Estimation of cefepime, piperacillin, and tazobactam clearance with iohexol-based glomerular filtration rate in paediatric patients

• Published in: European journal of clinical pharmacology 2022-06, Vol.78 (6), p.989-1001
• Main Authors: Soeorg, Hiie, Noortoots, Aveli, Karu, Maarja, Saks, Kadri, Lass, Jana, Lutsar, Irja, Kõrgvee, Lenne-Triin
• Format: Article
• Language: English
• Subjects: Adolescent; Age; Biomedical and Life Sciences; Biomedicine; Cefepime; Child; Creatinine; Cystatin C; Epidermal growth factor receptors; Glomerular Filtration Rate; Humans; Iohexol - pharmacokinetics; Kidney Function Tests; Neurotoxicity; Patients; Pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology/Toxicology; Piperacillin; Renal function; Tazobactam; Young Adult; Young adults
• ISSN: 0031-6970; 1432-1041
• DOI: 10.1007/s00228-022-03307-0

Purpose Estimated glomerular filtration rate (eGFR) equations reflect kidney function imprecisely. We aimed to describe whether iohexol-based GFR or eGFRs predict clearance of cefepime, piperacillin, and tazobactam in pharmacokinetic (PK) models in this population and its clinical significance. Methods Hospitalized patients (0.5–25 years) with haemato-oncological disease and infection receiving cefepime or piperacillin/tazobactam were included. PK samples were collected at a steady state concomitantly with samples for iohexol-based GFR. PK models were developed in NONMEM. Weight, postmenstrual age, iohexol-based GFR, different eGFR equations (Schwartz updated, Lund-Malmö revised, CKD-EPI, Bouvet, Schwartz cystatin C-based) were tested as covariates. Probabilities of neurotoxic/therapeutic concentrations were assessed by simulations. Results Fifteen patients receiving cefepime and 17 piperacillin/tazobactam were included (median (range) age 16.2 (1.9–26.0) and 10.5 (0.8–25.6) years, iohexol-based GFR 102 (68–140) and 116 (74–137) mL/min/1.73 m 2 , respectively). Two-compartment model provided the best fit for all drugs. Weight was covariate for central and peripheral compartment, clearance and intercompartmental clearance (only tazobactam), and postmenstrual age for clearance (excluding cefepime). Iohexol-based GFR was the best predictor of clearance. The model of cefepime without vs with iohexol-based GFR underestimated the probability of neurotoxic concentrations (28.3–28.6% vs 52.1–69.3%) and overestimated the probability of therapeutic concentrations (> 90% vs 81.9–87.1%) in the case of iohexol-based GFR 70–80 and 130–140 mL/min/1.73 m 2 , respectively. Conclusion Iohexol-based GFR can predict better than eGFRs the clearance of cefepime, piperacillin, and tazobactam in children and young adults with haemato-oncological disease and infection, warranting further investigation as an indicator of renal function to improve targeting of therapeutic window. Trial registration number and date of registration EudraCT 2015–000,631-32, EudraCT 2016–003,374-40 (24.10.2016).