A microdose study of (14)C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung.

European journal of clinical pharmacology

PubMedID: 23739997

Lappin G, Boyce MJ, Matzow T, Lociuro S, Seymour M, Warrington SJ. A microdose study of (14)C-AR-709 in healthy men: pharmacokinetics, absolute bioavailability and concentrations in key compartments of the lung. Eur J Clin Pharmacol. 2013;69(9):1673-82.
PURPOSE
To 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.

METHODS
Four healthy men each received two single, 100 µg microdoses of (14)C-AR-709, 7 days apart: the first was administered intravenously (IV), the second orally. Plasma pharmacokinetics of (14)C 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 (14)C-AR-709 IV. Plasma, bronchoalveolar lavage fluid, alveolar macrophages and bronchial mucosal biopsy samples were analysed by AMS.

RESULTS
After 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, (14)C concentrations in lung samples were 15- (bronchial mucosa) to 200- (alveolar macrophages) fold higher than in plasma. In alveolar macrophages, (14)C was still mostly associated with AR-709 at 12 h after dosing.

CONCLUSIONS
The 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.