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.

• Authors: Luning Zhuang, Yichao Yu, Xiaohui Wei, Jeffry Florian, Seong H Jang, Kellie S Reynolds, Yaning Wang
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 60 Issue 8 Pg. 1011-1021 (08 2020) ISSN: 1552-4604 [Electronic] England
• PMID: 32149406 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Published 2020. This article is a U.S. Government work and is in the public domain in the USA.

Chemical References

• Anti-Bacterial Agents
• Boronic Acids
• Drug Combinations
• Heterocyclic Compounds, 1-Ring
• meropenem and vaborbactam
• Creatinine
• Meropenem

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Anti-Bacterial Agents (administration & dosage, pharmacokinetics)
• Area Under Curve
• Boronic Acids (administration & dosage, blood, pharmacokinetics, urine)
• Clinical Trials as Topic
• Computer Simulation
• Creatinine (blood)
• Drug Administration Schedule
• Drug Combinations
• Glomerular Filtration Rate
• Heterocyclic Compounds, 1-Ring (administration & dosage, blood, pharmacokinetics, urine)
• Humans
• Infusions, Intravenous
• Kidney Failure, Chronic (metabolism, physiopathology)
• Meropenem (administration & dosage, blood, pharmacokinetics, urine)
• Middle Aged
• Models, Biological
• Renal Dialysis (adverse effects)
• Young Adult