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

2020 ◽  
Vol 11 ◽  
Author(s):  
Tao Zhang ◽  
Dan Sun ◽  
Zuocheng Shu ◽  
Ziyun Duan ◽  
Yang Liu ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Pediatric Population ◽  
Severe Infection ◽  
Volume Of Distribution ◽  
Hospitalized Children ◽  
Loading Dose ◽  
Dosage Regimens ◽  
Optimal Dosing ◽  
Dosing Regimens ◽  
Dosing Optimization

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.

scholarly journals Evaluation of the Effects of Extracorporeal Membrane Oxygenation on Antiepileptic Drug Serum Concentrations in Pediatric Patients

2017 ◽  
Vol 22 (5) ◽  
pp. 352-357 ◽  
Author(s):  
Nicholas O. Dillman ◽  
Mindl M. Messinger ◽  
Kimberly N. Dinh ◽  
Jennifer L. Placencia ◽  
Brady S. Moffett ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Extracorporeal Membrane Oxygenation ◽  
Pediatric Patients ◽  
Pediatric Population ◽  
Volume Of Distribution ◽  
Serum Concentrations ◽  
Inclusion Criteria ◽  
Lower Serum ◽  
Membrane Oxygenation ◽  
Dosing Strategies

OBJECTIVES Patients supported on extracorporeal membrane oxygenation (ECMO) have an increased incidence of seizures. Phenobarbital (PB) and fosphenytoin (fos-PHT) are common antiepileptic drugs (AEDs) used to manage seizures in the pediatric population; however, it is unknown what effect ECMO has on the serum concentrations of AEDs. The purpose of this study is to evaluate the effect of ECMO on AED serum concentrations. METHODS A retrospective, matched-cohort study was performed in patients younger than 18 years who received ECMO and were treated with intravenous (IV) PB or fos-PHT at Texas Children's Hospital between 2004 and 2014. Patients receiving IV AED therapy and ECMO were matched, based on age, sex, and weight, with patients receiving IV AED therapy without ECMO. The 24-hour cumulative AED dose, serum concentrations, number of doses per serum concentration drawn ratio, volume of distribution, therapeutic serum concentrations, and time to therapeutic serum concentration were compared between both groups. The fos-PHT and PB groups were analyzed in all patients and in neonates only. RESULTS Fourteen patients met inclusion criteria. The fos-PHT neonatal (20.1 vs 11.3 mg/kg/day, p = 0.044), PB composite (33.9 vs 21.6 mg/kg/day, p = 0.012), and PB neonatal (40.3 vs 20 mg/kg/day, p = 0.04) had larger 24-hour cumulative doses compared with non-ECMO patients. Lower serum concentrations were observed in the PB composite ECMO group (19.1 vs 35.4 mg/L, p < 0.001) and the PB neonatal ECMO group (20.5 vs 27.8 mg/L, p = 0.01) compared with non-ECMO patients. CONCLUSION Pediatric patients receiving PB on ECMO and neonatal patients receiving fos-PHT on ECMO required larger doses, and in pediatric patients achieved lower serum concentrations, suggesting the necessity for alternative dosing strategies in these populations.

scholarly journals Population Pharmacokinetics Analysis To Inform Efavirenz Dosing Recommendations in Pediatric HIV Patients Aged 3 Months to 3 Years

2016 ◽  
Vol 60 (6) ◽  
pp. 3676-3686 ◽  
Author(s):  
Man Luo ◽  
Sunny Chapel ◽  
Heather Sevinsky ◽  
Ishani Savant ◽  
Brenda Cirincione ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Pediatric Population ◽  
The United States ◽  
Volume Of Distribution ◽  
Time Profile ◽  
Pediatric Hiv ◽  
Target Range ◽  
Population Pharmacokinetic ◽  
The European Union ◽  
The Impact

