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

Scott Van Wart, Donald E Mager, Cindy J Bednasz, Marjan Huizing, Nuria Carrillo, Scott Van Wart, Donald E Mager, Cindy J Bednasz, Marjan Huizing, Nuria Carrillo

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 (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.

Conflict of interest statement

This study was partially funded through Cooperative Research and Development Agreements (CRADA) with Escala Therapeutics, Inc. Dr Huizing is a co-inventor on patent US Patent No. 8,410,063. “N-acetylmannosamine as a Therapeutic Agent”.

Figures

Fig. 1
Fig. 1
Neu5Ac (sialic acid) biosynthesis pathway. The first committed step of cytosolic Neu5Ac (sialic acid) biosynthesis is the conversion of UDP-GlcNAc to ManNAc by 2-epimerase activity of the bifunctional GNE enzyme, immediately followed by conversion of ManNAc to ManNAc-6-P by the kinase activity of the same GNE enzyme. ManNAc-6-P undergoes two more steps to form cytoplasmic free sialic acid. A nuclear step activates free sialic acid to CMP-sialic acid, which translocates back to the cytosol, where is utilized by the Golgi complex to sialylate glycans (glycoproteins and glycolipids). Cytoplasmic CMP-sialic acid also strongly feedback-inhibits the UDP-GlcNAc 2-epimerase enzymatic activity in its allosteric site (dashed line). Subjects with GNE myopathy have deficiency of GNE UDP-GlcNAc 2-epimerase and ManNAc kinase activity, resulting in decreased sialic acid production. Supplementation of ManNAc circumvents the feedback inhibition step in this pathway and increases sialic acid production. ManNAc can be converted to ManNAc-6-P by the ancillary enzyme GlcNAc kinase [24], which likely occurs in subjects with GNE myopathy with ManNAc kinase deficiency. PEP phosphoenolpyruvate. Figure reprinted from Xu et al. 2018 [11] with permission
Fig. 2
Fig. 2
Diagram of final structural pharmacokinetic model for ManNAc and Neu5Ac. F oral bioavailability, ka first-order oral absorption rate-constant for exogenously administered ManNAc (h−1), ksyn zero-order endogenous production rate constant for ManNAc (μg/h), CMT compartment, CLM apparent clearance for ManNAc (L/h), M0 initial endogenous plasma ManNAc concentration (ng/mL), VM apparent volume of distribution for ManNAc (L), kpro zero-order production rate constant for Neu5Ac in precursor compartment (ng/mL·h), Pre-Neu5Ac Neu5Ac precursor, kout first-order elimination rate constant for Neu5Ac (h−1), N0 initial endogenous plasma Neu5Ac concentration (ng/mL)
Fig. 3
Fig. 3
VPC for plasma ManNAc concentrations. The final population pharmacokinetic model was used to generate VPCs, stratified by ManNAc dose group, following single-dose administration of ManNAc to subjects with GNE myopathy. VPCs visual predictive checks
Fig. 4
Fig. 4
VPC for plasma Neu5Ac concentrations. The final population pharmacokinetic model was used to generate VPCs, stratified by ManNAc dose group, following single-dose administration of ManNAc to subjects with GNE myopathy. VPCs visual predictive checks
Fig. 5
Fig. 5
VPC for plasma ManNAc concentrations. The final population pharmacokinetic model was used to generate VPCs, stratified by ManNAc dose group, following repeated-dose administration of ManNAc to subjects with GNE myopathy. VPCs visual predictive checks
Fig. 6
Fig. 6
VPC for plasma Neu5Ac concentrations. The final population pharmacokinetic model was used to generate VPCs, stratified by ManNAc dose group, following repeated-dose administration of ManNAc to subjects with GNE myopathy. VPCs visual predictive checks

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