Abstract Background The fixed-dose combination of aztreonam/avibactam is administered with a loading dose (LD), resulting in systematic drug wastage in patients with preserved renal function. Whether the LD can be reduced remains unclear. Objectives To evaluate in silico the pharmacokinetic (PK) and pharmacodynamic (PD) consequences of reducing the current LD in patients with normal renal function, using a population PK model and Monte Carlo simulations. Methods A published two-compartment population PK model was implemented. We performed 10 000 Monte Carlo simulations of virtual patients with normal renal function (creatinine clearance > 80 mL/min), receiving the standard LD (2 g/0.67 g over 3 h) or a reduced LD (1.5 g/0.5 g over 3 h), followed by standard maintenance doses every 6 h. PK metrics (C0, AUC) and probability of target attainment were compared between the two regimens. Results Reducing the LD decreased early exposure (AUC0–24 h) from 1281 ± 497 to 1200 ± 464 mg h/L for aztreonam and from 276 ± 118 to 258 ± 110 mg h/L for avibactam, but steady-state AUC24–48 h was identical between regimens. PTA differences for intermediate PD thresholds were modest and transient. Conclusions Lowering the LD in patients with preserved renal function had only a short-lived impact on early exposure and did not compromise PK/PD performance. These results support dose adaptation to reduce unnecessary drug waste.