Optimizing aminoglycoside dosing regimens for critically-ill pediatric patients with augmented renal clearance: a convergence of parametric and non-parametric population approaches.

Objective: Augmented renal clearance (ARC) can occur in critically-ill pediatric patients receiving aminoglycosides such as gentamicin and tobramycin, yet optimal dosing strategies for ARC are undefined. We evaluated the probability of achieving efficacious or toxic exposures in pediatrics.Methods: Parallel population modeling of concentration strategies were pursued using Pmetrics v1.5.2 (non-parametric) and Monolix v2019R2 (parametric). Bayesian exposures were used to classify ARC based on total CL. The effect of SCR, CRCL, TBW, post-natal age (PNA), and ARC were explored as covariates. Probabilities of target attainment (PTA) (i.e., Cmax/MIC, AUC:MIC) and of toxic exposure (PTE) (i.e., Cmin>2 mcg/mL) were calculated according to PNA and ARC.Results: 123 patients (1-21yrs, 56%female) contributed 304 concentrations. A two-compartment was superior to a one-compartment model in both approaches. Bayesian posterior predicted concentrations from the non-parametric base model fitted the data well (R2=0.96) and classified 34 patients as having ARC (28%). Both the non-parametric and parametric approaches resulted in allometrically scaling of TBW on V and CL. ARC modified CL and central V. CRCL and a maturation function modified CL. ARC was associated with a 1.49- vs. 1.66-fold increase in CL and a 1.56- vs 1.66-fold increase in the central V (non-parametric vs. parametric). High dose of 12 mg/kg/day was required to achieve adequate PTA when MIC were 1-2 mcg/mL; ARC lowered achievable MICs. When PNA< 2 years, PTE was increased.Conclusions: Aminoglycoside monotherapy should be avoided in critically-ill pediatric patients with ARC when MICs exceed 1 mcg/mL, as optimal exposures are unachievable with standard dosing.