Population pharmacokinetic/pharmacodynamic modeling to optimize aztreonam-avibactam dose regimens for adult patients.

Abstract

Aztreonam-avibactam, a fixed-ratio (3:1) β-lactam/β-lactamase inhibitor combination, was approved in Europe in 2024 for adults with complicated intra-abdominal infection (cIAI), complicated urinary tract infection, hospital-acquired/ventilator-associated pneumonia, and other infections due to aerobic gram-negative organisms with limited treatment options. Pharmacokinetic data from two phase 3 trials were added to previous data to develop a simultaneous aztreonam and avibactam population pharmacokinetic model. The final model was used to simulate exposures by infection type and renal function and estimate the joint probability of pharmacodynamic target attainment (PTA) for phase 3 patients (aztreonam 60% fT >MIC_ATM-AVI of 8 mg/L and avibactam 50% fT >C_T of 2.5 mg/L). Additional simulations evaluated simplified loading doses, regimens for end-stage renal disease, and ceftazidime-avibactam + aztreonam regimens. The final model included 4,914 aztreonam plasma samples (431 subjects) and 18,222 avibactam plasma samples (2,635 subjects). A two-compartment model with zero-order infusion and first-order elimination best fit the data. Time-varying creatinine clearance was a key covariate on clearance for both drugs, whereas infection type was a key covariate on clearance and volume, with the lowest exposures observed in patients with cIAI. Final aztreonam-avibactam dose regimens achieved joint PTA 89% to >99% at steady state across renal function groups. Ceftazidime-avibactam + aztreonam dose regimens proposed by the Infectious Diseases Society of America (IDSA) achieved joint PTA <85% due to insufficient avibactam exposures. Approved aztreonam-avibactam dose regimens (single loading dose and regular maintenance doses, all 3 h intravenous infusions) are optimized for joint PTA across renal function groups and infection types.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT03329092 and NCT03580044.