Mean half—Life of fosmetpantotenate and diastereomers after incubation with blood from various species at 37°C for 60 min^a.

<p>Mean half—Life of fosmetpantotenate and diastereomers after incubation with blood from various species at 37°C for 60 min<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192028#t002fn001" target="_blank">^a</a>.</p

Effects of 1 μM fosmetpantotenate TID for 5 consecutive days in shRNA PanK2 knockdown human neuroblastoma cells.

<p>(A) Intracellular CoA concentrations, n = 3. (B) Western blot densitometry values. β-actin was used for normalization. Two experiments in duplicate. Two sided t-test; *p ≤0.05, **p ≤0.01, ***p ≤0.001. Gel images can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192028#pone.0192028.s002" target="_blank">S2 Fig</a>.</p

Fosmetpantotenate (RE-024), a phosphopantothenate replacement therapy for pantothenate kinase-associated neurodegeneration: Mechanism of action and efficacy in nonclinical models

<div><p>In cells, phosphorylation of pantothenic acid to generate phosphopantothenic acid by the pantothenate kinase enzymes is the first step in coenzyme A synthesis. Pantothenate kinase 2, the isoform localized in neuronal cell mitochondria, is dysfunctional in patients with pantothenate kinase-associated neurodegeneration. Fosmetpantotenate is a phosphopantothenic acid prodrug in clinical development for treatment of pantothenate kinase-associated neurodegeneration, which aims to replenish phosphopantothenic acid in patients. Fosmetpantotenate restored coenzyme A in short-hairpin RNA pantothenate kinase 2 gene-silenced neuroblastoma cells and was permeable in a blood-brain barrier model. The rate of fosmetpantotenate metabolism in blood is species-dependent. Following up to 700 mg/kg orally, blood exposure to fosmetpantotenate was negligible in rat and mouse, but measurable in monkey. Consistent with the difference in whole blood half-life, fosmetpantotenate dosed orally was found in the brains of the monkey (striatal dialysate) but was absent in mice. Following administration of isotopically labeled-fosmetpantotenate to mice, ~40% of liver coenzyme A (after 500 mg/kg orally) and ~50% of brain coenzyme A (after 125 μg intrastriatally) originated from isotopically labeled-fosmetpantotenate. Additionally, 10-day dosing of isotopically labeled-fosmetpantotenate, 12.5 μg, intracerebroventricularly in mice led to ~30% of brain coenzyme A containing the stable isotopic labels. This work supports the hypothesis that fosmetpantotenate acts to replace reduced phosphopantothenic acid in pantothenate kinase 2-deficient tissues.</p></div

Fosmetpantotenate, PPA, and total PA in monkey blood.

<p>Concentrations of fosmetpantotenate, PPA, and PA after a single oral administration of fosmetpantotenate in cynomolgus monkeys at 300 mg/kg (N = 2).</p

PPA and total PA in mouse and rat blood.

<p>Concentration-versus-time plots of PPA and PA after a single oral administration of fosmetpantotenate at 100, 300, or 700 mg/kg in CD1 mice (N = 4 per time point) or Sprague Dawley rats (N = 3 per time point).</p

Scheme depicting the different metabolic paths to CoA formation from either pantothenic acid or fosmetpantotenate.

<p>Scheme depicting the different metabolic paths to CoA formation from either pantothenic acid or fosmetpantotenate.</p

Apparent in vitro permeability of diastereomers of fosmetpantotenate, PA, and PPA in a blood—Brain barrier permeability model using co-cultured porcine brain endothelial cells and rat astrocytes^a.

<p>Apparent in vitro permeability of diastereomers of fosmetpantotenate, PA, and PPA in a blood—Brain barrier permeability model using co-cultured porcine brain endothelial cells and rat astrocytes<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0192028#t003fn001" target="_blank">^a</a>.</p

Fosmetpantotenate, PPA, and total PA in mouse brain striatal dialysate.

<p>Single administration of fosmetpantotenate in C57Bl6 mice (700 mg/kg orally or 125 μg intrastriatally).</p

Area under the curve for circulating metabolites as a percentage of fosmetpantotenate (parent) after a single oral administration of 100, 300, or 700 mg/kg to mice, rats, and monkeys.

<p>Area under the curve for circulating metabolites as a percentage of fosmetpantotenate (parent) after a single oral administration of 100, 300, or 700 mg/kg to mice, rats, and monkeys.</p

Fosmetpantotenate, PPA, and total PA in monkey blood and brain striatal dialysate.

<p>Single oral administration to cynomolgus monkeys (100 and 300 mg/kg).</p