Characterization Of Oritavancin Pharmacokinetics (Pk) In Plasma And Blister Fluid In Normal Healthy Volunteers
Background: Oritavancin is a novel glycopeptide antibiotic currently being developed for the treatment of complicated skin/skin structure infections (cSSSI), including those caused by multi-drug resistant Gram-positive pathogens. The disposition of oritavancin in skin structures was investigated using a cantharide-induced blister fluid model. Methods: 16 healthy male volunteers (8/dose group) received oritavancin 200 mg QD for three days (Grp A) or 800 mg as one single dose (Grp B). Grp A plasma, and exudates from blister samples, were collected on Days 3, 4, 7, 9, and 12, and on Days 3, 4, 7, and 9, respectively. Grp B samples were collected on Days 1, 2, 5, 7, and 10, and on Days 1, 2, 5, and 7, respectively. Drug concentration was determined using a LC/MS/MS assay and noncompartmental PK analysis was performed to generate parameter estimates for each group in both plasma and blister fluid. Differences between treatment groups in AUCblister fluid/AUCplasma ratios were evaluated using a t-test (α=0.05).
Results: Mean (SD) PK parameter estimates for plasma and blister fluid in each Grp are presented below (see table). Mean (SD) AUCblister fluid/AUCplasma ratios at 24 h were 0.190 (0.052) and 0.182 (0.062) for Grps A and B, respectively (p = 0.791). Overall, oritavancin was well tolerated.
Conclusions: To place these results in a clinical context, the oritavancin MIC90 of S. aureus is 2 μg/ml. Following administration of both dosing regimens, mean oritavancin concentrations in blister fluid exceed the MIC90 of S. aureus by approximately 2- to 5.5-fold at 12 h and 1.5- to 3-fold at 24 h. These results support the potential use of oritavancin for the treatment of cSSSI.
Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, Illinois, September 2003
By G.J. Fetterly, C. Ong, S.M. Bhavnani, J.S. Loutit, S.P. Porter, P.G. Ambrose, and D.P. Nicolau