PURPOSETo explore, in a microdose (phase-0) study, the pharmacokinetics, bioavailability and concentrations in key compartments of the lung, of AR-709, a novel diaminopyrimidine antibiotic for the treatment of respiratory infection.METHODSFour healthy men each received two single, 100 μg microdoses of ¹⁴C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of ¹⁴C and unchanged AR-709 were obtained by high-performance liquid chromatography and accelerator mass spectrometry (AMS). Next, 15 healthy men received a single, 100 μg microdose of ¹⁴C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS.RESULTSAfter IV administration, clearance of AR-709 was 496 mL/min, volume of distribution was 1,700 L and the absolute oral bioavailability was 2.5 %. Excretion in urine was negligible. At 8-12 h after IV dosing, ¹⁴C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, ¹⁴C was still mostly associated with AR-709 at 12 h after dosing.CONCLUSIONSThe results of this microdose study indicate that AR-709 attains concentrations appreciably higher within the lung than in plasma. Its low oral bioavailability however, precludes oral administration. Although IV administration would appear to be an effective route of administration, this would limit the use of AR-709 to a clinical setting and would therefore be economically unsustainable. If further clinical development were to be undertaken, therefore, an alternative route of administration would be necessary.

01 Jun 2008·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Antistreptococcal Activity of AR-709 Compared to That of Other Agents

Q2 · MEDICINE

Article

Author: Hawser, Stephen ; Lociuro, Sergio ; Smith, Kathy ; Ednie, Lois M. ; Appelbaum, Peter C.

ABSTRACTAgainst 300 strains of pneumococci and 100 group A streptococci of differing β-lactam, macrolide, and quinolone resistance phenotypes, AR-709 was very active, with all MICs being ≤2 μg/ml. Furthermore, AR-709 was active against strains that were both susceptible and resistant to trimethoprim-sulfamethoxazole.

01 Mar 2008·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

In Vitro Activity of AR-709 against Streptococcus pneumoniae

Q2 · MEDICINE

Article

Author: Jansen, W. T. M. ; Verhoef, J. ; Milatovic, D. ; Verel, A.

ABSTRACT We investigated the in vitro activity of AR-709, a novel diaminopyrimidine antibiotic currently in development for treatment of community-acquired upper and lower respiratory tract infections, against 151 Streptococcus pneumoniae strains from various European countries. AR-709 showed excellent activity against both drug-susceptible and multidrug-resistant pneumococci.

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Indication	Highest Phase	Country/Location	Organization	Date
Respiratory Tract Infections	Phase 1	EU	Evolva Holding SA	-
Respiratory Tract Infections	Phase 1	EU	Evolva Holding SA	-

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