A Comprehensive Physiologically Based Pharmacokinetic Framework of Ofloxacin: Predicting Disposition in Renal Impairment.

Abstract

Background: In the last several years, "physiologically based pharmacokinetic (PBPK) modeling" has gathered significant emphasis in the modeling of drug absorption, disposition, and metabolism. This research study aims to elaborate the plasma/serum concentration-time profiles and pharmacokinetics (PK) of ofloxacin by establishing a PBPK model in healthy subjects and those suffering from renal impairment (RI). Methods: A comprehensive literature analysis was conducted to screen out all the systemic PK profiles and parameters specific to ofloxacin, followed by their implementation in PK-Sim^® version 12 software. This model-driven approach begins by developing the model in healthy populations using both intravenous (IV) and per-oral (PO) routes and then extrapolating it to the diseased population. The model evaluation was then strengthened for different PK variables such as the maximal plasma/serum concentration (C_max), the area under the curve from 0 to t (AUC_0-t), and plasma/serum clearance (CL) by employing various metrics such as predicted/observed ratios (R_pre/obs), visual predictive checks, the average fold error (AFE), root mean squared error (RMSE), and mean absolute error (MAE). Results: The AFE, RSME, and MAE for C_max in RI were 1.10, 0.22, and 0.16, respectively, which fell within the acceptable simulated error range. Furthermore, dosage adjustments for individuals with mild, moderate, and severe RI were presented by box-whisker plots to compare their systemic exposure with that of the healthy population. Conclusions: These model predictions have confirmed the PK variations in ofloxacin, which may assist the clinicians in optimizing dosage schedules in healthy and various categories of RI populations.