Abstract
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 (k(a)) = 0.256 h(-1), relative bioavailability relationship with dose (F-Dose) slope = -0.405 (where F = 1 for 6-g dose), apparent clearance (CL(M)/F) = 631 L/h, volume of distribution (V(M)/F) = 506 L, Neu5Ac elimination rate constant (k(out)) = 0.283 h(-1), initial ManNAc to Neu5Ac conversion (SLP(0)) = 0.000619 (ng/mL)(-1) and at steady-state (SLP(SS)) = 0.00334 (ng/mL)(-1), with a rate-constant of increase (k(inc)) = 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.