Pharmacokinetic Analysis of Drug Concentration Data Obtained during Repetitive Drug Administration

1977 ◽  
Vol 66 (4) ◽  
pp. 530-533 ◽  
Author(s):  
Colburn Wayne A ◽  
Milo Gibaldi
Keyword(s):  
Drug Administration ◽  
Drug Concentration ◽  
Pharmacokinetic Analysis ◽  
Concentration Data

scholarly journals Population Pharmacokinetics Modelling and Simulation of Mitotane in Patients with Adrenocortical Carcinoma: An Individualized Dose Regimen to Target All Patients at Three Months?

Pharmaceutics ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 566 ◽  
Author(s):  
Yoann Cazaubon ◽  
Yohann Talineau ◽  
Catherine Feliu ◽  
Céline Konecki ◽  
Jennifer Russello ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Plasma Concentrations ◽  
Therapeutic Index ◽  
Compartment Model ◽  
Volume Of Distribution ◽  
Pharmacokinetic Analysis ◽  
Concentration Data ◽  
Starting Dose ◽  
Dosing Regimens ◽  
Data Files

Mitotane is the most effective agent in post-operative treatment of adrenocortical carcinoma. In adults, the starting dose is 2–3 g/day and should be slightly increased to reach the therapeutic index of 14–20 mg/L. This study developed a population PK model for mitotane and to simulate recommended/high dosing regimens. We retrospectively analyzed the data files of 38 patients with 503 plasma concentrations for the pharmacokinetic analysis. Monolix version 2019R1 was used for non-linear mixed-effects modelling. Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA ≥ 14 mg/L) at one month and at three months. Mitotane concentration data were best described by a linear one-compartment model. The estimated PK parameters (between-subject variability) were: 8900 L (90.4%) for central volume of distribution (V) and 70 L·h−1 (29.3%) for clearance (Cl). HDL, Triglyceride (Tg) and a latent covariate were found to influence Cl. The PTA at three months for 3, 6, 9, and 12 g per day was 10%, 55%, 76%, and 85%, respectively. For a loading dose of 15 g/day for one month then 5 g/day, the PTA in the first and third months was 57 and 69%, respectively. This is the first PKpop model of mitotane highlighting the effect of HDL and Tg covariates on the clearance as well as a subpopulation of ultrafast metabolizer. The simulations suggest that recommended dose regimens are not enough to target the therapeutic threshold in the third month.

scholarly journals Pharmacokinetic analysis of coronary venous retroinfusion: A comparison with anterograde coronary artery drug administration using metoprolol as a tracer

1991 ◽  
Vol 18 (2) ◽  
pp. 603-612 ◽  
Author(s):  
Lars Rydén ◽  
Hiroyuki Tadokoro ◽  
Per-Ove Sjöquist ◽  
Carl Regardh ◽  
Shiro Kobayashi ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Drug Administration ◽  
Pharmacokinetic Analysis

scholarly journals vCOMBAT: a novel tool to create and visualize a computational model of bacterial antibiotic target-binding

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Vi Ngoc-Nha Tran ◽  
Alireza Shams ◽  
Sinan Ascioglu ◽  
Antal Martinecz ◽  
Jingyi Liang ◽  
...  
Keyword(s):  
Drug Concentration ◽  
Computational Models ◽  
Treatment Strategies ◽  
Extended Model ◽  
Concentration Data ◽  
Bacterial Populations ◽  
Web Based ◽  
Antibiotic Target ◽  
Dosing Regimens ◽  
Target Binding

Abstract Background As antibiotic resistance creates a significant global health threat, we need not only to accelerate the development of novel antibiotics but also to develop better treatment strategies using existing drugs to improve their efficacy and prevent the selection of further resistance. We require new tools to rationally design dosing regimens from data collected in early phases of antibiotic and dosing development. Mathematical models such as mechanistic pharmacodynamic drug-target binding explain mechanistic details of how the given drug concentration affects its targeted bacteria. However, there are no available tools in the literature that allow non-quantitative scientists to develop computational models to simulate antibiotic-target binding and its effects on bacteria. Results In this work, we have devised an extension of a mechanistic binding-kinetic model to incorporate clinical drug concentration data. Based on the extended model, we develop a novel and interactive web-based tool that allows non-quantitative scientists to create and visualize their own computational models of bacterial antibiotic target-binding based on their considered drugs and bacteria. We also demonstrate how Rifampicin affects bacterial populations of Tuberculosis bacteria using our vCOMBAT tool. Conclusions The vCOMBAT online tool is publicly available at https://combat-bacteria.org/.

scholarly journals REGEN-COV® antibody cocktail bioanalytical strategy: comparison of LC-MRM-MS and immunoassay methods for drug quantification

