Population Pharmacokinetics and Model-Based Dosing Optimization of Teicoplanin in Pediatric Patients

Abstract

Objectives: The pharmacokinetics (PK) of teicoplanin differs in children compared with adults. Our aim was to determine the PK of teicoplanin in an Asian pediatric population and to optimize dosage regimens.Methods: This was a retrospective PK study and all the data were collected from hospitalized children. We developed a population PK model using sparse data, and Monte Carlo simulation was used to assess the ability of standard teicoplanin regimen and other different dosage regimens. The optimal dosing regimens were defined as achieving the target trough concentration (Cmin) of 10 mg/L and pharmacokinetic/pharmacodynamic (PK/PD, [AUC24/MIC]) of 125 for moderate infection. For severe infection, the optimal dosing regimens were defined as achieving the target 15 mg/L and AUC24/MIC of 345.Results: 159 children were included and 1.5 samples/children on average were provided. Estimated clearance of teicoplanin was 0.694 L/h (0.784/L/h/70 kg) and volume of distribution was 1.39 L. Teicoplanin standard loading dose was adequate for moderate infection, while 13 mg/kg was needed for severer infection. With standard maintenance doses, both patients with moderate and severe infection failed to achieve the target Cmin. 12 and 16 mg/kg/day were required to achieve a Cmin ≥ 10 and 15 mg/L, respectively. However, standard maintenance dose was adequate to achieve AUC24/MIC ≥ 125 for moderate infection, and 12 mg/kg/day was needed to achieve AUC24/MIC ≥ 345 for severe infection. Lower weight and serum creatinine were associated with higher dose.Conclusion: Optimal doses based on the target Cmin were higher than that based on the PK/PD target. To achieve the Cmin and PK/PD targets simultaneously, a standard loading dose was adequate for moderate infection based on simulation, while dosing higher than standard doses were required in other situation. Further clinical studies with rich sampling from children is required to confirm our findings.

Physiologically Based Pharmacokinetic Modeling and Dose Adjustment of Teicoplanin in Pediatric Patients With Renal Impairment

“…In healthy adults, the theoretical CL R of teicoplanin by filtration was 1.01 L/h, which was close to the 0.98 L/h value reported in the literature 31 . The mean CL R (0.701 L/h) in children with normal renal function was similar to that of Chinese children (0.694 L/h), 10 but higher than that of French children with malignant hematological disease (0.485/h) 7 . Specifically, the predicted data were reasonably consistent with the observed data, and the predictions of PK values (AUC, C max ) were within 1.36‐fold error.…”

“…Furthermore, our analysis showed that the standard dosing regimen results in underdosing based on the PK/PD index used for infections in the upper MIC range, and a previously empirical study of Asian pediatric patients confirms this viewpoint. 7,10 The developed teicoplanin PBPK model may offer significant implications for promoting reasonable medication and guaranteeing therapeutic effectiveness.…”

“…According to a medication guide, therapeutic drug monitoring is an important way to ensure the safety and efficacy of teicoplanin. Exposureresponse relationships for safety suggested that trough concentration of ≥60 mg/L was associated with a higher rate of adverse reactions, 9,10 and the target trough concentration for effective treatment against pathogens is 10 to 30 mg/L. 11,12 Interestingly, in most medical centers, therapeutic drug monitoring is still not routine practice.…”

Construction and Interpretation of Prediction Model of Teicoplanin Trough Concentration via Machine Learning

“…Consistently, our results indicated that the teicoplanin trough concentrations of patients with ECMO and CRRT therapy showed a downward trend. In our study, pediatric patients (aged <14 years) were excluded because of their diverse pharmacokinetics ( 36 ). According to the medication instruction, no dose adjustment is required for the elderly patients.…”

Population pharmacokinetics and initial dose optimization of tacrolimus in children with severe combined immunodeficiency undergoing hematopoietic stem cell transplantation

“…Chen et al reported population pharmacokinetics and initial dose optimization of sirolimus improving drug blood level for seizure control in pediatric patients with tuberous sclerosis complex (Xiao Chen et al, 2021). Zhang et al (2020) reported population pharmacokinetics and model-based dosing optimization of teicoplanin in pediatric patients. Based on these precedents, population pharmacokinetics and Monte Carlo simulations were used to recommend optimal initial dosing of tacrolimus in children with SCID undergoing HSCT in our study.…”