1. Population Pharmacokinetic Data and Parameter Estimation Based on Their First Two Statistical Moments

1984 ◽  
Vol 15 (1-2) ◽  
pp. 173-193 ◽  
Author(s):  
Stuart L. Beal
Keyword(s):  
Parameter Estimation ◽  
Statistical Moments ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data

scholarly journals Fluoxetine pharmacokinetics and tissue distribution suggest a possible role in reducing SARS-CoV-2 titers

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 477
Author(s):  
Andy R. Eugene
Keyword(s):  
Tissue Distribution ◽  
Day Treatment ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Pharmacokinetic Data ◽  
Human Lung Cells ◽  
Retrospective Clinical Study ◽  
Target Plasma Concentration

Background.  Recent in vitro studies have shown fluoxetine inhibits the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen, including variants B.1.1.7 and B.1.351, SARS-CoV-2 spike mutations (E484K, K417N, N501Y), and one retrospective clinical study reported fluoxetine exposure at a median dose of 20 mg in patients with the SARS-CoV-2 coronavirus disease 2019 (COVID-19) had a significantly lower risk of intubation and death. The aim of this study is to conduct in silico population pharmacokinetic dosing simulations to quantify the percentage of patients achieving a trough level for the effective concentration resulting in 90% inhibition (EC90) of SARS-CoV-2 as reported in Calu-3 human lung cells.  Methods.  Population pharmacokinetic parameter estimates for a structural one-compartment model with first-order absorption were used to simulate fluoxetine pharmacokinetic data. A population of 1,000 individuals were simulated at standard fluoxetine doses (20 mg/day, 40 mg/day, and 60 mg/day) to estimate the percentage of the patients achieving a trough plasma level for the EC90 SARS-CoV-2 inhibitory concentration for a 10 day treatment period. All analyses were conducted via statistical programming in R.  Results.  Standard fluoxetine antidepressant doses resulted in a range of 81% to 97% of the patient population achieving a trough target plasma concentration of 23.2 ng/ml at day 10 and translates to a lung-tissue distribution coefficient of 60-times higher (EC90 of 4.02 mM). At a dose of 40 mg per day, at least 87% of patients will reach the trough target EC90 concentration within three days.   Conclusion. Overall, the findings of this population pharmacokinetic dosing study corroborates in vitro and observational clinical studies reporting the first selective serotonin reuptake inhibitor fluoxetine inhibits the SARS-CoV-2 pathogen at commonly treated doses in the practice of psychiatry.

Is the subcutaneous route an alternative for administering ertapenem to older patients? PHACINERTA study

2019 ◽  
Vol 74 (12) ◽  
pp. 3546-3554 ◽  
Author(s):  
Claire Roubaud Baudron ◽  
Rachel Legeron ◽  
Julien Ollivier ◽  
Fabrice Bonnet ◽  
Carine Greib ◽  
...  
Keyword(s):  
Older Patients ◽  
Older Persons ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Antibiotic Administration ◽  
Subcutaneous Route ◽  
Final Model ◽  
Once Daily ◽  
The Mean ◽  
Pharmacodynamic Data

Abstract Background Antibiotic administration by subcutaneous (SC) injection is common practice in French geriatric wards as an alternative to the intravenous (IV) route, but few pharmacokinetic/pharmacodynamic data are available. Ertapenem is useful for the treatment of infections with ESBL-producing enterobacteria. Objectives To report and compare ertapenem pharmacokinetic data between IV and SC routes in older persons. Methods Patients >65 years of age receiving ertapenem (1 g once daily) for at least 48 h (IV or SC, steady-state) were prospectively enrolled. Total ertapenem concentrations [residual (C0), IV peak (C0.5) and SC peak (C2.5)] were determined by UV HPLC. Individual-predicted AUC0–24 values were calculated and population pharmacokinetic analyses were performed. Using the final model, a Monte Carlo simulation involving 10 000 patients evaluated the influence of SC or IV administration on the PTA. Tolerance to ertapenem and recovery were also monitored. ClinicalTrials.gov identifier: NCT02505386. Results Ten (mean ± SD age=87±7 years) and 16 (age=88±5 years) patients were included in the IV and SC groups, respectively. The mean C0 and C2.5 values were not significantly different between the IV and SC groups (C0=12±5.9 versus 12±7.4 mg/L, P=0.97; C2.5=97±42 versus 67±41 mg/L, P=0.99). The mean C0.5 was higher in the IV group compared with the SC group (C0.5=184±90 versus 51±66 mg/L, P=0.001). The mean individual AUCs (1126.92±334.99 mg·h/L for IV versus 1005.3±266.0 mg·h/L for SC, P=0.38) and PTAs were not significantly different between groups. No severe antibiotic-related adverse effects were noted. Conclusions SC administration of ertapenem is an alternative to IV administration in older patients.

