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Quantitation of a Novel Engineered Anti-infective Host Defense Peptide, ARV-1502: Pharmacokinetic Study of Different
Alexandra Brakel1,2, Daniela Volke1,2, Carl N Kraus3
1Faculty of Chemistry and Mineralogy, Institute of Bioanalytical Chemistry, Universität Leipzig, Leipzig, Germany.
Abstract:
The designer proline-rich antimicrobial peptide (PrAMP) Chex1-Arg20 amide (ARV-1502) is active against Gram-negative and Gram-positive pathogens in different murine 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 3.4 μg/mL 2 min 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 15 min post-injection at 1 μg/mL (dogs) and 12 μg/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.
Insights
The antimicrobial peptide ARV-1502 shows promising pharmacokinetics in rats and dogs after intravenous or intramuscular administration. Its blood concentrations remain above inhibitory levels for hours, suggesting efficacy against resistant bacteria.
Area of Science:
- Pharmacology
- Microbiology
- Drug Development
Background:
- Designer proline-rich antimicrobial peptides (PrAMPs) like ARV-1502 exhibit broad-spectrum activity against Gram-negative and Gram-positive pathogens.
- ARV-1502 has demonstrated efficacy in murine infection models and possesses a wide therapeutic index.
Purpose of the Study:
- To characterize the pharmacokinetics of ARV-1502 following intramuscular and intravenous administration in Sprague Dawley rats and Beagle dogs.
- To establish and validate a quantitative method for ARV-1502 in plasma.
Main Methods:
- Development and validation of a parallel reaction monitoring (PRM) method using high-resolution mass spectrometry coupled with ultra-high-performance liquid chromatography (uHPLC).
- Pharmacokinetic analysis of ARV-1502 after intravenous (75 and 250 μg/kg) and intramuscular (0.75 mg/kg in dogs, 2.5 mg/kg in rats) administration in rats and dogs.
- Quantification of ARV-1502 plasma concentrations over time.
Main Results:
- A sensitive and robust PRM method was validated with a limit of detection of 2 ng/mL and a limit of quantitation of 4 ng/mL in rat and dog plasma.
- Following IV administration, ARV-1502 plasma concentrations declined exponentially, reaching 2-4 ng/mL after 2 hours.
- Intramuscular administration led to peak plasma concentrations at 15 minutes, with concentrations decreasing within 3 hours, indicating sustained presence in the bloodstream.
Conclusions:
- ARV-1502 exhibits favorable pharmacokinetic properties in rats and dogs, with sustained plasma concentrations after both IV and IM administration.
- Observed blood concentrations suggest ARV-1502 may remain above the minimal inhibitory concentration for multidrug-resistant Enterobacteriaceae for extended periods.
- These findings support the potential of ARV-1502 as a therapeutic agent for bacterial infections, with sufficient duration of action to suppress bacterial growth and modulate the immune system.