Efavirenz (EFV) is a nonnucleoside reverse transcriptase inhibitor approved worldwide for the treatment of HIV in adults and children over 3 years of age or weighing over 10 kg. Only recently EFV was approved in children over 3 months and weighing at least 3.5 kg in the United States and the European Union. The objective of this analysis was to support the selection of an appropriate dose for this younger pediatric population and to explore the impact of CYP2B6 genetic polymorphisms on EFV systemic exposures. A population pharmacokinetic (PPK) model was developed using data from three studies in HIV-1-infected pediatric subjects (n= 168) and one study in healthy adults (n= 24). The EFV concentration-time profile was best described by a two-compartment model with first-order absorption and elimination. Body weight was identified as a significant predictor of efavirenz apparent clearance (CL), oral central volume of distribution (VC), and absorption rate constant (Ka). The typical values of efavirenz apparent CL,VC, oral peripheral volume of distribution (VP), andKafor a reference pediatric patient were 4.8 liters/h (4.5 to 5.1 liters/h), 84.9 liters (76.8 to 93.0 liters), 287 liters (252.6 to 321.4 liters), and 0.414 h−1(0.375 to 0.453 h−1), respectively. The final model was used to simulate steady-state efavirenz concentrations in pediatric patients weighing <10 kg to identify EFV doses that produce comparable exposure to adult and pediatric patients weighing ≥10 kg. Results suggest that administration of EFV doses of 100 mg once daily (QD) to children weighing ≥3.5 to <5 kg, 150 mg QD to children weighing ≥5 to <7.5 kg, and 200 mg QD to children weighing ≥7.5 to <10 kg produce exposures within the target range. Further evaluation of the impact of CYP2B6 polymorphisms on EFV PK showed that the identification of CYP2B6 genetic status is not predictive of EFV exposure and thus not informative to guide pediatric dosing regimens.

scholarly journals Challenges of Vancomycin Dosing and Therapeutic Monitoring in Neonates

2020 ◽  
Vol 25 (6) ◽  
pp. 476-484
Author(s):  
Jennifer T. Pham
Keyword(s):  
Pediatric Patients ◽  
Late Onset ◽  
Therapeutic Monitoring ◽  
Pharmacokinetic Parameters ◽  
Coagulase Negative Staphylococci ◽  
Optimal Dosing ◽  
Increased Risk ◽  
Dosing Regimens ◽  
Vancomycin Trough ◽  
Trough Concentrations

Late-onset sepsis in neonates can lead to significant morbidity and mortality, especially in preterm infants. Vancomycin is commonly prescribed for the treatment of Gram-positive organisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococci, and ampicillin-resistant Enterococcus species in adult and pediatric patients. Currently, there is no consensus on optimal dosing and monitoring of vancomycin in neonates. Different vancomycin dosing regimens exist for neonates, but with many of these regimens, obtaining therapeutic trough concentrations can be difficult. In 2011, the Infectious Diseases Society of America recommended vancomycin trough concentrations of 15 to 20 mg/L or an AUC/MIC ratio of ≥400 for severe invasive diseases (e.g., MRSA) in adult and pediatric patients. Owing to recent reports of increased risk of nephrotoxicity associated with vancomycin trough concentrations of 15 to 20 mg/L and AUC/MIC of ≥400, a revised consensus guideline, recently published in 2020, no longer recommends monitoring vancomycin trough concentrations in adult patients. The guideline recommends an AUC/MIC of 400 to 600, which has been found to achieve clinical efficacy while reducing nephrotoxicity. However, these recommendations were derived solely from adult literature, as there are limited clinical outcomes data in pediatric and neonatal patients. Furthermore, owing to the variation of vancomycin pharmacokinetic parameters among the neonatal population, these recommendations for achieving vancomycin AUC/MIC of 400 to 600 in neonates require further investigation. This review will discuss the challenges of achieving optimal vancomycin dosing and monitoring in neonatal patients.

scholarly journals Impact of Albumin and Omeprazole on Steady-State Population Pharmacokinetics of Voriconazole and Development of a Voriconazole Dosing Optimization Model in Thai Patients with Hematologic Diseases

Antibiotics ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 574
Author(s):  
Buddharat Khan-asa ◽  
Baralee Punyawudho ◽  
Noppaket Singkham ◽  
Piyawat Chaivichacharn ◽  
Ekapun Karoopongse ◽  
...  
Keyword(s):  
Steady State ◽  
Compartment Model ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Albumin Level ◽  
Hematologic Diseases ◽  
Mixed Effects Modeling ◽  
Dosing Regimens ◽  
The One ◽  
Dosing Optimization

