Population pharmacokinetics and pharmacokineticpharmacodynamic metrics for delafloxacin
Abstract number: O519
Rubino C., Burak E., Bhavnani S., Forrest A., Ambrose P.
Objectives: To develop a population pharmacokinetic (PK) model for delafloxacin (DFX) and use that model to estimate pharmacokineticpharmacodynamic (PK-PD) indices in Phase 2 patients treated for complicated skin and skin structure infections (cSSSI).
Methods: Data from 3 Phase 1 studies (1 single dose, two multiple dose) and 1 Phase 2, cSSSI study were pooled to develop a population pharmacokinetic model. All doses were administered by IV infusion; doses ranged from 50 to 600 mg. The Phase 2 study employed doses of 300 or 450 mg BID. Intensive PK sampling was employed in all Phase 1 studies while Phase 2 patients contributed 45 samples at steady-state over one dosing interval. Population PK modeling was performed using Monte Carlo Parametric Expectation Maximization as implemented in S-ADAPT 1.5.6. Two and 3 compartment models were explored using linear and/or nonlinear elimination. Steady-state AUC and Cmax estimates were calculated using individual PK parameter estimates for Phase 2 patients and indexed to observed pathogen MICs to calculate PK-PD indices. Previous animal studies have indicated that free-drug AUC:MIC ratios (fAUC:MIC) of 9.3 and 14.3 are associated with net bacterial stasis and 1-log10 CFU reduction, respectively, for Staphylococcus aureus.
Results: The final analysis dataset included 103 subjects (86 from Phase 1, 17 from Phase 2) and 2273 plasma concentrations. A 2 compartment model with a mix of linear and nonlinear elimination provided the most robust fit to the data (r2 = 0.965, observed=1.02*fitted 0.032). All parameters were estimated with excellent precision; inter-individual variability in the parameters that define clearance (linear clearance, intrinsic clearance, and Michaelis-Menten constant) ranged from 2470%. Twelve patients had requisite MIC data to calculate a PK-PD index, all fAUCss:MIC estimates were above 100 (range: 1083754); all 12 patients were classified as clinical and microbiological cures. The median (min max) fCmax:MIC ratio was 191 (18.8565). Seven patients had MRSA as their primary pathogen; MIC values were universally low (0.0040.06).
Conclusions: Development of a population PK model allowed for the estimation of drug exposure in a Phase 2 cSSSI study using relatively sparse PK sampling. Based on PK-PD indices from the Phase 2 study, 300 and 450 mg (BID) clinical doses were appropriate for the treatment of cSSSI. Results also support coverage of MIC values up to 1.0 mcg/mL.
|Session name:||Abstracts 20th European Congress of Clinical Microbiology and Infectious Diseases|
|Location:||Vienna, Austria, 10 - 13 April 2010|
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