Abstract
BACKGROUND: Current dogma suggests optimizing AG doses based on peak concentration (C(max)), without consideration of daily drug exposure (AUC(24)). The correlation between attainment of the TOB pharmacokinetic-pharmacodynamic (PK-PD) targets, C(max):MIC and AUC(24):MIC ratio was explored using a TOB population PK (PPK) model, Monte Carlo simulation, and PA nonclinical PK-PD data. METHODS: Simulated TOB plasma concentration-time profiles for traditional (TD) and extended interval (EID) dosing regimens were generated using a published PPK model [Aarons. Br J Clin Pharmacol 1989;28:305–14]. Simulations were performed by bootstrapping from a database of >1,400 infected patients enrolled in clinical trials to achieve n = 1,000 per renal function group defined by varying creatinine clearance ranges. Variability in average TOB AUC(24) and C(min) over 48 hours was assessed to determine dosing regimens that produced, for each renal group, (1) ≤50% difference in median AUC(24) compared with that of normal renal function (90–120 mL/minute); (2) ≤25% of simulated AUC(24) values beyond the fifth and 95(th) percentiles of the AUC(24) distribution for normal renal function; and (3) ≤20% of C(min) values >2 mg/L. Once these requirements were met across renal groups, the percentages of simulated patients achieving the C(max):MIC target ≥10 and AUC(24):MIC target for 1-log(10)CFU reduction (≥83.9) at MIC values of 0.5–2 mg/L were assessed. RESULTS: Distributions of simulated TOB AUC(24) and C(min) values by renal group are shown in Figure 1. Figures 2 and 3 depict the discordance between C(max):MIC and AUC(24):MIC target attainment for TD and EID, respectively. Of 6,000 simulated patients receiving TD, 20.0% achieved the AUC(24):MIC target at an MIC = 1 mg/L without producing a C(max):MIC ≥10, whereas 55.1% of 5,000 simulated patients receiving EID failed to achieve the AUC(24):MIC target despite producing a C(max):MIC ≥10. CONCLUSION: At clinically relevant MICs, AG TD regimens optimized based on C(max) may result in patients receiving higher than necessary doses, while EID regimens may lead to underdosing. Given the transient nature of a peak concentration compared with overall drug exposure, the adequacy of AG dosing should consider variability in drug clearance (AUC(24)) over variability in distributional volume (C(max)). DISCLOSURES: All authors: No reported disclosures.