Absolute bioavailability and intravenous pharmacokinetics of N-acetyl-D-mannosamine in humans

N-acetyl-D-mannosamine monohydrate (ManNAc) is a naturally occurring monosaccharide that has attracted considerable attention for its potential in treating GNE myopathy, a rare autosomal recessive muscle disorder. Despite its promise as an oral treatment, the absolute bioavailability of oral ManNAc has not been determined and there has been no evaluation of the ManNAc pharmacokinetics following intravenous administration in humans. The aim of this study was to investigate the pharmacokinetics of intravenous ManNAc and to characterize its absolute bioavailability following a single oral dose.

In this single-centre, open-label, crossover study, six healthy adult males were administered ManNAc as a single oral dose (1000 mg) and intravenous dose (100 mg). Blood samples were collected over a 48 h period after dose administration for the quantification of plasma ManNAc concentrations. Non-compartmental pharmacokinetic analysis was performed using baseline-corrected plasma concentration-time data.

After intravenous dosing, the mean plasma clearance of ManNAc was 10.1 ± 1.94 L/h, volume of distribution was 24.1 ± 4.98 L and elimination half-life was 1.67 ± 0.251 h. The mean absolute bioavailability of oral ManNAc at a dose of 1000 mg was 4.01 ± 1.82%. Deconvolution analysis revealed a zero-order absorption rate of about 10 mg per hour in the initial 3 h after dosing.

The low oral bioavailability of ManNAc is likely due to poor absorption (rather than first-pass hepatic extraction) due to its high polarity. In addition, zero-order absorption explains why the systemic exposure to ManNAc does not increase proportionally with dose.