Physiologically-based pharmacokinetic modelling and dosing evaluation of gentamicin in neonates using PhysPK

Abstract

Each year, infections caused around the 25% of neonatal deaths. Early empirical treatments help to reduce this mortality, although optimized dosing regimens are still lacking. The aims were to develop and validate a gentamicin physiologically-based pharmacokinetic (PBPK) model and then potentially explore dosing regimens in neonates using pharmacokinetic and pharmacodynamic criteria. The PBPK model developed consisted of 2 flow-limited tissues: kidney and other tissues. It has been implemented on a new tool called PhysPK, which allows structure reusability and evolution as predictive engine in Model-Informed Precision Dosing (MIPD). Retrospective pharmacokinetic information based on serum levels data from 47 neonates with gestational age between 32 and 39 weeks and younger than one-week postnatal age were used for model validation. The minimal PBPK model developed adequately described the gentamicin serum concentration-time profile with an average fold error nearly 1. Extended interval gentamicin dosing regimens (6 mg/kg q36h and 6 mg/kg q48h for term and preterm neonates, respectively) showed efficacy higher than 99% with toxicity lower than 10% through Monte Carlo simulation evaluations. The gentamicin minimal PBPK model developed in PhysPK from literature information, and validated in preterm and term neonates, presents adequate predictive performance and could be useful for MIPD strategies in neonates.

Keywords: PBPK; PhysPK software; TDM; dosing evaluation; gentamicin; neonates.

FIGURE 1

Schematic diagram of the minimal PBPK model developed in PhysPK. Black solid circles are Boolean components for activation/deactivation of processes (i.e., dose administration); pink and blue solid circles, are recording components of the system (i.e., drug concentration in a specific region of the system such as plasma, tissue, etc.,). Organ with an E inside means that it has elimination. The purple T next to the syringe means that the administration has a rate and it can be multiple.

FIGURE 2

Visual Predicted Check (VPC) in preterm (left) and term (right) neonates. Dotted lines represent, from the bottom to the upper panel, the 10th, 25th, 75th, and 90th percentiles of the gentamicin concentrations simulated vs. time. Shaded areas represent, from outside to inside, the 90% and 50% prediction intervals. Solid lines represent the median gentamicin simulated concentration-time profile. Open blue circles represent the observed gentamicin concentrations dose-normalized.

FIGURE 3

Probability of target attainment (PTA) to reach the C_max/MIC ≥8 ratio for each gentamicin dosage regimen: conventional (4 mg/kg q24h) and extended interval regimen (6 mg/kg q48h and 6 mg/kg q36h for preterm and term, respectively).