scholarly journals Modeling and Simulation Analysis of Aprepitant Pharmacokinetics in Pediatric Patients With Postoperative or Chemotherapy-Induced Nausea and Vomiting

2020 ◽  
Vol 25 (6) ◽  
pp. 528-539
Author(s):  
Anne Chain ◽  
Rebecca Wrishko ◽  
Grygoriy Vasilinin ◽  
Samer Mouksassi
Keyword(s):  
Pediatric Patients ◽  
Simulation Analysis ◽  
Pediatric Population ◽  
Plasma Concentrations ◽  
Model Development ◽  
Postoperative Nausea And Vomiting ◽  
Nausea And Vomiting ◽  
Fixed Dose ◽  
Population Pharmacokinetic ◽  
Population Pk

OBJECTIVES Aprepitant is effective for the prevention of chemotherapy-induced or postoperative nausea and vomiting (CINV/PONV). The aim of this study was to develop a population pharmacokinetic (PK) model of aprepitant in pediatric patients and to support dosing recommendations for oral aprepitant in pediatric patients at risk of CINV. METHODS A population PK model was constructed based on data from 3 clinical studies in which children (6 months to 12 years) and adolescents (12–19 years) were treated with a 3-day regimen of oral aprepitant (capsules or suspension), with or without intravenous fosaprepitant on day 1 (CINV), or a single dose of oral aprepitant (capsules or suspension; PONV). Nonlinear mixed-effects modeling was used for model development, and a stepwise covariate search determined factors influencing PK parameters. Simulations were performed to guide final dosing strategies of aprepitant in pediatric patients. RESULTS The analysis included 1326 aprepitant plasma concentrations from 147 patients. Aprepitant PK was described by a 2-compartment model with linear elimination and first-order absorption, with allometric scaling for central and peripheral clearance and volume using body weight, and a cytochrome P450 3A4 maturation component for the effect of ontogeny on systemic clearance. Simulations established that application of a weight-based (for those <12 years) and fixed-dose (for those 12–17 years) dosing regimen results in comparable exposures to those observed in adults. CONCLUSIONS The developed population PK model adequately described aprepitant PK across a broad pediatric population, justifying fixed (adult) dosing for adolescents and weight-based dosing of oral aprepitant for children.

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 Aggressive Prophylactic Treatments for Postoperative Nausea and Vomiting Improve Outcomes in Pediatric Adenotonsillectomy Procedure

2020 ◽  
Vol 25 (4) ◽  
pp. 303-308
Author(s):  
Tatyana Demidovich ◽  
Orlando Perez-Franco ◽  
Marco Silvestrini-Suarez ◽  
Pin Yue
Keyword(s):  
Risk Factors ◽  
High Risk ◽  
General Anesthesia ◽  
Postoperative Nausea ◽  
Pediatric Patients ◽  
Pediatric Population ◽  
Postoperative Nausea And Vomiting ◽  
Nausea And Vomiting ◽  
Antiemetic Drugs ◽  
Pacu Stay

OBJECTIVE Postoperative nausea and vomiting (PONV) is an extremely common side effect of general anesthesia that is difficult to manage. We tested a hypothesis that an aggressive prophylactic intervention with additional antiemetic drugs will reduce the incidence of PONV in a high-risk pediatric population undergoing adenotonsillectomy. METHODS In this retrospective study, pediatric patients undergoing adenotonsillectomy were screened for their risk factors for PONV. Patients who had 3 or more risk factors were identified as high risk and received either scopolamine patch preoperatively (for patients over 40 kg body weight) or diphenhydramine immediately postextubation in addition to ondansetron and dexamethasone, which are given routinely. Incidences of PONV within the first 60 minutes of a postanesthesia care unit (PACU) stay were collected and analyzed. RESULTS Overall postoperative vomiting rates during the first hour of a PACU stay were 4.3% for the group that was treated with dexamethasone and ondansetron only and 3.9% for the group that was treated with additional antiemetic drugs. Aggressive prophylactic management of PONV did reduce the rate of nausea and vomiting in a group of high-risk patients (p &lt; 0.0001). The postoperative antiemetic drug usage was also decreased during the first 60 minutes of a PACU stay. However, the approach did not reduce the overall rate of PONV for the entire study population (p = 0.1612 for nausea and p = 0.0678 for vomiting). CONCLUSION Aggressive intraoperative management of PONV with additional antiemetic drugs are beneficial in high-risk pediatric population. Intraoperative diphenhydramine usage decreased the rate of PONV. However, preoperative scopolamine patch prevention did not improve PONV, which may be related to the drug's longer onset of action. Our result suggests that current clinical practice is undertreating PONV in pediatric patients receiving general anesthesia.

