, 2-sequence, crossover study, 16 healthy women and men were administered a single oral dose of ManNAc under fasting and fed conditions. Blood samples were collected for 48 hours after dosing for quantification of plasma ManNAc and Neu5Ac concentrations. Noncompartmental pharmacokinetic and deconvolution analyses were performed using baseline-corrected plasma concentration data. Administration of ManNAc in the fed state resulted in a 1.6-fold increase in ManNAc exposure, compared to fasting conditions. A concurrent increase in Neu5Ac exposure was observed in the presence of food. Deconvolution analysis indicated that the findings were attributed to prolonged absorption rather than an enhanced rate of absorption. The impact of food on ManNAc pharmacokinetics was greater in women than men (fed/fasted area under the concentration-time curve from time 0 to infinity mean ratio: 198% compared to 121%). It is hypothesized that the presence of food slows gastric emptying, allowing a gradual release of ManNAc into the small intestine, translating into improved ManNAc absorption. The results suggest that taking ManNAc with food may enhance its therapeutic activity and/or reduce the daily dosage requirement.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 The Author(s). Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.
Références
Celeste FV, Vilboux T, Ciccone C, et al. Mutation update for GNE gene variants associated with GNE myopathy. Hum Mutat. 2014;35(8):915‐926.
Huizing M, Carrillo‐Carrasco N, Malicdan MCV, et al. GNE myopathy: new name and new mutation nomenclature. Neuromuscul Disord. 2014;24(5):387‐389.
Amir SM, Barker SA, Butt WR, Crooke AC, Davies AG. Administration of N‐Acetyl‐D‐mannosamine to mammals. Nature. 1966;211(5052):976‐977.
Gagiannis D, Orthmann A, Danßmann I, Schwarzkopf M, Weidemann W, Horstkorte R. Reduced sialylation status in UDP‐N‐acetylglucosamine‐2‐epimerase/N‐acetylmannosamine kinase (GNE)‐deficient mice. Glycoconj J. 2007;24(2‐3):125‐130.
Galeano B, Klootwijk R, Manoli I, et al. Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N‐acetylmannosamine. J Clin Invest. 2007;117(6):1585‐1594.
Malicdan MCV, Noguchi S, Hayashi YK, Nonaka I, Nishino I. Prophylactic treatment with sialic acid metabolites precludes the development of the myopathic phenotype in the DMRV‐hIBM mouse model. Nat Med. 2009;15(6):690.
Niethamer TK, Yardeni T, Leoyklang P, et al. Oral monosaccharide therapies to reverse renal and muscle hyposialylation in a mouse model of GNE myopathy. Mol Genet Metab. 2012;107(4):748‐755.
Thomas GH, Scocca J, Miller CS, Reynolds LW. Accumulation of N‐acetylneuraminic acid (sialic acid) in human fibroblasts cultured in the presence of N‐acetylmannosamine. Biochim Biophys Acta. 1985;846(1):37‐43.
Xu X, Wang AQ, Latham LL, et al. Safety, pharmacokinetics and sialic acid production after oral administration of N‐acetylmannosamine (ManNAc) to subjects with GNE myopathy. Mol Genet Metab. 2017;122(1‐2):126‐134.
Carrillo N, Malicdan MC, Leoyklang P, et al. Safety and efficacy of N‐acetylmannosamine (ManNAc) in patients with GNE myopathy: an open‐label phase 2 study. Genet Med. 2021;23:2067‐2075.
Food and Drug Administration. Guidance for Industry; Food‐Effect Bioavailability and Fed Bioequivalence Studies. Center for Drug Evaluation and Research, U.S. Department of Health and Human Services; 2002.
Shi Y, Xu X, Fang M, et al. Quantitative hydrophilic interaction chromatography–mass spectrometry analysis of N‐acetylneuraminic acid and N‐acetylmannosamine in human plasma. J Chromatogr B. 2015;1000:105‐111.
Zou H, Banerjee P, Leung SSY, Yan X. Application of pharmacokinetic‐pharmacodynamic modeling in drug delivery: development and challenges. Review Front Pharmacol. 2020;11:997.
Schwartz JB. The influence of sex on pharmacokinetics. Clin Pharmacokinet. 2003;42(2):107‐121.
Van Wart S, Mager DE, Bednasz CJ, Huizing M, Carrillo N. Population pharmacokinetic model of N‐acetylmannosamine (ManNAc) and N‐acetylneuraminic acid (Neu5Ac) in subjects with GNE myopathy. Drugs R D. 2021;21(2):189‐202.
Koziolek M, Alcaro S, Augustijns P, et al. The mechanisms of pharmacokinetic food‐drug interactions ‐ A perspective from the UNGAP group. Eur J Pharm Sci. 2019;134:31‐59.
Welling PG. Effects of food on drug absorption. Pharmacol Ther. 1989;43(3):425‐441.
Deng J, Zhu X, Chen Z, et al. A review of food‐drug interactions on oral drug absorption. Drugs. 2017;77(17):1833‐1855.
Bennink R, Peeters M, Van den Maegdenbergh V, et al. Comparison of total and compartmental gastric emptying and antral motility between healthy men and women. Eur J Nucl Med. 1998;25(9):1293‐1299.
Datz FL, Christian PE, Moore J. Gender‐related differences in gastric emptying. J Nucl Med. 1987;28(7):1204‐1207.