Erin M B Scholz1, Yanguang Cao1, Angela D M Kashuba1,2. 1. Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, 301 Pharmacy Lane, Chapel Hill, NC 27599, USA. 2. School of Medicine, University of North Carolina at Chapel Hill, 321 S Columbia Street, Chapel Hill, NC 27516, USA.
Abstract
BACKGROUND: Investigating antiretroviral (ARV) penetration and pharmacology in lymph nodes is crucial to understanding mechanisms of HIV persistence in tissue, but sampling these tissues in humans is invasive and costly. Physiologically based pharmacokinetic (PBPK) modelling is a non-invasive solution for understanding lymph node penetration of ARVs across multiple species. OBJECTIVES: To develop customized PBPK models with a novel lymph node compartment, and use these models to describe the distribution of three ARVs-tenofovir, emtricitabine and efavirenz-into the plasma and lymph nodes of non-human primates (NHPs) and humans. MATERIALS AND METHODS: In this analysis, we utilized standard monkey and human PBPK models in PK-Sim, and added a novel lymph node compartment using MoBi. We used these models to describe the distribution of tenofovir, emtricitabine and efavirenz into NHP and human plasma and lymph nodes, and compared model-predicted versus observed AUC and Cmax. RESULTS: For all three ARVs, population simulations using the base and final models reasonably characterized observed plasma and tissue data in NHPs and humans, with predicted/observed AUC and Cmax ratios within 0.7-2.0. CONCLUSIONS: Overall, our novel PBPK model provides a framework for understanding lymph node penetration of ARVs or future HIV cure therapies.
BACKGROUND: Investigating antiretroviral (ARV) penetration and pharmacology in lymph nodes is crucial to understanding mechanisms of HIV persistence in tissue, but sampling these tissues in humans is invasive and costly. Physiologically based pharmacokinetic (PBPK) modelling is a non-invasive solution for understanding lymph node penetration of ARVs across multiple species. OBJECTIVES: To develop customized PBPK models with a novel lymph node compartment, and use these models to describe the distribution of three ARVs-tenofovir, emtricitabine and efavirenz-into the plasma and lymph nodes of non-human primates (NHPs) and humans. MATERIALS AND METHODS: In this analysis, we utilized standard monkey and human PBPK models in PK-Sim, and added a novel lymph node compartment using MoBi. We used these models to describe the distribution of tenofovir, emtricitabine and efavirenz into NHP and human plasma and lymph nodes, and compared model-predicted versus observed AUC and Cmax. RESULTS: For all three ARVs, population simulations using the base and final models reasonably characterized observed plasma and tissue data in NHPs and humans, with predicted/observed AUC and Cmax ratios within 0.7-2.0. CONCLUSIONS: Overall, our novel PBPK model provides a framework for understanding lymph node penetration of ARVs or future HIV cure therapies.
Authors: Erin Burgunder; John K Fallon; Nicole White; Amanda P Schauer; Craig Sykes; Leila Remling-Mulder; Martina Kovarova; Lourdes Adamson; Paul Luciw; J Victor Garcia; Ramesh Akkina; Philip C Smith; Angela D M Kashuba Journal: J Pharmacol Exp Ther Date: 2019-06-24 Impact factor: 4.030
Authors: William R McManus; Michael J Bale; Jonathan Spindler; Ann Wiegand; Andrew Musick; Sean C Patro; Michele D Sobolewski; Victoria K Musick; Elizabeth M Anderson; Joshua C Cyktor; Elias K Halvas; Wei Shao; Daria Wells; Xiaolin Wu; Brandon F Keele; Jeffrey M Milush; Rebecca Hoh; John W Mellors; Stephen H Hughes; Steven G Deeks; John M Coffin; Mary F Kearney Journal: J Clin Invest Date: 2019-07-30 Impact factor: 14.808
Authors: Mary F Kearney; Ann Wiegand; Wei Shao; William R McManus; Michael J Bale; Brian Luke; Frank Maldarelli; John W Mellors; John M Coffin Journal: Open Forum Infect Dis Date: 2017-09-19 Impact factor: 3.835
Authors: Koen K A Van Rompay; Raman P Singh; Bapi Pahar; Donald L Sodora; Casey Wingfield; Jonathan R Lawson; Marta L Marthas; Norbert Bischofberger Journal: J Virol Date: 2004-05 Impact factor: 5.103
Authors: J B Dumond; J W Collins; M L Cottrell; C R Trezza; Hma Prince; C Sykes; C Torrice; N White; S Malone; R Wang; K B Patterson; N E Sharpless; A Forrest Journal: CPT Pharmacometrics Syst Pharmacol Date: 2016-12-26
Authors: J B Dumond; J Chen; M Cottrell; C R Trezza; Hma Prince; C Sykes; C Torrice; N White; S Malone; R Wang; K B Patterson; N E Sharpless; A Forrest Journal: CPT Pharmacometrics Syst Pharmacol Date: 2016-12-29
Authors: Ramon Lorenzo-Redondo; Helen R Fryer; Trevor Bedford; Eun-Young Kim; John Archer; Sergei L Kosakovsky Pond; Yoon-Seok Chung; Sudhir Penugonda; Jeffrey Chipman; Courtney V Fletcher; Timothy W Schacker; Michael H Malim; Andrew Rambaut; Ashley T Haase; Angela R McLean; Steven M Wolinsky Journal: Nature Date: 2016-01-27 Impact factor: 49.962
Authors: Kevin M Watt; Michael Cohen-Wolkowiez; Jeffrey S Barrett; Michael Sevestre; Ping Zhao; Kim L R Brouwer; Andrea N Edginton Journal: CPT Pharmacometrics Syst Pharmacol Date: 2018-08-13