Population pharmacokinetics of total and free ceftriaxone in critically ill and non-critically ill hospitalised adult patients

• First description of ceftriaxone pharmacokinetics in a Southeast Asian population • Renal function is the primary determinant of ceftriaxone pharmacokinetics • Standard once-daily dosing was sub-optimal in normal or augmented renal clearance • 1 g q24H for ≤60 mL/min/1.73 m 2 and 1 g q12H for >60 mL/min/1.73 m 2 is recommended To characterise the population pharmacokinetics of total and free ceftriaxone in critically ill and non-critically ill Indonesian patients, define optimised dosing regimens against common hospital pathogens implicated in severe pneumonia and complicated urinary tract infections (UTI), and compare these findings with published data to support broader applicability. This study recruited critically ill and non-critically ill adults receiving intravenous ceftriaxone. Serial plasma samples were collected over one dosing interval. Total and free ceftriaxone concentrations were measured using a validated UHPLC-MS/MS method. Population pharmacokinetic analysis was performed using Monolix. Dosing simulations were performed to assess the probability of efficacy (100%fT>MIC for a given MIC) and toxicity risk (total trough concentration >100 mg/L) on days 1 and 3 of therapy. Fractional target attainment was evaluated using EUCAST MIC distributions for common pathogens implicated in severe pneumonia and complicated UTI. Fifty-three patients were recruited (median age, 57 years [IQR 39-65]; median eGFR CKD-EPI 67 mL/min/1.73 m 2 [31.4-92.3]; 26 males; 42% ICU). A two-compartment model with complex protein binding best described the data with eGFR CKD-EPI as the primary determinant of clearance. Once-daily intermittent infusion regimens (1 and 2 g every 24 hours) failed to achieve optimal efficacy targets in patients with preserved or augmented renal function (eGFR CKD-EPI ≥60 mL/min/1.73 m 2 ). A simplified renal function-stratified dosing strategy provided the best balance between safety and efficacy for empirical treatment; 1 g every 24 hours for patients with eGFR CKD-EPI ≤60 mL/min/1.73 m 2 and 1 g every 12 hours for patients with eGFR CKD-EPI >60 mL/min/1.73 m 2 .