The designer proline-rich antimicrobial peptide (PrAMP) Chex1-Arg20 amide (ARV-1502)
is active against Gram-negative and Gram-positive pathogens in differentmurine infection
models when administered parenterally and possesses a wide therapeutic index. Here
we studied the pharmacokinetics of ARV-1502 for the first time when administered
intramuscularly or intravenously (IV) in Sprague Dawley rats and Beagle dogs. First, a
specific and robust quantitation method relying on parallel reaction monitoring (PRM)
using a high-resolution hybrid quadrupole-Orbitrap mass spectrometer coupled on-line
to reversed-phase uHPLC was established and validated. The limit of detection was
2 ng/mL and the limit of quantitation was 4 ng/mL when spiked to pooled rat and dog
plasma. When ARV-1502 was administered IV at doses of 75 and 250 μg/kg in dogs
and rats, the plasma concentrations were 0.7 and 3.4μg/mL 2min post-administration,
respectively. ARV-1502 plasma concentrations declined exponentially reaching levels
between 2 and 4 ng/mL after 2 h. Intramuscular administration of 0.75 mg/kg in dogs
and 2.5 mg/kg in rats resulted in a different pharmacokinetics profile. The plasma
concentrations peaked at 15min post-injection at 1μg/mL (dogs) and 12μg/mL (rats)
and decreased exponentially within 3 h to 4 and 16 ng/mL, respectively. The initial
plasma concentrations of ARV-1502 and the decay timing afterwards indicated that
the peptide circulated in the blood stream for several hours, at some point above the
minimal inhibitory concentration against multidrug-resistant Enterobacteriaceae, with
blood concentrations sufficient to suppress bacterial growth and to modulate the
immune system.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:84525 |
| Date | 03 April 2023 |
| Creators | Brakel, Alexandra, Volke, Daniela, Kraus, Carl N., Otvos, Laszlo, Hoffmann, Ralf |
| Publisher | Frontiers Research Foundation |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2296-2646, 753 |
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