This study aimed to identify factors that significantly influence the pharmacokinetics of voriconazole in Thai adults with hematologic diseases, and to determine optimal voriconazole dosing regimens. Blood samples were collected at steady state in 65 patients (237 concentrations) who were taking voriconazole to prevent or treat invasive aspergillosis. The data were analyzed using a nonlinear mixed-effects modeling approach. Monte Carlo simulation was applied to optimize dosage regimens. Data were fitted with the one-compartment model with first-order absorption and elimination. The apparent oral clearance (CL/F) was 3.43 L/h, the apparent volume of distribution (V/F) was 47.6 L, and the absorption rate constant (Ka) was fixed at 1.1 h−1. Albumin and omeprazole ≥ 40 mg/day were found to significantly influence CL/F. The simulation produced the following recommended maintenance doses of voriconazole: 50, 100, and 200 mg every 12 h for albumin levels of 1.5–3, 3.01–4, and 4.01–4.5 g/dL, respectively, in patients who receive omeprazole ≤ 20 mg/day. Patients who receive omeprazole ≥ 40 mg/day and who have serum albumin level 1.5–3 and 3.01–4.5 g/dL should receive voriconazole 50 and 100 mg, every 12 h, respectively. Albumin level and omeprazole dosage should be carefully considered when determining the appropriate dosage of voriconazole in Thai patients.

Impact of Obesity on Fosphenytoin Volume of Distribution in Pediatric Patients

2018 ◽  
Vol 33 (8) ◽  
pp. 534-536 ◽  
Author(s):  
Ashley B. Prusakov ◽  
Anup D. Patel ◽  
Justin W. Cole
Keyword(s):  
Pediatric Patients ◽  
Volume Of Distribution ◽  
Total Serum ◽  
Loading Dose ◽  
Single Center ◽  
Inclusion Criteria ◽  
Obese Children ◽  
Body Habitus ◽  
The Impact ◽  
Nonobese Group

The impact of body habitus on fosphenytoin pharmacokinetics is poorly understood in pediatric patients. This retrospective, single-center review examined differences in fosphenytoin volume of distribution (VD) between children with normal and obese body habitus. From 2013 to 2015, patients 2 to 18 years of age who received a loading dose of fosphenytoin were identified. Thirty-seven patients met inclusion criteria. Mean total serum phenytoin concentration was 25.3 ± 6.5 μg/mL in the nonobese group and 29.5 ± 7.6 μg/mL in the obese group ( P = .09). VD was not significantly different between obese and nonobese groups, 0.92 ± 0.26 L/kg and 0.97 ± 0.48 L/kg ( P = .76), respectively. In contrast to adult studies, these data suggest that fosphenytoin dose adjustments for obese children may be unnecessary.

scholarly journals Clindamycin Pharmacokinetics and Safety in Preterm and Term Infants

2016 ◽  
Vol 60 (5) ◽  
pp. 2888-2894 ◽  
Author(s):  
Daniel Gonzalez ◽  
Paula Delmore ◽  
Barry T. Bloom ◽  
C. Michael Cotten ◽  
Brenda B. Poindexter ◽  
...  
Keyword(s):  
Volume Of Distribution ◽  
Safety Study ◽  
Term Infants ◽  
Content Type ◽  
Acid Glycoprotein ◽  
Optimal Dosing ◽  
Population Pk ◽  
Postmenstrual Age ◽  
Dosing Regimens ◽  
State Concentration

ABSTRACTClindamycin may be active against methicillin-resistantStaphylococcus aureus, a common pathogen causing sepsis in infants, but optimal dosing in this population is unknown. We performed a multicenter, prospective pharmacokinetic (PK) and safety study of clindamycin in infants. We analyzed the data using a population PK analysis approach and included samples from two additional pediatric trials. Intravenous data were collected from 62 infants (135 plasma PK samples) with postnatal ages of <121 days (median [range] gestational age of 28 weeks [23 to 42] and postnatal age of 17 days [1 to 115]). In addition to body weight, postmenstrual age (PMA) and plasma protein concentrations (albumin and alpha-1 acid glycoprotein) were found to be significantly associated with clearance and volume of distribution, respectively. Clearance reached 50% of the adult value at PMA of 39.5 weeks. Simulated PMA-based intravenous dosing regimens administered every 8 h (≤32 weeks PMA, 5 mg/kg; 32 to 40 weeks PMA, 7 mg/kg; >40 to 60 weeks PMA, 9 mg/kg) resulted in an unbound, steady-state concentration at half the dosing interval greater than a MIC forS. aureusof 0.12 μg/ml in >90% of infants. There were no adverse events related to clindamycin use. (This study has been registered at ClinicalTrials.gov under registration no. NCT01728363.)