scholarly journals O06 Methadone dosing strategies in preterm neonates can be simplified

2019 ◽  
Vol 104 (6) ◽  
pp. e3.1-e3
Author(s):  
T van Donge ◽  
S Samiee-Zafarghandy ◽  
M Pfister ◽  
G Koch ◽  
M Kalani ◽  
...  
Keyword(s):  
Gestational Age ◽  
Clinical Investigation ◽  
Withdrawal Symptoms ◽  
Preterm Neonates ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Open Label ◽  
Elimination Kinetics ◽  
Dosing Strategies ◽  
Dosing Strategy

AimsA dramatic increase in newborn infants with neonatal abstinence syndrome has been observed and these neonates are frequently treated with complex methadone dosing schemes to control their withdrawal symptoms. Despite its abundant use, hardly any data on the pharmacokinetics of methadone is available in preterm neonates. Therefore we investigated developmental pharmacokinetics of methadone and evaluated current dosing strategies and possible simplification in this vulnerable population.MethodsA single center open-label prospective study was performed to collect pharmacokinetic data after a single oral dose of methadone in preterm neonates. A population pharmacokinetic model was built to characterize developmental pharmacokinetics of methadone and to assess the effects of weight and age on clearance and volume of distribution. In addition, simulation techniques were applied to evaluate reported dosing scenarios, investigate methadone exposure levels and examine the feasibility of simplified dosing recommendations.ResultsIn total, 121 methadone concentrations were collected from 31 preterm neonates. The median weight and gestational age amounted 1.6 kg and 32 weeks, respectively. A one-compartment model with first order absorption and elimination kinetics best described the data for (R)- and (S)-methadone. Clearance was observed to be higher for the (R)-enantiomer as compared to the (S)-enantiomer (0.244 versus 0.167 L/h). Target exposures, based on simulations, can be maintained with a simplified dosing strategy during the first four days of treatment. It is therefore questionable if there is a need for the currently used more extended dosing regimen of methadone in neonates.conclusionsThis clinical investigation demonstrates that the clearance of methadone increases with advancing gestational age and higher clearance values and volumes of distribution can be observed for (R)-methadone as compared to (S)-methadone in preterm neonates. Simulations that account for developmental pharmacokinetics indicate that a simplified methadone dosing strategy can maintain target exposure to control withdrawal symptoms in preterm neonates.Disclosure(s)Nothing to disclose

scholarly journals Population Pharmacokinetics of Ceftizoxime Administered by Continuous Infusion in Clinically Ill Adult Patients

1998 ◽  
Vol 42 (7) ◽  
pp. 1783-1787 ◽  
Author(s):  
Bryan Facca ◽  
Bill Frame ◽  
Steve Triesenberg
Keyword(s):  
Serum Creatinine ◽  
Continuous Infusion ◽  
Population Pharmacokinetics ◽  
Bacterial Infections ◽  
Pharmacokinetic Analysis ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Beta Lactam ◽  
Serum Samples ◽  
Mixed Effect

ABSTRACT Ceftizoxime is a widely used beta-lactam antimicrobial agent, but pharmacokinetic data for use with clinically ill patients are lacking. We studied the population pharmacokinetics of ceftizoxime in 72 clinically ill patients at a community-based, university-affiliated hospital. A population pharmacokinetic model for ceftizoxime was created by using a prospective observational design. Ceftizoxime was administered by continuous infusion to treat patients with proven or suspected bacterial infections. While the patients were receiving infusions of ceftizoxime, serum samples were collected for pharmacokinetic analysis with the nonlinear mixed-effect modeling program NONMEM. In addition to clearance and volume of distribution, various comorbidities were examined for their influence on the kinetics. All 72 subjects completed the study, and 114 serum samples were collected. Several demographic and comorbidity variables, namely, age, weight, serum creatinine levels, congestive heart failure, and long-term ventilator dependency, had a significant impact on the estimate for ceftizoxime clearance. A mixture model, or two populations for estimation of ceftizoxime clearance, was discovered. One population presented with an additive clearance component of 1.6 liters per h. In addition, a maximizer function for serum creatinine levels was found. In summary, two models for ceftizoxime clearance, mixture and nonmixture, were found and are presented. Clearance for ceftizoxime can be estimated with commonly available clinical information and the models presented. From the clearance estimates, the dose of ceftizoxime to maintain the desired concentration in serum can be determined. Work is needed to validate the model for drug clearance and to evaluate its predictive performance.