scholarly journals Optimizing Ceftobiprole Dosage in Pediatric Patients: A Model-Based Approach

2021 ◽  
Author(s):  
Christopher M. Rubino ◽  
Anthony P. Cammarata ◽  
Anne Smits ◽  
Sebastian Schröpf ◽  
Mark Polak ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Plasma Concentrations ◽  
Compartment Model ◽  
Generation Cephalosporin ◽  
Population Pharmacokinetic ◽  
Model Based ◽  
Final Population ◽  
Pediatric Study ◽  
Population Pk ◽  
Neonates And Infants

Ceftobiprole is an advanced-generation cephalosporin for intravenous administration with activity against Gram-positive and Gram-negative organisms. A population pharmacokinetic (PK) model characterizing the disposition of ceftobiprole in plasma using data from patients in three pediatric studies was developed. Model-based simulations were subsequently performed to assist in dose optimization for the treatment of pediatric patients with hospital-acquired or community-acquired pneumonia. The population PK dataset comprised 518 ceftobiprole plasma concentrations from 107 patients aged 0 (birth) to 17 years. Ceftobiprole PK was well described by a three-compartment model with linear elimination. Ceftobiprole clearance was modeled as a function of glomerular filtration rate; other PK parameters were scaled to body weight. The final population PK model provided a robust and reliable description of the PK of ceftobiprole in the pediatric study population. Model-based simulations using the final model suggested that a ceftobiprole dose of 15 mg/kg infused over 2 hours and administered every 12 hours in neonates and infants <3 months or every 8 hours in older pediatric patients would result in a ceftobiprole exposure consistent with that in adults and good pharmacokinetic-pharmacodynamic target attainment. The dose should be reduced to 10 mg/kg every 12 hours in neonates and infants <3 months who weigh <4 kg to avoid high exposures. Extended intervals and reduced doses may be required for pediatric patients older than 3 months of age with renal impairment.

scholarly journals The first study in pediatric: Population pharmacokinetics of sirolimus and its application in Chinese children with immune cytopenia

2020 ◽  
Vol 34 ◽  
pp. 205873842093493
Author(s):  
Xiaoling Cheng ◽  
Yiming Zhao ◽  
Hao Gu ◽  
Libo Zhao ◽  
Yannan Zang ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Total Bilirubin ◽  
Pediatric Population ◽  
Visual Predictive Check ◽  
Individual Variability ◽  
Chinese Children ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Dose Individualization ◽  
Population Pk

The narrow therapeutic index and large inter-individual variability in sirolimus pharmacokinetics (PK) make therapeutic drug monitoring (TDM) necessary. Factors responsible for PK variability are not well understood, and published PK studies do not include pediatric patients with immune cytopenia. The objective of this study was to characterize the PK of sirolimus in pediatric patients with immune cytopenia and to develop a population PK model in Chinese children and evaluate its utility for dose individualization. A total of 27 children with either acquired or congenital immune cytopenia aged 8.16 ± 3.60 years (range: 1–15 years) were included. TDM data for sirolimus were collected. The population PK model of sirolimus was described using the nonlinear mixed-effects modeling (Phoenix NLME 1.3 software) approach. Covariate analysis was applied to select candidate factors associated with PK parameters. The final model was validated using bootstrap (1000 runs) and visual predictive check (VPC) method. A one-compartment model with first-order absorption and elimination was developed. The outcome parameters were as follows: apparent clearance (CL/F) 5.63 L/h, apparent distribution volume (V/F) 144.16 L. Inter-individual variabilities for CL/F and V/F were 3.53% and 7.27%, respectively. The intra-individual variability of proportional error model was 22.45%. The covariate test found that body weight and total bilirubin were strongly associated with clearance; however, we did not find the relevance between the covariate and volume of distribution of sirolimus. Personalized dosage regimens were provided based on Bayesian method. The oral dose should be adjusted according to weight and total bilirubin. This is the first study to describe a population PK model of sirolimusin pediatric patients with immune cytopenia. Population pharmacokinetic (PPK) model–based dose individualization of sirolimus and the design of future clinical studies in children will be facilitated by the developed model in this study.

scholarly journals Population Pharmacokinetic and Pharmacokinetic/Pharmacodynamic Analyses of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Patients with Pneumonia, Bloodstream Infection/Sepsis, or Complicated Urinary Tract Infection

