Use of pharmacokinetic-pharmacodynamic principles for decision support for short-course oritavancin dosing regimens for complicated skin and skin structure infections
Abstract number: O152
Rubino C.M., Bhavnani S.M., Forrest A., Okusanya O.O., Lehoux D., Drusano G.L., Rodvold K.A., Craig W.A., Parr Jr. T.R., Ambrose P.G.
Objectives: Optimal dose selection for Phase 2/3 clinical trials is critical for successful drug development. Application of pharmacokinetic-pharmacodynamic (PK-PD) principles provides a scientific basis for optimising both dose and duration of therapy. Dosing regimens for short-course therapy were evaluated for oritavancin (ORI), a novel glycopeptide currently in development for complicated skin and skin structure infections (cSSSI).
Methods: Using PK data from 20 intensively-sampled subjects who received ORI 800 mg IV Q24h x 5 days, a population PK model was developed. PK parameter estimates based on this model were used to conduct simulations to evaluate daily and cumulative free-drug plasma AUC values following front-loaded ORI regimens (i.e., the majority of the AUC is delivered on Day 1) of 800 to 1200 mg. Both single-and multiple-dose regimens were evaluated. Multiple-dose regimens involved a loading dose followed by a booster dose (400 or 800 mg) on Day 4, 5 or 6. Population PK analysis and simulations were performed using S-ADAPT 1.53. Free-drug AUC values for each regimen were assessed relative to those associated with a 1 and 2 log10 CFU decrease in S. aureus using data from a neutropenic murine-thigh infection model (Craig WA, Andres DR. ICAAC 2004, Abstr. A-1863). Single-dose free-drug AUC values in mice corresponding to a 1 and 2 log10 CFU decrease were 61 and 159, respectively. Free-drug AUC values were also assessed relative to those successfully studied for previous cSSSI studies (200 mg Q24h X 37 days) and S. aureus MIC population statistics.
Results: A 3-compartment model with zero-order input and linear clearance best described the PK data. Plasma concentrations were well fit by the model (r2 = 0.966). ORI 1200 mg X 1 dose or 800 mg on Day 1 followed by 400 mg on Day 5 provided mean cumulative free-drug AUC values which exceeded non-clinical free-drug AUC targets and which were similar to those values for the previously studied 37 day 200 mg Q24h regimen (see Table).
Discussion/Conclusion: The approach to support selection of short-course dosing regimens described herein is especially useful for agents such as ORI, which display a concentration-dependent pattern of bactericidal activity and a long half-life. It is predicted that front-loaded ORI regimens will result in improved response rates for patients with cSSSI relative to those regimens previously studied. These data were used to support dose selection for a Phase 2 cSSSI study.
|Session name:||18th European Congress of Clinical Microbiology and Infectious Diseases|
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