Bioanalysis ◽  
2021 ◽  
Author(s):  
Susan C Irvin ◽  
Samit Ganguly ◽  
Rachel Weiss ◽  
Chinnasamy Elango ◽  
Xuefei Zhong ◽  
...  
Keyword(s):  
Drug Concentration ◽  
Multiple Reaction Monitoring ◽  
Pharmacokinetic Data ◽  
Sample Analysis ◽  
Concentration Data ◽  
Phase Study ◽  
The Usa ◽  
Linear Correlations ◽  
Antibody Cocktail

Aim: In response to the COVID-19 pandemic, Regeneron developed the anti-SARS-CoV-2 monoclonal antibody cocktail, REGEN-COV® (RONAPREVE® outside the USA). Drug concentration data was important for determination of dose, so a two-part bioanalytical strategy was implemented to ensure the therapy was rapidly available for use. Results & methodology: Initially, a liquid chromatography-multiple reaction monitoring-mass spectrometry (LC-MRM-MS) assay, was used to analyze early-phase study samples. Subsequently, a validated electrochemiluminescence (ECL) immunoassay was implemented for high throughput sample analysis for all samples. A comparison of drug concentration data from the methods was performed which identified strong linear correlations and for Bland-Altman, small bias. In addition, pharmacokinetic data from both methods produced similar profiles and parameters. Discussion & conclusion: This novel bioanalytical strategy successfully supported swift development of a critical targeted therapy during the COVID-19 public health emergency.

Evaluation of PEG-FVIII Molecules with Prolonged Half-Lives in a Murine FVIII-Dependent Bleeding Model.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1624-1624 ◽  
Author(s):  
Kyle A. Landskroner ◽  
Zhi-Hua Cui ◽  
James Newgren ◽  
Michael Fournel ◽  
Glenn F. Pierce ◽  
...  
Keyword(s):  
Mouse Model ◽  
Drug Administration ◽  
Hemophilia A ◽  
Plasma Concentrations ◽  
Bleeding Event ◽  
Pharmacokinetic Analysis ◽  
Acute Hemorrhage ◽  
Acute Bleeding ◽  
Injury Model

Abstract Current treatment of patients with hemophilia A often requires the frequent infusion of Factor VIII (FVIII) due to its short circulating half-life. A longer-acting FVIII molecule could profoundly impact patients’ lives by extending bleeding protection with a reduced frequency of infusions. Several strategies to prolong plasma concentrations of FVIII have been attempted. In particular, targeting domains on FVIII that bind to LRP, the putative clearance receptor, has been a popular strategy. We have investigated the use of site-directed pegylation of B-domain deleted (BDD) FVIII to evaluate the utility of PEG as a method to decrease FVIII clearance through steric hindrance of LRP binding, or other unknown clearance mechanisms, while minimizing decreases in vWF binding and in vivo activity. The evaluation of novel constructs required the development of in vivo pharmacokinetic models and a FVIII-dependent bleed model. We describe the development of an acute bleed model following uniform tail transection in the hemophilia A mouse that is FVIII dependent and allows the evaluation of the acute pharmacologic effects of FVIII or variants in vivo. Pharmacokinetic analysis of recombinant FVIII (rFVIII) and its variants was performed in rabbits over 32-hours and rFVIII or variants were measured using a modified Coatest® to differentiate endogenous rabbit FVIII from the administered human FVIII. For efficacy evaluations, hemophilia A mice were anesthetized with isoflurane and their pre-warmed tail was cut by a scalpel and placed into a new tube of warmed saline (37–40°C). Blood was collected over 40 minutes and blood loss was measured gravimetrically. Three modes of treatment were evaluated: prevention of bleeding (drug was administered 5 minutes before injury), treatment of an acute bleeding event (drug was administered 5 minutes after injury), and a delayed injury model (tail cut occurred at 20 or 24 hours after the drug administration). Over the course of 40 minutes control (C57BL6) mice demonstrated negligible bleeding (approximately 41 ± 8 μL) compared to 919 ± 26 μL in hemophilia A mice. A dose response curve was constructed for doses ranging from 0.1 to 5.0 IU of human rFVIII per mouse. Hemophilia A mice treated with 200 IU/kg of human rFVIII (5 IU/mouse) lost a similar volume of blood as control mice. The protective effect was rFVIII dose dependent over a range of 4–200 IU/kg (0.1–5 IU/mouse). In contrast, more rFVIII was required to stop an acute bleeding event when administered after the injury. In the delayed injury model, mice injured 24 hours after drug administration had a significantly larger mean blood volume loss compared to mice injured 20 hours post drug administration. Pegylated rFVIII constructs with longer half-lives also had increased activity over time compared to non-pegylated rFVIII in this mouse model. These results describe a superior hemophilia A tail bleed model that demonstrates FVIII-dependent bleeding reduction in response to acute hemorrhage over a 40 minute time course. This is the first demonstration of a hemophilia A mouse model in which all untreated animals uniformly bleed and all control animals demonstrate negligible bleeding. This model was used to evaluate the in vivo hemostatic efficacy of new rFVIII molecules that were designed to have superior pharmacologic and/or pharmacokinetic properties compared to rFVIII.

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