2020 ◽  
Author(s):  
Nao Kawaguchi ◽  
Takayuki Katsube ◽  
Roger Echols ◽  
Toshihiro Wajima
Keyword(s):  
Urinary Tract Infection ◽  
Renal Function ◽  
Urinary Tract ◽  
Tract Infection ◽  
Bloodstream Infection ◽  
Plasma Concentrations ◽  
Complicated Urinary Tract Infection ◽  
Population Pharmacokinetic ◽  
Dosing Regimen ◽  
Population Pk

Cefiderocol is a novel siderophore cephalosporin with antibacterial activity against Gramnegative bacteria including carbapenemresistant strains. The standard dosing regimen of cefiderocol is 2 g administered every 8 hours over 3 hours infusion in patients with creatinine clearance (CrCL) of 60 to 119 mL/min, and it is adjusted for patients with < 60 mL/min or ≥ 120 mL/min CrCL. A population pharmacokinetic (PK) model was constructed using 3427 plasma concentrations from 91 uninfected subjects and 425 infected patients with pneumonia, bloodstream infection/sepsis (BSI/sepsis), and complicated urinary tract infection (cUTI). Plasma cefiderocol concentrations were adequately described by the population PK model, and CrCL was the most significant covariate. No other factors including infection sites and mechanical ventilation were clinically relevant, although the effect of infection sites was identified as a statistically significant covariate in the population PK analysis. No clear pharmacokinetic/pharmacodynamic relationship was found for any of the microbiological outcome, clinical outcome, or vital status. This is because the estimated percentage of time for which free plasma concentrations exceed the minimum inhibitory concentration (MIC) over dosing interval (%fT>MIC) was 100% in most of the enrolled patients. The probability of target attainment (PTA) for 100% fT>MIC was > 90% against MICs ≤ 4 μg/mL for all infection sites and renal function groups except for BSI/sepsis patients with normal renal function (85%). These study results support adequate plasma exposure can be achieved at the cefiderocol recommended dosing regimen for the infected patients including the patients with augmented renal function, ventilation, and/or severe illness.

Alfentanil Causes Less Postoperative Nausea and Vomiting than Equipotent Doses of Fentanyl or Sufentanil in Outpatients 

1999 ◽  
Vol 91 (6) ◽  
pp. 1666-1666 ◽  
Author(s):  
Stephan Langevin ◽  
Martin R. Lessard ◽  
Claude A. Trépanier ◽  
Jean-Pierre Baribault
Keyword(s):  
Postoperative Nausea ◽  
Randomized Study ◽  
Recovery Period ◽  
Plasma Concentrations ◽  
Postoperative Nausea And Vomiting ◽  
Nausea And Vomiting ◽  
Oxygen Mixture ◽  
Postanesthesia Care Unit ◽  
Outpatient Basis ◽  
Opioid Administration

Background The relative potencies of alfentanil, fentanyl, and sufentanil as a risk factor for postoperative nausea and vomiting have not been determined. They were compared in a randomized study designed to obtain equipotent plasma concentrations of these three opioids at the beginning of the recovery period. Methods The study included 274 patients treated on an outpatient basis. The steady state opioid plasma concentration providing a predicted 50% reduction of the minimum alveolar concentration of isoflurane was used to determine the relative potency of the opioids. The opioids were prepared in equal volumes at concentrations of alfentanil 150 microg/ml, fentanyl 50 microg/ml, and sufentanil 5 microg/ml and were administered in vol/kg. Anesthesia was induced in a blinded fashion with a bolus of the study opioid (0.05 ml/kg) and 4-6 mg/kg thiopental and was maintained with isoflurane (0.6-1%) in a nitrous oxide-oxygen mixture with a continuous infusion of the study opioid (0.06 ml x kg(-1) x h(-1)). If necessary, up to five additional boluses of opioid (0.02 ml/kg) could be given. This opioid administration protocol was tested by pharmacokinetic simulations. Results The incidence of postoperative nausea and vomiting was not different in the postanesthesia care unit, but in the ambulatory surgery unit it was significantly lower for alfentanil compared with fentanyl and sufentanil (12, 34, and 35%, respectively P &lt; 0.005). Pharmacokinetic modeling showed that the end-anesthesia opioid plasma concentrations were approximately equipotent in the three groups. However, modeling does not support that the difference between groups in the postoperative period can be explained by a more rapid disappearance of alfentanil from the plasma. Conclusions Alfentanil, compared with approximately equipotent doses of fentanyl and sufentanil, is associated with a lower incidence of postoperative nausea and vomiting in outpatients.

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