scholarly journals A Population Pharmacokinetic Model for Vancomycin in Pediatric Patients and Its Predictive Value in a Naive Population

2000 ◽  
Vol 44 (2) ◽  
pp. 278-282 ◽  
Author(s):  
Patrice Lamarre ◽  
Denis Lebel ◽  
Murray P. Ducharme
Keyword(s):  
Pediatric Patients ◽  
Pediatric Population ◽  
Predictive Ability ◽  
Volume Of Distribution ◽  
Population Characteristics ◽  
Rank Test ◽  
Population Pharmacokinetic ◽  
Good Precision ◽  
Weighted Residuals ◽  
Population Pk

ABSTRACT The objectives of this study were to (i) construct a population pharmacokinetic (PK) model able to describe vancomycin (VAN) concentrations in serum in pediatric patients, (ii) determine VAN PK parameters in this population, and (iii) validate the predictive ability of this model in a naive pediatric population. Data used in this study were obtained from 78 pediatric patients (under 18 years old). PK analyses were performed using compartmental methods. The most appropriate model was chosen based on the evaluation of pertinent graphics and calculation of the Akaike information criterion test. The population PK analysis was performed using an iterative two-stage method. A two-compartment PK model using age, sex, weight, and serum creatinine as covariates was determined to be the most appropriate one to describe serum VAN concentrations. The quality of fit was very good, and the distribution of weighted residuals was found to be homoscedastic (Wilcoxon signed rank test). Fitted population PK parameters (mean ± standard deviation) were as follows: central clearance (0.1 ± 0.05 liter/h/kg), central volume of distribution (0.27 ± 0.07 liter/kg), peripheral volume of distribution (0.16 ± 0.07 liter/kg), and distributional clearance (0.16 ± 0.07 liter/kg). The predictive ability of the developed model (including the above-mentioned covariates) was evaluated in a naive population of 19 pediatric patients. The predictability was very good. Precision (±95% confidence interval [CI]) (peak, 4.1 [±1.4], and trough, 2.2 [±0.7]) and bias (±95% CI) (peak, −0.58 [±2.2], and trough, 0.63 [±1.1] mg/liter) were significantly (P < 0.05) superior to those obtained using a conventional method (precision [±95% CI]: peak, 8.03 [±2.46], and trough, 2.7 [±0.74]; bias: peak, −7.1 [±2.9], and trough, −1.35 [±1.2] mg/liter). We propose the use of this population PK model to optimize VAN clinical therapies in our institution and others with similar patient population characteristics.

scholarly journals Integrated Population Pharmacokinetic Analysis of Voriconazole in Children, Adolescents, and Adults

2012 ◽  
Vol 56 (6) ◽  
pp. 3032-3042 ◽  
Author(s):  
Lena E. Friberg ◽  
Patanjali Ravva ◽  
Mats O. Karlsson ◽  
Ping Liu
Keyword(s):  
Pediatric Population ◽  
Compartment Model ◽  
Population Pharmacokinetic Analysis ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Loading Dose ◽  
Time Curve ◽  
Individual Parameter ◽  
Dosing Regimens

ABSTRACTTo further optimize the voriconazole dosing in the pediatric population, a population pharmacokinetic analysis was conducted on pooled data from 112 immunocompromised children (2 to <12 years), 26 immunocompromised adolescents (12 to <17 years), and 35 healthy adults. Different maintenance doses (i.e., 3, 4, 6, 7, and 8 mg/kg of body weight intravenously [i.v.] every 12 h [q12h]; 4 mg/kg, 6 mg/kg, and 200 mg orally q12h) were evaluated in these children. The adult dosing regimens (6 mg/kg i.v. q12h on day 1, followed by 4 mg/kg i.v. q12h, and 300 mg orally q12h) were evaluated in the adolescents. A two-compartment model with first-order absorption and mixed linear and nonlinear (Michaelis-Menten) elimination adequately described the voriconazole data. Larger interindividual variability was observed in pediatric subjects than in adults. Deterministic simulations based on individual parameter estimates from the final model revealed the following. The predicted total exposure (area under the concentration-time curve from 0 to 12 h [AUC0-12]) in children following a 9-mg/kg i.v. loading dose was comparable to that in adults following a 6-mg/kg i.v. loading dose. The predicted AUC0-12s in children following 4 and 8 mg/kg i.v. q12h were comparable to those in adults following 3 and 4 mg/kg i.v. q12h, respectively. The predicted AUC0-12in children following 9 mg/kg (maximum, 350 mg) orally q12h was comparable to that in adults following 200 mg orally q12h. To achieve voriconazole exposures comparable to those of adults, dosing in 12- to 14-year-old adolescents depends on their weight: they should be dosed like children if their weight is <50 kg and dosed like adults if their weight is ≥50 kg. Other adolescents should be dosed like adults.

