Cefazolin population pharmacokinetics in children undergoing maintenance hemodialysis for kidney failure

We aimed to develop a population pharmacokinetic model of cefazolin in children undergoing maintenance hemodialysis for kidney failure and simulate dosing regimens to optimize patients' exposure. Cefazolin plasma concentrations were quantified using high-performance liquid chromatography. A non-linear mixed-effect modeling approach was used to investigate cefazolin pharmacokinetics. Optimal dosing regimens were determined using Monte Carlo simulations targeting 100% of the time a free plasma concentration four times above the minimum inhibitory concentration (MIC) and total plasma concentration less than 80 mg/L (100% fT > 4 × MIC and C < 80 mg/L). Eighty-three samples were analyzed from six patients aged 1.3-14.6 years and weighing 11.4-51 kg. A one-compartment model with first-order elimination best fitted the data, with a significant between-subject variability (BSV). Body weight (BW), using the allometric rule, was a significant predictor of residual elimination clearance (CL) and volume of distribution (Vd), while dialysis membrane surface area (DMSA) explained almost all the BSV on dialysis clearance (CLdial). The parameter relationships were Vd_i(L) = 14.6 × (BW_i/70), CL_i(L/h) = 0.186 × (BW_i/70)^0.75, CLdial_i(L/h)=1.98 × (DMSA_i/1)^1.26, CLtot_i = CL_i + CLdial_DMSAi, where the subscript i denotes the i^th patient's covariate value. Dosing regimens were simulated for six CL ranges, targeting two concentration intervals: 40-80 mg/L and 20-80 mg/L for MIC of 2 and 1 mg/L, respectively. In children on maintenance hemodialysis for kidney failure, due to the persistence of a large unexplained BSV on CL that substantially affects them, optimal dosing regimen would not be accurately determined a priori and should be individually determined using therapeutic drug monitoring, taking BW, DMSA, and CL into account.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT02539407.