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Omalizumab is widely used in clinical practice; however, knowledge gaps in the dosage of omalizumab for children aged 2–6 years with moderate‐to‐severe persistent allergic asthma have been identified. The aim of this study was to explore dosing regimens for moderately‐to‐severely allergic pediatric patients aged 2–6 years. The physiologically‐based pharmacokinetic (PBPK) model of omalizumab was developed and verified in adult patients, extrapolated to pediatric patients, and simulated for omalizumab by adding two observation chambers (free IgE and total IgE). The simulation results showed that the fold errors of the predicted and observed values of the area under the curve (AUC) and peak plasma concentration (Cmax) were between 0.5 and 2.0, and the average folding error and the absolute average folding error values for all concentration‐time data points were 1.09 and 1.48, respectively. The PBPK model combined with pharmacokinetic/pharmacodynamic analysis of omalizumab demonstrated that both the model‐derived dose and the original dose could control the average free IgE of 2–6‐year‐old children with moderate‐to‐severe allergic asthma below 25 ng/mL, and some of the model‐derived doses were lower. This conclusion provides a basis for the selection of dosage in clinical practice reference. [ABSTRACT FROM AUTHOR]

Pregabalin (PGB) is widely used clinically; however, its pharmacokinetics (PK) has not been studied in pediatric patients with renal impairment (RI). To design optimized PGB regimens for pediatric patients with varying degrees of RI and predict exposure to PGB, physiologically based pharmacokinetic (PBPK) models of PGB were developed and verified, and its disposition was simulated in the healthy population and adults with RI. The simulated results from the PBPK models after single-dose and multi-dose administrations of PGB were consistent with the corresponding observed data based on the fold error values of less than 2. The area under curve ratios were 1.23 ± 0.06, 2.02 ± 0.10, 3.86 ± 0.21, and 9.92 ± 0.79 in pediatric patients with mild, moderate, severe, and end-stage RI, respectively. Based on the predictions for pediatric patients with moderate, severe, and end-stage RI, the maximum dose should not exceed 7, 3.5, and 1.4 mg/kg/day, respectively, among those weighing < 30 kg, and it should not exceed 5, 2.5, and 1 mg/kg/day, respectively, among those weighing > 30 kg. In conclusion, the developed PBPK model is a valuable tool for predicting PGB dosage for pediatric patients with RI. [ABSTRACT FROM AUTHOR]

Ceftaroline fosamil is a fifth‐generation cephalosporin approved as a treatment for adults and children with community‐acquired bacterial pneumonia and acute bacterial skin and skin structure infections. However, its pharmacokinetics have not been fully evaluated in children with renal impairment. This study aimed to propose proper ceftaroline dosages optimized for the renally impaired pediatric population using physiologically based pharmacokinetic (PBPK) modeling. A PBPK model of ceftaroline was established and verified to simulate its disposition in the healthy population and renally impaired adults and to predict the exposure in renally impaired pediatric patients. Consistency was confirmed between simulated and observed data after intravenous administration of various ceftaroline regimens; fold errors were within the 2‐fold error range. Among 6‐year‐old children, healthy subjects had 1.5‐fold, 2‐fold, and 2.6‐fold lower areas under the plasma concentration–time curve (AUCs) than the moderate, severe, and end‐stage renally impaired patient groups, respectively; among 1‐year‐old children, healthy subjects had 1.5‐fold, 2.1‐fold, and 2.5‐fold lower AUCs than the respective renally impaired patient groups; among 1‐month‐old children, healthy subjects had 1.5‐fold, 1.8‐fold, and 2.2‐fold lower AUCs than the respective renally impaired patient groups. The proposed dosage should be adjusted to 8, 6, and 5 mg/kg every 8 hours for patients aged ≥2 years to <18 years (≤33 kg) with moderate, severe, and end‐stage renal impairment, respectively; 5, 4, and 3 mg/kg every 8 hours for patients aged 2 months to <2 years with moderate, severe, and end‐stage renal impairment, respectively; 4, 3.5, and 2.5 mg/kg every 8 hours for patients 0 to <2 months of age with moderate, severe, and end‐stage renal impairment, respectively. Furthermore, pharmacodynamic investigations demonstrated that adequate antimicrobial effects were attained at the proposed doses in 3 age groups. Hence, our PBPK model can be an effective tool to support ceftaroline dosage proposals for renally impaired pediatric patients. [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic (PBPK) modeling has unique advantages in investigating the pharmacokinetics of drugs in special populations. Our aim is to design optimized dosing regimens for ceftazidime in renally-impaired pediatric patients using PBPK modeling. Models for healthy and renally-impaired adults were developed, verified, and adapted for children to predict ceftazidime exposure in pediatric patients with varying degrees of renal impairment, capturing age- and weight-related pharmacokinetic changes. We derived a dosage-adjusted regimen for renally-impaired children based on pharmacokinetic data and evaluated the pharmacodynamics of ceftazidime. The PBPK models adequately predicted ceftazidime exposures in populations after single- and multi-dose administrations, with fold error values within 1.1 between simulated and observed data. In moderate, severe, and end-stage renally-impaired pediatric patients, the areas under the plasma concentration-time curves (AUCs) were 1.87-fold, 3.56-fold, and 6.19-fold higher, respectively, than in healthy children when treated with the same dose of 50 mg/kg. Pharmacodynamic verification indicated that the recommended doses of 28, 15, and 8 mg/kg administered three times daily (every 8 h) to pediatric patients with moderate, severe, and end-stage renal disease, respectively, were sufficient to attain the target of maintaining the free plasma concentration at or above minimum inhibitory concentration (MIC) during 70% of the dosing interval (70% fT > MIC: nearly 100% target attainment for susceptible MIC of 4 mg/L and >70% for intermediate MIC of 8 mg/L). Our PBPK model can be an effective tool to support dosing recommendations in pediatric patients with different degrees of renal impairment. [ABSTRACT FROM AUTHOR]

