Population pharmacokinetic analyses for sulbactam-durlobactam using Phase 1, 2, and 3 data

Sulbactam-durlobactam is a β-lactam/β-lactamase inhibitor combination approved in the United States for the treatment of hospital-acquired and ventilator-associated bacterial pneumonia caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus in adults. A population pharmacokinetic (PK) model of sulbactam-durlobactam in plasma was developed using data from eight Phase 1-3 studies. A total of 432 subjects and 8,100 plasma concentrations were available for the population PK data set. The combined model was a four-compartment (two compartments per drug) model with linear kinetics. Both renal clearance and nonrenal clearance were estimated, and total clearance was calculated as the sum of renal and nonrenal clearance. Individual renal clearances were scaled by baseline creatinine clearance. The sampling-importance-resampling analysis indicated that the parameters were estimated reliably with adequate precision. Hemodialysis (HD) and epithelial lining fluid (ELF) sub-models were developed for each analyte separately. Intermittent HD resulted in an approximately 30% decrease in the daily area under the concentration-time curve (AUC_0-24) when HD was started 1 hour after the end of the infusion. Assuming protein binding estimates of 10% and 38% for durlobactam and sulbactam, respectively, ELF penetration ratios were found to be 41.3% for durlobactam and 86.0% for sulbactam. Of the statistically significant covariates of PK identified, which included body weight, body mass index, infection type, and region of origin, renal function was the only clinically relevant covariate. Overall, a robust description of the plasma PK of sulbactam and durlobactam was achieved. The resultant population PK model was expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships.