scholarly journals A population pharmacokinetic model for escitalopram and its major metabolite in depressive patients during the perinatal period: Prediction of infant drug exposure through breast milk

2020 ◽  
Vol 86 (8) ◽  
pp. 1642-1653
Author(s):  
Etienne Weisskopf ◽  
Monia Guidi ◽  
Céline J. Fischer ◽  
Myriam Bickle Graz ◽  
Etienne Beaufils ◽  
...  
Keyword(s):  
Breast Milk ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Perinatal Period ◽  
Major Metabolite ◽  
Population Pharmacokinetic ◽  
Depressive Patients

scholarly journals Population Pharmacokinetic Model for Gatifloxacin in Pediatric Patients

2007 ◽  
Vol 51 (4) ◽  
pp. 1246-1252 ◽  
Author(s):  
Christopher M. Rubino ◽  
Edmund V. Capparelli ◽  
John S. Bradley ◽  
Jeffrey L. Blumer ◽  
Gregory L. Kearns ◽  
...  
Keyword(s):  
Body Weight ◽  
Surface Area ◽  
Body Surface Area ◽  
Body Surface ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Population Pharmacokinetic ◽  
Forward Selection ◽  
Once Daily

ABSTRACT The broad spectrum of antimicrobial activity, oral bioavailability, extensive tissue distribution, and once-daily intravenous or oral dosing of gatifloxacin, an expanded-spectrum 8-methoxy fluoroquinolone, make it a potentially useful agent for the treatment of pediatric infections. A population pharmacokinetic model was developed to describe the pharmacokinetics of gatifloxacin in children. Data for analysis were obtained from a single-dose safety/pharmacokinetic study utilizing intensive blood sampling in patients aged 6 months to 16 years. Each subject received a single oral dose of gatifloxacin as a suspension, at doses of 5, 10, or 15 mg/kg of body weight. A total of 845 samples were obtained from 82 patients. A one-compartment model with first-order absorption and elimination was the most appropriate to describe the gatifloxacin concentrations. Covariate analysis using forward selection and backward elimination found that apparent clearance was related to body surface area, and apparent volume of distribution was related to body weight. No effect of age on drug clearance could be identified once clearance was corrected for body surface area. Based on pharmacokinetic simulations, the 10-mg/kg (maximum, 400 mg) once-daily dose of gatifloxacin is expected to provide drug exposure similar to that in healthy adults. The population pharmacokinetic model described herein will be used for Bayesian analyses of sparse pharmacokinetic sampling in phase II/III clinical trials and for Monte Carlo simulation experiments. The success of this strategy provides a model for future pediatric drug development programs.

Population pharmacokinetics of fondaparinux administered at prophylactic doses after major orthopaedic surgery in everyday practice

2010 ◽  
Vol 104 (08) ◽  
pp. 252-260 ◽  
Author(s):  
Paul Zufferey ◽  
Denis Baylot ◽  
Philippe Nguyen ◽  
Jeanne-Yvonne Borg ◽  
Michaela Fontenay ◽  
...  
Keyword(s):  
Body Weight ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Compartment Model ◽  
Individual Variability ◽  
Everyday Practice ◽  
Population Pharmacokinetic ◽  
Antithrombotic Agent ◽  
Orthopaedic Patients

SummaryFondaparinux is a synthetic antithrombotic agent with specific anti-factor Xa activity. A population pharmacokinetic model of fondaparinux, based on data obtained in patients included in phase II/III trials, has been described. However, the validity of this model in everyday practice needed to be confirmed. This study was a multicenter, prospective cohort study in consecutive orthopaedic patients treated with 2.5 mg of fondaparinux. Anti-Xa activities were recorded in 809 patients. Population parameters and inter-individual variability were estimated using NONMEM VI software. A two-compartment model with first-order absorption best described fondaparinux pharmacokinetics. Covariates partly explaining inter-individual variability were body weight, age and creatinine clearance estimated by the simplified Modification of Diet in Renal Disease formula (MDRD). A body weight less than 50 kg and moderate renal failure increased drug exposure. Although the population pharmacokinetic model of fondaparinux was described, this one requires to be validated in everyday practice.

scholarly journals Development of population and Bayesian models for applied use in patients receiving cefepime

