Background: Current dogma suggests optimizing AG doses based on peak concentration (Cmax), without consideration of daily drug exposure (AUC24). The correlation between attainment of the TOB pharmacokinetic-pharmacodynamic (PK-PD) targets, Cmax:MIC and AUC24:MIC ratio was explored using a TOB population PK (PPK) model, Monte Carlo simulation, and PA non-clinical 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 >1400 infected patients enrolled in clinical trials to achieve n=1000 per renal function group defined by varying creatinine clearance ranges. Variability in average TOB AUC24 and Cmin over 48 hours was assessed to determine dosing regimens that produced, for each renal group, (1) ≤50% difference in median AUC24 compared to that of normal renal function (90-120 mL/min); (2) ≤25% of simulated AUC24 values beyond the 5th and 95th percentiles of the AUC24 distribution for normal renal function; and (3) ≤20% of Cmin values >2 mg/L. Once these requirements were met across renal groups, the percentages of simulated patients achieving the Cmax:MIC target ≥10 and AUC24:MIC target for 1-log10 CFU reduction (≥83.9) at MIC values of 0.5-2 mg/L were assessed.
Results: Distributions of simulated TOB AUC24 and Cmin values by renal group are shown in Figure 1. Figures 2 and 3 depict the discordance between Cmax:MIC and AUC24:MIC target attainment for TD and EID, respectively. Of 6,000 simulated patients receiving TD, 20.0% achieved the AUC24:MIC target at an MIC = 1 mg/L without producing a Cmax:MIC ≥10, whereas 55.1% of 5,000 simulated patients receiving EID failed to achieve the AUC24:MIC target despite producing a Cmax:MIC ≥10.
Conclusion: At clinically relevant MICs, AG TD regimens optimized based on Cmax 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 to overall drug exposure, the adequacy of AG dosing should consider variability in drug clearance (AUC24) over variability in distributional volume (Cmax).
N. J. Onufrak,
J. M. Pogue, None
C. M. Rubino, None