Pharmacokinetics of alafosfalin, alone and in combination with cephalexin, in humans.

Alafosfalin is a phosphonodipeptide with significant activity as an antibacterial agent and as a potentiator of beta-lactam antibiotics. Studies in humans showed that oral doses of 50 to 2,500 mg were well absorbed, but some metabolic hydrolysis occurred before the drug reached the general circulation. Oral bioavailability was approximately 50% and was largely independent of dose. Alafosfalin has an elimination half-life of about 60 min and does not accumulate during chronic administration. Healthy volunteers excreted intact phosphonodipeptide in the urine. The recovery was dose dependent and increase from 6 +/- 1% after 50-mg doses to 17 +/- 1% after 2,500-mg doses. This change with dose occurred because the human kidney has a small, saturable capacity for reabsorbing the phosphonopeptide. Less alafosfalin was excreted in the urine of subjects with impaired glomerular function. When alafosfalin was coadministered with cephalexin, both compounds wer absorbed, distributed, and eliminated at virtually identical rates. Oral administration of 500 mg of the phosphonodipeptide plus 250 mg of the beta-lactam antibiotic gave approximately equal concentrations of the drugs in plasma, with a fourfold excess of cephalexin in the urine. This 2:1 combination is being tested in the clinic.