2019 ◽  
Author(s):  
Jiajun Liu ◽  
Michael Neely ◽  
Jeffrey Lipman ◽  
Fekade Sime ◽  
Jason Roberts ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Model Performance ◽  
Compartment Model ◽  
Population Pharmacokinetic ◽  
List Type ◽  
Beta Lactam ◽  
Lactam Antibiotic

AbstractUnderstanding exposures of cefepime, a β-lactam antibiotic, is crucial for developing regimens to achieve optimal exposure and improved clinical outcomes. This study sought to develop and evaluate a unified population pharmacokinetic model in both pediatric and adult patients receiving cefepime treatment. Multiple physiologically relevant models were fit to pediatric and adult subject data. To evaluate the final model performance, a withheld group of twelve pediatric and two separate adult populations were assessed. Seventy subjects with a total of 604 cefepime concentrations were included in this study. All adults (n=34) on average weighed 82.7 kg and displayed a mean creatinine clearance (CrCL) of 106.7 mL/min. All pediatric subjects (n=36) had mean weight and CrCL of 16.0 kg and 195.64 mL/min, respectively. A covariate-adjusted two compartment model described the observed concentrations well (population model R2, 87.0%; Bayesian model R2, 96.5%). In the evaluation subsets, the model performed similarly well (population R2, 84.0%; Bayesian R2, 90.2%). The identified model serves well for population dosing and as a Bayesian prior for precision dosing.Key pointsA unified cefepime population pharmacokinetic model has been developed from adult and pediatric patients and evaluates well in independent populations.When paired with real time beta-lactam assays, precision dosing approach will optimize drug exposure and improve clinical outcomes.

scholarly journals Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice—a prospective single-center trial

2021 ◽  
Author(s):  
Nora Isberner ◽  
Sabrina Kraus ◽  
Götz Ulrich Grigoleit ◽  
Fatemeh Aghai ◽  
Max Kurlbaum ◽  
...  
Keyword(s):  
Adverse Events ◽  
Graft Versus Host Disease ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Chronic Gvhd ◽  
Population Pharmacokinetic ◽  
Host Disease ◽  
Graft Versus Host ◽  
Trough Concentrations

Abstract Purpose Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects. Methods 262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed. Results Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6–99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05). Conclusion Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.

scholarly journals Population Pharmacokinetics of Micafungin in Pediatric Patients and Implications for Antifungal Dosing

2007 ◽  
Vol 51 (10) ◽  
pp. 3714-3719 ◽  
Author(s):  
William W. Hope ◽  
Nita L. Seibel ◽  
Cindy L. Schwartz ◽  
Antonio Arrieta ◽  
Patricia Flynn ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Pediatric Patients ◽  
Population Pharmacokinetic ◽  
Power Model ◽  
Pharmacokinetic Models ◽  
Dosage Regimens ◽  
Log Likelihood ◽  
Antifungal Efficacy

ABSTRACT The echinocandins potentially have an important role in treatment of infections caused by Candida spp. and Aspergillus spp. in immunocompromised children. However, there are no population pharmacokinetic models of the echinocandins for pediatric patients. The safety and descriptive pharmacokinetics of micafungin in children were recently reported. However, a population pharmacokinetic model in children is needed in order to accurately determine the dosage of micafungin that produces an equivalent magnitude of drug exposure to that observed in adults. In order to explore the effect of weight on micafungin pharmacokinetics, a standard two-compartment pharmacokinetic model, a linear model, and an allometric power model were developed. For all three models, the fit to the data was excellent, with comparable measures of precision and bias. However, the superior log-likelihood value of the allometric power model suggested that it best reflected the data and was therefore chosen for a more detailed analysis of the magnitude and pattern of drug exposure which develop following the administration of micafungin. The allometric power model suggested that clearance in smaller children is higher than that predicted on the basis of weight alone. Consequently, a degree of dosage increase is required in smaller children to ensure comparable levels of drug exposure to those observed in larger children and adults. The allometric power model developed in this study enables identification of pediatric dosage regimens of micafungin which, based upon Monte Carlo simulations, result in equivalent drug exposures to those observed in adults, for which antifungal efficacy has been established.

