Population Pharmacokinetic Model of N-acetylmannosamine (ManNAc) and N-acetylneuraminic acid (Neu5Ac) in Subjects with GNE Myopathy

Autor:	Scott A. Van Wart, Marjan Huizing, Nuria Carrillo, Donald E. Mager, Cindy J Bednasz
Rok vydání:	2021
Předmět:	Adult Male Population Pharmacology 030226 pharmacology & pharmacy 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Muscular Diseases Elimination rate constant Pharmacokinetics Oral administration N-Acetylmannosamine Humans Original Research Article education 030203 arthritis & rheumatology Volume of distribution education.field_of_study Chemistry Hexosamines N-Acetylneuraminic Acid NONMEM Bioavailability Distal Myopathies Female
Zdroj:	Drugs in R&D
ISSN:	1179-6901 1174-5886
DOI:	10.1007/s40268-021-00343-6
Popis:	Background GNE myopathy is a rare genetic muscle disease resulting from deficiency in an enzyme critical for the biosynthesis of N-acetylneuraminic acid (Neu5Ac, sialic acid). The uncharged Neu5Ac precursor, N-acetylmannosamine (ManNAc), is under development as an orphan drug for treating GNE myopathy. Methods A semi-mechanistic population pharmacokinetic model was developed to simultaneously characterize plasma ManNAc and its metabolite Neu5Ac following oral administration of ManNAc to subjects with GNE myopathy. Plasma ManNAc and Neu5Ac pharmacokinetic data were obtained from two clinical studies (ClinicalTrials.gov identifiers NCT01634750, NCT02346461) and were simultaneously modeled using NONMEM. Results ManNAc and Neu5Ac plasma concentrations were obtained from 34 subjects with GNE myopathy (16 male, 18 female, median age 39.5 years). The model parameter estimates included oral absorption rate (ka) = 0.256 h−1, relative bioavailability relationship with dose (F-Dose) slope = −0.405 (where F = 1 for 6-g dose), apparent clearance (CLM/F) = 631 L/h, volume of distribution (VM/F) = 506 L, Neu5Ac elimination rate constant (kout) = 0.283 h−1, initial ManNAc to Neu5Ac conversion (SLP0) = 0.000619 (ng/mL)−1 and at steady-state (SLPSS) = 0.00334 (ng/mL)−1, with a rate-constant of increase (kinc) = 0.0287 h−1. Goodness-of-fit plots demonstrated an acceptable and unbiased fit to the plasma ManNAc and Neu5Ac concentration data. Visual predictive checks demonstrated reasonable agreement between the 5th, 50th, and 95th percentiles of the observed and simulated data. Conclusions This population pharmacokinetic model can be used to evaluate ManNAc dosing regimens and to calculate Neu5Ac production and exposure following oral administration of ManNAc in subjects with GNE myopathy. Supplementary Information The online version contains supplementary material available at 10.1007/s40268-021-00343-6.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fdb0e0099a75b288121e52c5558d9e93 https://doi.org/10.1007/s40268-021-00343-6 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
Nepřihlášeným uživatelům se plný text nezobrazuje	K zobrazení výsledku je třeba se přihlásit.