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

Autor:	Zazo H; Pharmaceutical Sciences Department, University of Salamanca, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Lagarejos E; Pharmaceutical Sciences Department, University of Salamanca, Salamanca, Spain., Prado-Velasco M; Multiscale Modelling in Bioengineering Research Group and Department of Graphic Engineering, University of Seville, Seville, Spain., Sánchez-Herrero S; Simulation Department, Empresarios Agrupados Internacional S.A., Madrid, Spain., Serna J; Simulation Department, Empresarios Agrupados Internacional S.A., Madrid, Spain., Rueda-Ferreiro A; Simulation Department, Empresarios Agrupados Internacional S.A., Madrid, Spain., Martín-Suárez A; Pharmaceutical Sciences Department, University of Salamanca, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Calvo MV; Pharmaceutical Sciences Department, University of Salamanca, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Pérez-Blanco JS; Pharmaceutical Sciences Department, University of Salamanca, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain., Lanao JM; Pharmaceutical Sciences Department, University of Salamanca, Salamanca, Spain.; Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain.
Jazyk:	angličtina
Zdroj:	Frontiers in pharmacology [Front Pharmacol] 2022 Sep 28; Vol. 13, pp. 977372. Date of Electronic Publication: 2022 Sep 28 (Print Publication: 2022).
DOI:	10.3389/fphar.2022.977372
Abstrakt:	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. Competing Interests: Preliminary results of this research were presented at XIV Jornadas de modelización y simulación en biomedicina, in November 2021 in Barcelona, Spain. SS-H, JS and AR-F were employees of “Empresarios Agrupados SA” at the time the analysis was conducted. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2022 Zazo, Lagarejos, Prado-Velasco, Sánchez-Herrero, Serna, Rueda-Ferreiro, Martín-Suárez, Calvo, Pérez-Blanco and Lanao.)
Databáze:	MEDLINE
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