Single-Center Evaluation of the Pharmacokinetics of WCK 5222 (Cefepime-Zidebactam Combination) in Subjects with Renal Impairment [Pharmacology]

WCK 5222 is a novel β-lactam-β-lactam enhancer combination of cefepime (FEP) and zidebactam (ZID). ZID is a novel β-lactam enhancer with a dual action of binding to Gram-negative PBP2 and β-lactamase inhibition. WCK 5222 is being developed as a new therapeutic option for the treatment of complicated multidrug-resistant Gram-negative pathogens. We investigated the effect of renal impairment on the pharmacokinetics (PK) and safety of WCK 5222 in forty-eight subjects based on Cockcroft-Gault-estimated creatinine clearance (CLCR). We enrolled mild (n = 6; CLCR 60 to < 90 mL/min), moderate (n = 6; CLCR 30 to < 60 mL/min), severe (n = 6; CLCR < 30 mL/min; not on dialysis), end-stage renal disease (ESRD) on hemodialysis (HD) (n = 6), and matched normal controls (n = 24; CLCR ≥ 90 mL/min). Healthy control subjects, mild and moderate renal impairment subjects received a single 60-min IV infusion of 3 g WCK 5222 (2 g FEP/1 g ZID); severe renal impairment and HD subjects received a single 60-min IV infusion of WCK 5222, 1.5 g (1 g FEP/0.5 g ZID). Body and renal clearance decreased and plasma half-life (T_1/2) and AUC_0- (hr*µg/mL) increased in a graded relationship with severity of renal impairment for both FEP and ZID. Our findings suggest that dose adjustments for WCK 5222 will be required according to the degree of renal impairment. Overall, WCK 5222 (FEP-ZID) was found to be safe and well tolerated in subjects with normal and impaired renal function.

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