The relationship between simulated milrinone exposure and hypotension in children

2021 ◽  
pp. 1-7
Author(s):  
Sarah Jane Commander ◽  
Daniel Gonzalez ◽  
Karan R. Kumar ◽  
Tracy Spears ◽  
Michael Cohen-Wolkowiez ◽  
...  
Keyword(s):  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Multivariable Analysis ◽  
Population Pharmacokinetic ◽  
Maximum Plasma ◽  
Electronic Health Record Data ◽  
Clinically Significant ◽  
The Relationship

Abstract Introduction: Hypotension is an adverse event that may be related to systemic exposure of milrinone; however, the true exposure–safety relationship is unknown. Methods: Using the Pediatric Trials Network multicentre repository, we identified children ≤17 years treated with milrinone. Hypotension was defined according to age, using the Pediatric Advanced Life Support guidelines. Clinically significant hypotension was defined as hypotension with concomitant lactate >3 mg/dl. A prior population pharmacokinetic model was used to simulate milrinone exposures to evaluate exposure–safety relationships. Results: We included 399 children with a median (quarter 1, quarter 3) age of 1 year (0,5) who received 428 intravenous doses of milrinone (median infusion rate 0.31 mcg/kg/min [0.29,0.5]). Median maximum plasma milrinone concentration was 110.7 ng/ml (48.4,206.2). Median lowest systolic and diastolic blood pressures were 74 mmHg (60,85) and 35 mmHg (25,42), respectively. At least 1 episode of hypotension occurred in 178 (45%) subjects; clinically significant hypotension occurred in 10 (2%). The maximum simulated milrinone plasma concentrations were higher in subjects with clinically significant hypotension (251 ng/ml [129,329]) versus with hypotension alone (86 ng/ml [44, 173]) versus without hypotension (122 ng/ml [57, 208], p = 0.002); however, this relationship was not retained on multivariable analysis (odds ratio 1.01; 95% confidence interval 0.998, 1.01). Conclusions: We successfully leveraged a population pharmacokinetic model and electronic health record data to evaluate the relationship between simulated plasma concentration of milrinone and systemic hypotension occurrence, respectively, supporting the broader applicability of our novel, efficient, and cost-effective study design for examining drug exposure–response and –safety relationships.

scholarly journals Population Pharmacokinetic Model for Intravenous ASN100 in Healthy Subjects

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S529-S529
Author(s):  
Scott A Van Wart ◽  
Christopher Stevens ◽  
Zoltan Magyarics ◽  
Steven A Luperchio ◽  
Paul G Ambrose
Keyword(s):  
Healthy Subjects ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic

scholarly journals Pharmacokinetics and Pharmacogenetics of Cyclophosphamide in a Neonate and Infant Childhood Cancer Patient Population

2021 ◽  
Vol 14 (3) ◽  
pp. 272
Author(s):  
Shelby Barnett ◽  
Julie Errington ◽  
Julieann Sludden ◽  
David Jamieson ◽  
Vianney Poinsignon ◽  
...  
Keyword(s):  
Cancer Patient ◽  
Childhood Cancer ◽  
Patient Population ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Drug Clearance ◽  
Current Data ◽  
Population Pharmacokinetic ◽  
Older Children ◽  
Patient Groups

Infants and young children represent an important but much understudied childhood cancer patient population. The pharmacokinetics and pharmacogenetics of the widely used anticancer prodrug cyclophosphamide were investigated in children <2 years of age. Concentrations of cyclophosphamide and selected metabolites were determined in patients administered cyclophosphamide at doses ranging from 100–1500 mg/m2 (5–75 mg/kg), with various infusion times as determined by the standard treatment regimen that each patient was receiving. Polymorphisms in genes including CYP2B6 and CYP2C19 were investigated. Data generated for cyclophosphamide were analysed using a previously published population pharmacokinetic model. Cyclophosphamide pharmacokinetics was assessed in 111 samples obtained from 25 patients ranging from 4–23 months of age. The average cyclophosphamide clearance for the patients was 46.6 mL/min/m2 (ranging from 9.4–153 mL/min/m2), with marked inter-patient variability observed (CV 41%). No significant differences in cyclophosphamide clearance or exposure (AUC) were observed between patient groups as separated by age or body weight. However, marked differences in drug clearance and metabolism were noted between the current data in children <2 years of age and recently published results from a comparable study conducted by our group in older children, which reported significantly lower cyclophosphamide clearance values and metabolite exposures using the same population pharmacokinetic model for analysis. Whilst this study demonstrates no significant differences in cyclophosphamide clearance in patients <2 years, it highlights large differences in dosing protocols across tumour types. Furthermore, the study suggests marked differences in cyclophosphamide clearance in children less than two years of age as compared to older patients.

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