Phase 1 Study Assessing the Pharmacokinetic Profile and Safety of Avibactam in Patients With Renal Impairment

Abstract

Avibactam is a non-β-lactam β-lactamase inhibitor intended for use as a fixed-dose combination with ceftazidime for the treatment of certain serious Gram-negative infections. As avibactam is primarily excreted unchanged in the urine, renal impairment may affect its pharmacokinetics. This phase 1 study investigated the effect of renal impairment and hemodialysis on avibactam pharmacokinetics and safety. Healthy controls and subjects with increasing degrees of renal impairment received a single 30-minute intravenous (IV) infusion of avibactam (100 mg). Anuric subjects requiring hemodialysis received the same infusion pre- and posthemodialysis, separated by a 7- to 14-day washout. Blood and urine samples were collected, and pharmacokinetics were analyzed using noncompartmental methods. The relationships between avibactam total plasma clearance (CL) or renal clearance (CL ) and creatinine clearance (CrCL) were evaluated by linear correlation analysis. Safety was also monitored. Increasing severity of renal impairment was associated with decreasing CL and CL and increasing exposure and terminal half-life (t ). Avibactam CL and CL demonstrated an approximately linear relationship with CrCL comparable to that previously observed for ceftazidime. In patients requiring hemodialysis, >50% of the administered avibactam was removed during a 4-hour hemodialysis session, demonstrating that avibactam should be administered after hemodialysis. No new safety findings were reported. To conclude, avibactam dose adjustment is warranted in patients with renal impairment based on the severity of impairment. Because the slope of the linear relationship between avibactam total plasma CL and CrCL is similar to that of ceftazidime, renal impairment dose adjustments should maintain the currently advised 4:1 ratio of ceftazidime:avibactam.

Pharmacokinetics, Safety, and Tolerability of Intravenous Durlobactam and Sulbactam in Subjects with Renal Impairment and Healthy Matched Control Subjects

“…The observation of increasing RI resulting in increased systemic exposure to durlobactam and sulbactam has also been observed with other BLIs (19–21), as well as with sulbactam (17, 18), and is likely associated with significant renal elimination of these compounds. In addition, the effect of RI on PK parameter for sulbactam among subjects in this study was similar to results from previous studies of sulbactam (17, 18).…”

Selecting the dosage of ceftazidime–avibactam in the perfect storm of nosocomial pneumonia

“…The use of population PK models based on patients with cIAI was considered appropriate for dosage selection in NP, as the PK profile of ceftazidime alone was previously shown to be comparable across cIAI and NP patient populations [71,72]. We assumed that the same would be true for avibactam, given the generally similar PK profiles of the two compounds [73].…”

Estimating Renal Function in Drug Development: Time to Take the Fork in the Road

“…Subjects were enrolled in the dedicated renal impairment PK studies using the C-G equation for CZA, the MDRD equation for DLX, and a hybrid approach for M/V. 19,21,22 The hybrid approach used in the phase 1 study of M/V enrolled subjects in the healthy control group using the C-G equation (eCrCL > 90 mL/min) and the renal impairment groups via the MDRD equation (eGFR < 90 mL/min/1.73 m 2 ) to account for the limitations of the MDRD equation at near-normal values of eGFR. 22 Interestingly, despite the dedicated renal PK studies of both DLX and M/V used the MDRD equation to define renal impairment, exclusions and dose adjustments for renal dysfunction in their phase 2 and 3 trials were based on eCrCL rather than eGFR (Figure 1).…”