scholarly journals Vedolizumab: An Emerging Treatment Option for Pediatric Inflammatory Bowel Disease

2021 ◽  
Vol 26 (8) ◽  
pp. 795-801
Author(s):  
Pooja Shah ◽  
Danielle McDonald
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Randomized Trials ◽  
Pediatric Patients ◽  
Pediatric Population ◽  
Case Series ◽  
Pediatric Inflammatory Bowel Disease ◽  
Dosing Regimens ◽  
Inflammatory Bowel

Vedolizumab is a humanized α4β7-integrin antagonist that is currently FDA-approved for adult inflammatory bowel disease. Limited evidence is available to guide use in pediatric patients, though off-label use is described in the form of retrospective reviews and case series. Collectively these publications begin to establish safety and efficacy data in pediatric patients &lt; 18 years of age. Additionally, dosing regimens described in the literature serve to guide weight-based dosing, which is not established at this time. This narrative review aims to summarize the available literature and provide recommendations for vedolizumab use in the pediatric population. A literature search was performed in PubMed (January 2014–December 2020) using the keyword vedolizumab. Based on the available evidence, vedolizumab appears to be a safe and moderately effective agent for treatment of refractory pediatric inflammatory bowel disease. Prospective, randomized trials are warranted to optimize dosing regimens and to establish long-term safety.

scholarly journals Population Pharmacokinetics and Safety of Piperacillin-Tazobactam Extended Infusions in Infants and Children

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Céline Thibault ◽  
Jean Lavigne ◽  
Catherine Litalien ◽  
Nastya Kassir ◽  
Yves Théorêt ◽  
...  
Keyword(s):  
Adverse Event ◽  
Standard Of Care ◽  
Compartment Model ◽  
Central Compartment ◽  
Volume Of Distribution ◽  
Content Type ◽  
Final Population ◽  
Optimal Dosing ◽  
Population Pk ◽  
Dosing Regimens

ABSTRACT Piperacillin-tazobactam (TZP) is frequently used to treat severe hospital-acquired infections in children. We performed a single-center, pharmacokinetic (PK) trial of TZP in children ranging in age from 2 months to 6 years from various clinical subpopulations. Children who were on TZP per the standard of care were prospectively included and assigned to receive a dose of 80 mg/kg of body weight every 6 h infused over 2 h (ages 2 to 5 months) or a dose of 90 mg/kg every 8 h infused over 4 h (ages 6 months to 6 years). Separate population PK models were developed for piperacillin and tazobactam using nonlinear mixed-effects modeling. Optimal dosing was judged based on the ability to maintain free piperacillin concentrations above the piperacillin MIC for enterobacteria and Pseudomonas aeruginosa for ≥50% of the dosing interval. Any untoward event occurring during treatment was collected as an adverse event. A total of 79 children contributed 174 PK samples. The median (range) age and weight were 1.7 years (2 months to 6 years) and 11.4 kg (3.8 to 27.6 kg), respectively. A 2-compartment model with first-order elimination best described the piperacillin and tazobactam data. Both final population PK models included weight and concomitant furosemide administration on clearance and weight on the volume of distribution of the central compartment. The optimal dosing regimens in children with normal renal function, based on the piperacillin component, were 75 mg/kg/dose every 4 h infused over 0.5 h in infants ages 2 to ≤6 months and 130 mg/kg/dose every 8 h infused over 4 h in children ages >6 months to 6 years against bacteria with MICs up to 16 mg/liter. A total of 44 children (49%) had ≥1 adverse event, with 3 of these (site infiltrations) considered definitely associated with the extended infusions.

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