scholarly journals Population Pharmacokinetics and Dosing Optimization of Linezolid in Pediatric Patients

2019 ◽  
Vol 63 (4) ◽  
Author(s):  
Si-Chan Li ◽  
Qi Ye ◽  
Hua Xu ◽  
Long Zhang ◽  
Yang Wang
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetics ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Pediatric Patients ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Nonparametric Bootstrap ◽  
Bootstrap Analysis ◽  
Final Model

ABSTRACT Linezolid is a synthetic antibiotic very effective in the treatment of infections caused by Gram-positive pathogens. Although the clinical application of linezolid in children has increased progressively, data on linezolid pharmacokinetics in pediatric patients are very limited. The aim of this study was to develop a population pharmacokinetic model for linezolid in children and optimize the dosing strategy in order to improve therapeutic efficacy. We performed a prospective pharmacokinetic study of pediatric patients aged 0 to 12 years. The population pharmacokinetic model was developed using the NONMEM program. Goodness-of-fit plots, nonparametric bootstrap analysis, normalized prediction distribution errors, and a visual predictive check were employed to evaluate the final model. The dosing regimen was optimized based on the final model. The pharmacokinetic data from 112 pediatric patients ages 0.03 to 11.9 years were analyzed. The pharmacokinetics could best be described by a one-compartment model with first-order elimination along with body weight and the estimated glomerular filtration rate as significant covariates. Simulations demonstrated that the currently approved dosage of 10 mg/kg of body weight every 8 h (q8h) would lead to a high risk of underdosing for children in the presence of bacteria with MICs of ≥2 mg/liter. To reach the pharmacokinetic target, an elevated dosage of 15 or 20 mg/kg q8h may be required for them. The population pharmacokinetics of linezolid were characterized in pediatric patients, and simulations provide an evidence-based approach for linezolid dosage individualization.

scholarly journals A Population Pharmacokinetic Modeling Approach Shows that Serum Penicillin G Concentrations Are Below Inhibitory Concentrations by Two Weeks after Benzathine Penicillin G Injection in the Majority of Young Adults

2014 ◽  
Vol 58 (11) ◽  
pp. 6735-6741 ◽  
Author(s):  
Michael Neely ◽  
Edward L. Kaplan ◽  
Jeffrey L. Blumer ◽  
Dennis J. Faix ◽  
Michael P. Broderick
Keyword(s):  
Young Adults ◽  
Central Compartment ◽  
Penicillin G ◽  
Simulated Patients ◽  
Peripheral Compartment ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data ◽  
Benzathine Penicillin ◽  
Final Population ◽  
Benzathine Penicillin G

ABSTRACTSerum penicillin G falls to low levels 2 weeks after injection as benzathine penicillin G (BPG) in young adults. Using Pmetrics and previously reported penicillin G pharmacokinetic data after 1.2 million units were given as BPG to 329 male military recruits, here we develop the first reported population pharmacokinetic model of penicillin G after BPG injection. We simulated time-concentration profiles over a broad range of pediatric and adult weights after alternative doses and dose frequencies to predict the probability of maintaining serum penicillin G concentrations of >0.02 mg/liter, a proposed protective threshold against group AStreptococcus pyogenes(GAS). The final population model included linear absorption into a central compartment, distribution to and from a peripheral compartment, and linear elimination from the central compartment, with allometrically scaled volumes and rate constants. With 1.2 million units of BPG given intramuscularly every 4 weeks in four total doses, only 23.2% of 5,000 simulated patients maintained serum penicillin G trough concentrations of >0.02 mg/liter 4 weeks after the last dose. When the doses were 1.8 million units and 2.4 million units, the percentages were 30.2% and 40.7%, respectively. With repeated dosing of 1.2 million units every 3 weeks and every 2 weeks for 4 doses, the percentages of simulated patients with a penicillin G trough concentration of >0.02 mg/liter were 37.8% and 65.2%, respectively. Our simulations support recommendations for more frequent rather than higher BPG doses to prevent recurrent rheumatic heart disease in areas of high GAS prevalence or during outbreaks.

Evaluating the Accuracy of Using Population Pharmacokinetic Data to Predict Plasma Concentrations of Alfentanil

1988 ◽  
Vol 68 (1) ◽  
pp. 59-67 ◽  
Author(s):  
Pierre O. Maitre ◽  
Max E. Ausems ◽  
Samuel Vozeh ◽  
Donald R. Stanski
Keyword(s):  
Plasma Concentrations ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Data
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