Optimal Piperacillin/Tazobactam Dosing in Adults with Low Body Weight: A Population Pharmacokinetic and Simulation-Based Study.

BACKGROUND

Pharmacokinetic (PK) evidence for optimal piperacillin/tazobactam (TZP) dosing in adults with low body weight (LBW) is limited, and current dosing strategies are typically extrapolated from general populations. Physiological alterations associated with LBW including reduced muscle mass, altered body water distribution and potential for impaired renal function may affect drug exposure, increasing the risk of subtherapeutic treatment or toxicity. This study developed a population PK model of TZP in adults with LBW, and dosing strategies in this population were evaluated on the basis of efficacy and neurotoxicity considerations.

METHODS

Adults with a body mass index ≤ 18.5 kg/m2 receiving TZP were enrolled in a prospective observational study. Plasma piperacillin concentrations obtained during therapeutic drug monitoring were analyzed through nonlinear mixed-effects modeling. Structural models and covariates, particularly estimated renal function, were evaluated. Monte Carlo simulations were performed to assess the probability a patient would achieve the PK/PD target of 100% time above the minimum inhibitory concentration (100% fT > MIC). To evaluate safety, the probability that piperacillin would exceed a trough concentration of 361 mg/L associated with drug-related neurotoxicity was assessed.

RESULTS

This study included 29 patients (55 samples). A one compartment model adequately described piperacillin PK, and renal function estimated according to the 2021 CKD-EPI creatinine-cystatin C equation best explained piperacillin clearance. Body weight did not significantly improve model performance. The estimated typical values were 4.89 L/hr [relative standard error (RSE) 19.0%] for clearance and 11.95 L (RSE 36.5%) for volume of distribution, with an eGFR exponent of 1.12 on clearance. In addition, simulations indicated that prolonged infusion and increased dosing frequency improved target attainment, particularly at higher MICs and in patients with preserved or augmented renal clearance. Conversely, patients with renal dysfunction achieved PK/PD targets at lower dosing regimens and exhibited a reduced likelihood of exceeding the neurotoxicity threshold.

CONCLUSION

In adults with LBW, renal function and PK/PD principles should guide TZP dosing. Model-informed strategies to optimize infusion duration and dosing frequency may improve efficacy and limit neurotoxicity.