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Your search keyword '"Mackenzie L. Cottrell"' showing total 3 results
Start Over Author "Mackenzie L. Cottrell" Journal cpt: pharmacometrics & systems pharmacology
3 results on '"Mackenzie L. Cottrell"'

1. A multicompartment population PK model to predict tenofovir and emtricitabine mucosal tissue concentrations for HIV prevention

Author

Erick Leung, Mackenzie L. Cottrell, Craig Sykes, Nicole White, Angela D. M. Kashuba, and Julie B. Dumond

Subjects
Therapeutics. Pharmacology, RM1-950
Abstract

Abstract A priori use of mathematical modeling and simulation to predict outcomes from incomplete adherence or reduced frequency dosing strategies may mitigate the risk of clinical trial failure with HIV pre‐exposure prophylaxis regimens. We developed a semi‐physiologic population pharmacokinetic model for two antiretrovirals and their active intracellular metabolites in three mucosal tissues using pharmacokinetic data from a phase I, dose‐ranging study. Healthy female volunteers were given a single oral dose of tenofovir disoproxil fumarate (150, 300, or 600 mg) or emtricitabine (100, 200, or 400 mg). Simultaneous co‐modeling of all data was performed on a Linux cluster. A 16 compartment, bolus input, linear kinetic model best described the data, containing 986 observations in 23 individuals across three matrices and four analytes. Combined with a defined efficacious concentration target in mucosal tissues, this model can be used to optimize the dose and dosing frequency through Monte‐Carlo simulations.

Published
2023
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2. p16 INK4a , a Senescence Marker, Influences Tenofovir/Emtricitabine Metabolite Disposition in HIV‐Infected Subjects

Author

Julie B. Dumond, Alan Forrest, Ruili Wang, Stephanie Malone, Craig Sykes, Christine Trezza, Kristine B. Patterson, Heather M.A. Prince, Nicholas J. White, Chad Torrice, J. W. Collins, Mackenzie L. Cottrell, and Norman E. Sharpless

Subjects
0301 basic medicine, Senescence, education.field_of_study, business.industry, Metabolite, Population, Pharmacology, Emtricitabine, 030112 virology, Peripheral blood mononuclear cell, 3. Good health, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Pharmacokinetics, chemistry, Modeling and Simulation, Medicine, Pharmacology (medical), 030212 general & internal medicine, Young adult, business, education, Nucleoside, medicine.drug
Abstract

The goal of this study was to explore the relationships between tenofovir (TFV) and emtricitabine (FTC) disposition and markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression. Chronologic age is often explored in population pharmacokinetic (PK) analyses, and can be uninformative in capturing the impact of aging on physiology, particularly in human immunodeficiency virus (HIV)-infected patients. Ninety-one HIV-infected participants provided samples to quantify plasma concentrations of TFV/FTC, as well as peripheral blood mononuclear cell (PBMC) samples for intracellular metabolite concentrations; 12 participants provided 11 samples, and 79 participants provided 4 samples, over a dosing interval. Nonlinear mixed effects modeling of TFV/FTC and their metabolites suggests a relationship between TFV/FTC metabolite clearance (CL) from PBMCs and the expression of p16INK4a , a marker of cellular senescence. This novel approach to quantifying the influence of aging on PKs provides rationale for further work investigating the relationships between senescence and nucleoside phosphorylation and transport.

Published
2016
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3. Population Pharmacokinetics Modeling of Unbound Efavirenz, Atazanavir, and Ritonavir in HIV‐Infected Subjects With Aging Biomarkers

Author

Ruili Wang, Stephanie Malone, Kristine B. Patterson, Jingxian Chen, Mackenzie L. Cottrell, Nicholas J. White, Christine Trezza, Chad Torrice, Craig Sykes, Heather M.A. Prince, Norman E. Sharpless, Julie B. Dumond, and Alan Forrest

Subjects
0301 basic medicine, Drug, Adult, Cyclopropanes, Male, Efavirenz, Anti-HIV Agents, media_common.quotation_subject, Frail Elderly, Population, Atazanavir Sulfate, HIV Infections, Pharmacology, 030226 pharmacology & pharmacy, 03 medical and health sciences, chemistry.chemical_compound, Young Adult, 0302 clinical medicine, Pharmacokinetics, Medicine, Body Size, Humans, Pharmacology (medical), education, Cyclin-Dependent Kinase Inhibitor p16, media_common, Aged, education.field_of_study, Ritonavir, business.industry, Age Factors, Original Articles, Middle Aged, 030112 virology, 3. Good health, Atazanavir, Benzoxazines, chemistry, Nonlinear Dynamics, Modeling and Simulation, Alkynes, Original Article, Drug Therapy, Combination, Female, business, Body mass index, medicine.drug
Abstract

Unbound drug is the pharmacodynamically relevant concentration. This study aimed to determine if chronologic age or markers of biologic aging, such as the frailty phenotype and p16INK4a gene expression, altered unbound pharmacokinetics (PKs) of efavirenz (EFV) and atazanavir/ritonavir (ATV/RTV). Sixty human immunodeficiency virus (HIV)-infected participants receiving EFV and 31 receiving ATV/RTV provided 1 to 11 samples to quantify total and unbound plasma concentrations. Population PK models with total and unbound concentrations simultaneously described are developed for each drug. The unbound fractions for EFV, ATV, and RTV are 0.65%, 5.67%, and 0.63%, respectively. Covariate analysis suggests RTV unbound PK is sensitive to body size; unbound fraction of RTV is 34% lower with body mass index (BMI) above 30 kg/m2 . No alterations in drug clearance or unbound fraction with age, frailty, or p16INK4a expression were observed. Assessing functional and physiologic aging markers to inform potential PK changes is necessary to determine if drug/dosing changes are warranted in the aging population.

Published
2016

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