Population Pharmacokinetic Model for a Novel Oral Hypoglycemic Formed In Vivo: Comparing the Use of Active Metabolite Data Alone Versus Using Data of Upstream and Downstream Metabolites

2012 ◽  
Vol 52 (3) ◽  
pp. 404-415 ◽  
Author(s):  
Helen Kastrissios ◽  
Joseph R. Walker ◽  
Timothy J. Carrothers ◽  
Smita Kshirsagar ◽  
Tatiana Khariton ◽  
...  
Keyword(s):  
Active Metabolite ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Using Data

scholarly journals Bayesian Parameter Estimates of Nelfinavir and Its Active Metabolite, Hydroxy-tert-Butylamide, in Infants Perinatally Infected with Human Immunodeficiency Virus Type 1

2005 ◽  
Vol 49 (2) ◽  
pp. 525-535 ◽  
Author(s):  
Salomé Payen ◽  
Albert Faye ◽  
Alexandra Compagnucci ◽  
Carlo Giaquinto ◽  
Diana Gibbs ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Body Weight ◽  
Human Immunodeficiency Virus Type ◽  
Active Metabolite ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Parameter Estimates ◽  
Immunodeficiency Virus

ABSTRACT The objective of the present study was to develop a population pharmacokinetic model for nelfinavir mesylate (NFV) and nelfinavir hydroxy-tert-butylamide (M8), the most abundant metabolite of NFV, in infants vertically infected with human immunodeficiency virus type 1 and participating in the Paediatric European Network for Treatment of AIDS 7 study. Plasma NFV concentrations were determined during repeated NFV administrations (two to three times a day). Eighteen infants younger that age 2 years participated in this study. The doses administered ranged from 71 to 203 mg/kg of body weight/day. Pharmacokinetic parameter estimates were obtained by a compartmental approach by using a kinetic model to simultaneously fit NFV and M8 (active metabolite) concentrations. M8 was shown to be formation rate limited and was characterized by first-order rate constants of formation and elimination. Body weight was found to be a more appropriate predictor than age of the changes in (i) the rate of metabolism, (ii) the elimination rate constant of NFV, and (iii) NFV clearance. Population parameters were computed to account for the relationship between the rate of metabolism and body weight. The estimated NFV and M8 elimination half-lives were 4.3 and 2.04 h, respectively. The estimated NFV clearance was 2.13 liters/h/kg. The M8 concentration-to-NFV concentration ratio was 0.64 ± 0.44. In conclusion, the population pharmacokinetic model describing the dispositions of NFV and M8 should facilitate the design of future studies to elucidate the relative contributions of the parent compound and M8 to the pharmacological and toxic effects of NFV therapy.

Pharmacokinetic/pharmacodynamic analysis of romidepsin used as an HIV latency reversing agent

2020 ◽  
Author(s):  
José Moltó ◽  
Miriam Rosás-Umbert ◽  
Cristina Miranda ◽  
Christian Manzardo ◽  
Maria C Puertas ◽  
...  
Keyword(s):  
T Cells ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Hiv Latency ◽  
Apoptosis Markers ◽  
In Vivo Effects ◽  
The Relationship ◽  
Hiv 1

Abstract Objectives To develop a population pharmacokinetic model for romidepsin given as an HIV latency reversing agent (LRA) and to explore the relationship between romidepsin exposure and its in vivo effects on viral gene expression and antiviral immunity. Methods A population pharmacokinetic analysis was performed in 15 HIV-1-infected patients who received three weekly infusions of romidepsin (5 mg/m2) within the BCN02 clinical trial. A full pharmacokinetic profile was obtained for each participant at the first dose, and additional samples thereafter. A population pharmacokinetic model was developed. Bayesian estimates of the individual pharmacokinetic parameters of romidepsin were used to simulate individual time–concentration curves on each occasion. The relationship between romidepsin AUC0–∞ and its in vivo effects was assessed. Results Romidepsin pharmacokinetics were best described by a three-compartment model with linear kinetics. Body weight influenced romidepsin disposition. A significant relationship was observed between romidepsin AUC0–∞ and increases in expression of exhaustion markers by CD4+ and CD8+ T cells and apoptosis markers in CD4+, but not with histone acetylation levels or HIV-1 cell-associated RNA in CD4+ T cells. For each increase of 100 ng·h/mL in romidepsin AUC0–∞, CD4+ counts decreased by a mean (95% CI) of 74 (42–94) cells/mm3 after dosing. Conclusions A population model describing the pharmacokinetics of romidepsin as an HIV LRA was developed. Higher exposure to romidepsin resulted in higher expression of apoptosis markers and declines in CD4+ count but did not increase viral reactivation levels. These observations have important implications for the optimization of effective kick-and-kill strategies for an HIV-1 cure.

scholarly journals External Evaluation of a Gentamicin Infant Population Pharmacokinetic Model Using Data from a National Electronic Health Record Database

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Shufan Ge ◽  
Ryan J. Beechinor ◽  
Christoph P. Hornik ◽  
Joseph F. Standing ◽  
Kanecia Zimmerman ◽  
...  
Keyword(s):  
Electronic Health Record ◽  
Population Pharmacokinetic Model ◽  
Pharmacokinetic Model ◽  
Population Pharmacokinetic ◽  
Health Record ◽  
External Evaluation ◽  
Data Source ◽  
Electronic Health ◽  
Using Data ◽  
Neonates And Infants

ABSTRACTGentamicin is a common antibiotic used in neonates and infants. A recently published population pharmacokinetic (PK) model was developed using data from multiple studies, and the objective of our analyses was to evaluate the feasibility of using a national electronic health record (EHR) database for further external evaluation of this model. Our results suggest that, with proper data capture procedures, EHR data can serve as a potential data source for external evaluation of PK models.

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 Model-Informed Optimization of a Pediatric Clinical Pharmacokinetic Trial of a New Spironolactone Liquid Formulation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 849
Author(s):  
Manasa Tatipalli ◽  
Vijay Kumar Siripuram ◽  
Tao Long ◽  
Diana Shuster ◽  
Galina Bernstein ◽  
...  
Keyword(s):  
Pharmacokinetic Model ◽  
Allometric Scaling ◽  
Pediatric Patients ◽  
Reference Product ◽  
Population Pharmacokinetic ◽  
Liquid Formulation ◽  
Sampling Schemes ◽  
Quantitative Pharmacology ◽  
Using Data ◽  
Drug Pharmacokinetics

Quantitative pharmacology brings important advantages in the design and conduct of pediatric clinical trials. Herein, we demonstrate the application of a model-based approach to select doses and pharmacokinetic sampling scenarios for the clinical evaluation of a novel oral suspension of spironolactone in pediatric patients with edema. A population pharmacokinetic model was developed and qualified for spironolactone and its metabolite, canrenone, using data from adults and bridged to pediatrics (2 to <17 years old) using allometric scaling. The model was then used via simulation to explore different dosing and sampling scenarios. Doses of 0.5 and 1.5 mg/kg led to target exposures (i.e., similar to 25 and 100 mg of the reference product in adults) in all the reference pediatric ages (i.e., 2, 6, 12 and 17 years). Additionally, two different sampling scenarios were delineated to accommodate patients into sparse sampling schemes informative to characterize drug pharmacokinetics while minimizing phlebotomy and burden to participating children.

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