GarcÃa-Orueta, Gastón (1); F Trocóniz, Iñaki (1,2,3); Butragueño-Laiseca, Laura (4,5,6,7); Santiago, MarÃa José (4,5,6,7); Riva, Natalia (1,2)
(1) Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain. (2) Navarra Institute for Health Research (IdiSNA), Pamplona, Spain. (3) Institute of Data Science and Artificial Intelligence, DATAI, University of Navarra, Pamplona, Spain. (4) Pediatric Intensive Care Unit, Hospital General Universitario Gregorio Marañón, Madrid, Spain; (5) Gregorio Marañón Health Research Institute (IISGM), Madrid, Spain; (6) Pediatrics Department, Universidad Complutense de Madrid, Spain; (7) Maternal and Child Health and Development Research Network (REDSAMID), Institute of Health Carlos III, Madrid, Spain
Introduction: Pediatric patients undergoing continuous kidney replacement therapy (CKRT) in intensive care units (ICUs) may suffer from infections caused by Gram-positives, in which teicoplanin has shown efficacy [1]. It is important to achieve therapeutic concentrations to ensure efficacy and avoid antibiotic resistance. Therapeutic target often consists of a trough concentration of 10 mg/L [2], although some recent studies propose that efficacy can also be determined by the AUC0-24/MIC ratio, where a value of >800 h is optimal [3]. Dosing of teicoplanin in this special patient population has not been well established yet.
Objectives: The aim of this study is to develop a pharmacokinetic (PK) model to optimize teicoplanin dosing in children, including those receiving CKRT.
Methods: Data from 26 children between 3 months and 13 years old were collected with CKRT (n=12) and without CKRT (n=15), with one patient switching during the treatment. Data were available from 127 administrations and consisted of 72, 51 and 50 concentration levels measured in plasma, pre-filter and post-filter fluids, respectively. The current standard dosing regimen was administered, consisting of three loading doses of 10 mg/kg of teicoplanin administered as continuous intravenous infusion during 5 minutes every 12 h, increasing the dosing interval to 24 h for the maintenance doses [4]. In the case of patients undergoing hemofiltration, doses were reduced to 3.3 mg/kg due to their lower clearance. Data were analysed using the population analysis approach with NONMEM 7.4 . Simulations were performed to explore different dosing regimens, including the current standard dosing regimen. Both therapeutic targets were evaluated (Cmin > 10 mg/L and AUC0-24/MIC > 800 h) and probability of target attainment (%PTA) was calculated for each dosing regimen.
Results: The model that best described the pharmacokinetics of teicoplanin in the study cohort was a two-compartment model. According to this model, population estimates for total (CLT), hemofilter (CLCKRT), and distribution (Q) clearances were 0.169, 0.111, and 0.287 L/h respectively. Volumes of distribution of the central (V1) and peripheral (V2) compartments were 1.49 and 2.97 L. Weight was retained as a covariate in renal clearance and volume of distribution, while filter surface area influenced hemofilter clearance. The unexplained remaining variability in CLT, CLCKRT and V1 were 29.3, 12.9, and 42.5%, respectively. Simulations with the current standard dosing regimen showed that higher doses are necessary, as the %PTA for Cmin > 10 mg/L is 75% and for AUC24h/MIC is 26% (for a MIC of 1 mg/L).
Conclusions: The population PK characteristics of teicoplanin were described adequately for the first time in a pediatric population requiring CKRT. Model-based simulations will be performed to explore which of the possible dosing schemes is best to achieve a defined therapeutic goal. After external validation, this model may help in optimizing teicoplanin treatment for children with CKRT and without CKRT maximizing target attainment.
References:
[1] Chen J, Li S, Wang Q, Wang C, Qiu Y, Yang L, Han R, Du Q, Chen L, Dong Y, Wang T. Optimizing Antimicrobial Dosing for Critically Ill Patients with MRSA Infections: A New Paradigm for Improving Efficacy during Continuous Renal Replacement Therapy. Pharmaceutics. 2022 Apr 11;14(4):842.
[2] Zhang T, Sun D, Shu Z, Duan Z, Liu Y, Du Q, Zhang Y, Dong Y, Wang T, Hu S, Cheng H, Dong Y. Population Pharmacokinetics and Model-Based Dosing Optimization of Teicoplanin in Pediatric Patients. Front Pharmacol. 2020 Dec 8;11:594562.
[3] Choi JS, Yoon SH, Park HJ, Lee SY, Kim YJ. Optimal Use and Need for Therapeutic Drug Monitoring of Teicoplanin in Children: A Systematic Review. J Korean Med Sci. 2023 Feb 20;38(7):e62.
[4] EMC. Targocid 200 mg powder for solution for injection/infusion or oral solution. [Updated 2022]. [Accessed March 12, 2024]. https://www.medicines.org.uk/emc/product/2926/smpc .
[5] Beal SL, Sheiner LB, Boeckmann AJ, Bauer RJ. NONMEM 7.4. 3 users guides. Hanover, MD: USA ICON Dev Solut; 2018. 1989-2018
Reference: PAGE 32 (2024) Abstr 10977 [www.page-meeting.org/?abstract=10977]
Poster: Drug/Disease Modelling - Paediatrics