Evaluation of Hemodialysis Effect on Pharmacokinetics of Meropenem/Vaborbactam in End‐Stage Renal Disease Patients Using Modeling and Simulation

Abstract

The objectives of this study were to evaluate the effect of hemodialysis (HD) on the pharmacokinetics (PK) of meropenem/vaborbactam, an approved beta‐lactam/beta‐lactamase inhibitor combination, and provide the rationale for the recommended timing of meropenem/vaborbactam administration relative to HD in end‐stage renal disease (ESRD) patients. Population PK models were developed separately for meropenem and vaborbactam in subjects with normal renal function and different degrees of renal impairment, including those receiving HD. Simulations were performed to evaluate the exposure of meropenem and vaborbactam in ESRD patients who received a fixed dose of 0.5 g/0.5 g meropenem/vaborbactam every 12 hours as a 3‐hour intravenous infusion under various drug administration schedules relative to HD. The probability of target attainment (PTA) analyses were conducted with pharmacokinetic/pharmacodynamic (PK/PD) targets of meropenem and vaborbactam. Simulations showed that HD reduces the accumulation of vaborbactam, but the exposure of vaborbactam is still above the PK/PD target regardless of whether meropenem/vaborbactam is administered predialysis or postdialysis. For meropenem, drug infusion completed right prior to initiation of HD may substantially reduce exposure leading to poor PTA results. In contrast, drug infusion completed at least 2 hours prior to initiation of HD is not predicted to result in efficacy loss based on PTA analysis. The results of simulation indicate that meropenem/vaborbactam infusion completed at least 2 hours prior to initiation of HD or administered immediately after the end of HD can avoid potential efficacy loss in ESRD patients.

Pharmacokinetics of Non-β-Lactam β-Lactamase Inhibitors

“…It is worth noting that the pharmacokinetics of BLIs in patients with severely compromised renal function may be altered by the presence of hemodialysis (HD) that can remove nearly half a dose of AVI and VAB [79,[84][85][86]. In particular, the mean increase in systemic CL of VAB was 5.11-fold during HD [79], while median predicted values of HD CL for VAB and MER did not significantly differ (7.9 and 5.68 L/h, respectively) [87]. ESRD patients receiving DUR showed similar findings [81].…”

Pharmacokinetic/Pharmacodynamic Adequacy of Novel β-Lactam/β-Lactamase Inhibitors against Gram-Negative Bacterial in Critically Ill Patients

“…The PK/PD targets for ceftazidime, ceftolozane and meropenem were 50% f T > MIC, 40% f T > MIC, and 45% f T > MIC, respectively [ 13 , 32 , 33 ]. The PK/PD targets of the three antibacterial agents should be increased to 70% f T > MIC and 100% f T > MIC in critically ill patients [ 34 ].…”

“…The PK/PD target of vaborbactam was f AUC 24 /MIC > 9 [ 35 ]. The free drug fractions used in these simulations were 85%, 92%, 98%, and 67% for ceftazidime, avibactam, meropenem, and vaborbactam, respectively [ 33 , 36 ]. Notably, the original PK parameter of ceftolozane and tazobactam were obtained from unbound concentrations, and their PK data were used directly for analysis in this study [ 28 ].…”

Microbiological, Clinical, and PK/PD Features of the New Anti-Gram-Negative Antibiotics: β-Lactam/β-Lactamase Inhibitors in Combination and Cefiderocol—An All-Inclusive Guide for Clinicians

“…CrCl ≥90 mL/min: 1.25 g q 6 h CrCl 60-89 mL/min: 1 g q 6 h CrCl 30-59 mL/min: 0.75 g q 6 h CrCl 15-29 mL/min: 0.5 g q 6 h CrCl <15 mL/min: 0.5 g q 6 h yes [32,45,46] meropenem/ vaborbactam cUTI: 4 g q 8 h (5-14 days) CrCl ≥50 mL/min: 4 g q 8 h CrCl 30-49 mL/min: 2 g q 8 h CrCl 15-29 mL/min: 2 g q 12 h CrCl <15 mL/min: 1 g q 12 h yes [37,[47][48][49][50] meropenem/nacubactam Not available…”