Population cefazolin pharmacokinetics before, during and after cardiopulmonary bypass in children undergoing cardiac surgery
Pieter De Cock (1,2), Hussain Mulla (3), Karen Jacobs (2) Kim Vanderburght (2), Sarah Desmet (1), Brett McWhinney (4), Jacobus Ungerer (4), Filip De Somer (5), Annelies Moerman (6), Hugo Robays (1), Katrien Francois (5), Peter De Paepe (2)
(1) Department of Pharmacy, Ghent University Hospital, Ghent, Belgium, (2) Heymans Institute of Pharmacology, Ghent University, Ghent, Belgium, (3) Department of Pharmacy, University Hospitals of Leicester, Leicester, UK, (4) Department of Chemical Pathology, Pathology Queensland, Brisbane, Australia, (5) Department of Cardiac Surgery, Ghent University Hospital, Ghent, Belgium, (6) Department of Anaesthesiology, Ghent University Hospital, Ghent, Belgium
Objectives: Scarce data are available to guide cefazolin dosing in children undergoing cardiac surgery with cardiopulmonary bypass[1,2]. The objective of this trial is to derive a model-based dosing regimen for cefazolin in this patient population.
Methods: 56 infants and children were included (median age: 0.75 years; range:0.01-15 years) and received following intravenous dosing regimen: 25 mg/kg 30 minutes before surgical incision, just before start weaning of cardiopulmonary bypass, 8 hours after the 2nd dose and 8 hours after the 3rd dose. Blood, auricle and subcutaneous fat tissue samples were collected before, during and/or after cardiopulmonary bypass. NONMEM ®v7.2 was used for population PK modelling and covariate analysis of plasma and tissue data. Internal validation of the final model was performed using a non-parametric bootstrap and Visual Predictive Check (VPC).
Results: A two compartment model best described bound and unbound plasma concentrations. The effect of cardiopulmonary bypass was modelled using a separate compartment. The relationship between bound and unbound concentrations was described by a saturable binding model, and where plasma albumin levels was a significant covariate on maximum binding capacity (Bmax). Weight was identified as a significant covariate on all plasma and tissue clearance and volume parameters using allometric scaling. Implementation of estimated Glomerular Filtration Rate (eGFR) as a covariate on plasma clearance further improved the model.
Conclusions: The proposed model adequately describes cefazolin plasma and tissue pharmacokinetics in infants and children undergoing cardiac surgery with cardiopulmonary bypass. In a next step, Monte Carlo simulations will be performed to optimize dosing in this vulnerable patient population.
References:
[1] Himebauch AS et al. Skeletal muscle and plasma concentrations of cefazolin during cardiac surgery in infants. J Thorac Cardiovasc Surg 2014;148(6):2634-41
[2] Haessler D et al. Antibiotic prophylaxis with cefazolin and gentamicin in cardiac surgery for children less then ten kilograms. J Cardiothorac Vasc Anesth 2003;17(2):221-5.