Ticagrelor, a P2Y 12 receptor antagonist, has been highly recommended for use in acute coronary syndrome. The major active metabolite (AM) is similar to the parent drug, which exhibits antiplatelet activity. The inhibition of platelet aggregation (IPA) is used as an assay to demonstrate the anticoagulant efficacy of ticagrelor. In this study, we developed a physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of ticagrelor and its AM and combined this model with a pharmacodynamics model to reflect potential pharmacodynamic alterations in liver cirrhosis populations. The simulated results obtained using the PBPK model were validated by fold error values, which were all smaller than 2. Comparisons of exposure in different classifications of liver cirrhosis indicated that exposure to ticagrelor increased significantly with an increase in the degree of cirrhosis severity, whereas exposure to AM was decreased. The total concentration of ticagrelor and AM was related to the IPA included in the Sigmoid E max model. The PBPK model of ticagrelor and AM could predict the pharmacokinetics of all populations, and a combination of PD models was used to extrapolate for predicting unknown scenarios. Liver cirrhosis may result in prolonged IPA, depending on the severity degree of this disease. The combined PBPK model including IPA can reveal changes in pharmacokinetics and pharmacodynamics in populations affected by liver cirrhosis and indicate the risk potential. [ABSTRACT FROM AUTHOR]

Levetiracetam is currently being used to treat epilepsy in pregnant women. The plasma concentration of levetiracetam drops sharply during pregnancy, and the inability of pregnant women to maintain therapeutic concentrations can lead to seizures. This study aimed to predict the changes in fetal and maternal plasma exposure to levetiracetam during pregnancy and provide advice on dose adjustment. The physiology-based pharmacokinetics (PBPK) model was developed using PK-Sim and Mobi software, and validated following comparison of the observed plasma concentration and pharmacokinetic parameters. The levetiracetam PBPK model for mother and the fetus at various stages of pregnancy was successfully established and verified. Predictions indicated that the area under the steady-state concentration-time curve for levetiracetam decreased to 83, 62, and 67% of baseline values in the first, second, and third trimesters, respectively. Based on PBPK predictions, the recommended dose of levetiracetam is 1.2, 1.6, and 1.5 times the baseline dose in the first, second, and third trimesters, respectively, not exceeding 4000 mg/day in the third trimester due to fetal safety. The levetiracetam PBPK model for pregnancy was successfully developed and validated, and could provide alternative levetiracetam dosing regimens across the stages of pregnancy. [Display omitted] [ABSTRACT FROM AUTHOR]

Ertapenem is a widely used antibiotic; however, its pharmacokinetics has not been fully evaluated in children with renal impairment. A physiologically based pharmacokinetic (PBPK) model of ertapenem was established and validated to simulate its disposition in the healthy population and adults with renal impairment, as well as to predict the exposure in pediatric patients with renal impairment. The simulated PBPK modeling results and the observed data of ertapenem after intravenous administration of various regimens were consistent according to the fold error values of less than 2. Furthermore, %T > MIC of ertapenem was evaluated using the PBPK model. The C max was not significantly changed in pediatric patients with renal impairment compared to healthy children. However, the AUC was 1.42-fold, 1.84-fold, 2.37-fold, and 3.52-fold higher in mild, moderate, severe renal impairment, and end-stage renal disease, respectively, than that in healthy children and the doses of ertapenem were reduced to 13 mg/kg b.i.d, 9 mg/kg b.i.d, 6 mg/kg b.i.d, and 5 mg/kg b.i.d, respectively. The probability of achieving 40%T > MIC (MIC ≤ 4 μg/mL) was nearly 100% throughout the recommended dosing interval. In conclusion, our model can be used as a tool to generate better predictions for the most effective ertapenem dosing in pediatric patients. [ABSTRACT FROM AUTHOR]