Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for phase IIa and phase III evaluation

Purpose: A series of iterative population pharmacokinetic (PK) modelling and probability of target attainment (PTA) analyses were undertaken to support dose optimization for aztreonam-avibactam, a combination antibiotic. Methods: Joint PTA analyses (primary target: 60% f T>8 mg/L for aztreonam, 50% f T>2.5 mg/L for avibactam) explored the impact of patient variability, and evaluated loading doses and extended infusions, and adjustments for patients with moderate (estimated creatinine clearance [CrCL] >30 to ≤50 mL/min) and severe renal impairment (>15 to ≤30 mL/min). Achievement of >90% joint PTA, and the impact of differential renal clearance, were considerations in dose selection. Results: Dose selection for phase I and phase IIa (Cohort 1) was based on PK models of avibactam in patients and of aztreonam in healthy volunteers with ‘patient-like’ assumptions. Simulations demonstrated that: 3-h and continuous infusions provide comparable PTA; with patient variability, avibactam dose is the main driver of joint PTA; loading doses support more rapid joint target attainment. Aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h was selected for initial phase IIa evaluation in patients with complicated intra-abdominal infection. Later PTA analyses using expanded PK models supported an increased avibactam dose (500/167 mg loading; 1500/500 q6h maintenance) and were also used to select doses for renal impairment. Conclusion: Aztreonam-avibactam 3-h infusions administered q6h are necessary to optimize joint PTA. Aztreonam-avibactam 500/167 mg loading 30-min infusion followed by 1500/500 mg maintenance 3-h infusions q6h (for CrCL >50 mL/min) is undergoing phase III evaluation. Clinical trial registration: NCT01689207 (September 21, 2012); NCT02655419 (January 14, 2016); NCT03329092 (November 1, 2017); NCT03580044 (July 9, 2018)