Kalytera Provides Data Demonstrating that Prodrug R-107 Provides Sustained Release of Nitric Oxide - Seite 2

Results from this rat pharmacokinetic study, carried out at Envigo Labs in the United Kingdom, demonstrated a rapid buildup of the prodrug R-107, with peak plasma concentrations (Cmax) reached after 5 and 8 minutes (Tmax) in male and female rats, respectively. Conversion of R-107 to its active payload R-100 was extremely rapid, with R-100 attaining its peak plasma concentration (Cmax) only 15 minutes after the dosing of R-107. Thereafter, R-100 was cleared from the plasma with half-lives (t_½) of 2.7 and 7.7 hours in male and female rats, respectively. Given that R-107 and its payload, R-100, are hydrophobic, it was not unexpected to observe a large volume of distribution (Vd), indicative that they had partitioned into fat stores forming a functional drug depot. These findings predict that a single dose of the R-107 prodrug in humans will produce sustained plasma levels of the active payload R-100, which would then release nitric oxide into the lung over many hours.

Pharmacokinetic data are Indicative of Sustained Release of Nitric Oxide from Active Payload R-100 
In a follow-on pharmacokinetic study also carried out at Envigo Labs, the active payload R-100 was administered at a dose of 10 milligrams per kilogram to rats via an intravenous injection. The purpose of this investigation was to measure the levels of the metabolite HMP, which is formed when R-100 discharges nitric oxide. This study is also an obligatory component of the IND to be submitted to the FDA.  Results from this study showed a total exposure to HMP of less than 30% of the total R-100 administered, indicating that the release of nitric oxide from HMP is relatively slow. Accordingly, R-100 functions as a depot of nitric oxide, providing for sustained exposure to nitric oxide in tissues.  

Taken together, the interpretation of the findings from the above two studies is that R-107 is readily converted in vivo into its active payload R-100, which accumulates in a tissue depot and provides for a sustained release of nitric oxide into tissues. Pharmacokinetic studies taking place now in large animals will offer additional insight into the predicted exposure levels in humans dosed with R-107.

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