Phosphonopeptides as antibacterial agents: metabolism and pharmacokinetics of alafosfalin in animals and humans.

The metabolism and pharmacokinetics of a synthetic antibacterial phosphonodipeptide, alafosfalin, have been studied in rats, baboons, and human volunteers. The compound was rapidly absorbed from the injection site after subcutaneous and intramuscular administration and gave peak plasma concentrations at 15 to 20 min after dosing. Distribution studies showed that high drug concentrations were produced in inflammatory exudates and most tissues except brain. Alafosfalin was rapidly cleared from the general circulation, mainly by the kidney. Plasma half-lives were 20 min in rats and approximately 1 h in baboons and humans. Alafosfalin was well absorbed after oral administration, but was extensively hydrolyzed to alanine and L-1-aminoethylphosphonic acid before it reached the general circulation. This first-pass metabolism was less marked in humans than in animals. Administration of 200-mg intramuscular and 500-mg oral doses produced concentrations of intact phosphonodipeptide in human plasma and urine which were in excess of the in vitro minimal inhibitory concentrations for many pathogenic organisms. The rate of absorption and elimination of alafosfalin in humans were also very similar to published data on beta-lactam antibiotics. This suggests that the pharmacokinetics can be matched to provide synergistic combinations for clinical use.