Population Modeling Highlights Drug Disposition Differences Between Tenofovir Alafenamide and Tenofovir Disoproxil Fumarate in the Blood and Semen

被引：14

作者：

Greene, Stephen A. ^{[1
,4
]}

Chen, Jingxian ^{[1
,5
]}

Prince, Heather M. A. ^{[2
]}

Sykes, Craig ^{[1
]}

Schauer, Amanda P. ^{[1
]}

Blake, Kimberly ^{[1
]}

Nelson, Julie A. E. ^{[3
]}

Gay, Cynthia L. ^{[2
]}

Cohen, Myron S. ^{[2
]}

Dumond, Julie B. ^{[1
]}

机构：

[1] Univ N Carolina, Eshelman Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27515 USA

[2] Univ N Carolina, Sch Med, Dept Internal Med, Div Infect Dis, Chapel Hill, NC 27515 USA

[3] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27515 USA

[4] SK Life Sci Inc, Fair Lawn, NJ USA

[5] Merck Co, Philadelphia, PA USA

来源：

CLINICAL PHARMACOLOGY & THERAPEUTICS | 2019年 / 106卷 / 04期

关键词：

SANCTUARY SITES; GENITAL-TRACT; PHARMACOKINETICS; HIV; SAFETY; QUANTIFICATION; PRODRUG; SINGLE; CELLS; MEN;

D O I：

10.1002/cpt.1464

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

Understanding antiretroviral disposition in the male genital tract, a distinct viral compartment, can provide insight for the eradication of HIV. Population pharmacokinetic modeling was conducted to investigate the disposition of tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and emtricitabine and their metabolites in blood and semen. Blood plasma and seminal plasma (SP) concentrations of tenofovir and emtricitabine were measured, as were tenofovir-diphosphate and emtricitabine-triphosphate concentrations in peripheral blood mononuclear cells (PBMCs) and seminal mononuclear cells. Sequential compartmental modeling described drug disposition in blood and semen. Our modeling suggests slower elimination of apparent tenofovir-diphosphate PBMC and faster elimination of tenofovir SP after administration of TAF compared with TDF, likely reflecting flip-flop kinetics. Additionally, TAF metabolism to tenofovir appeared slower in semen compared with blood; however, SP elimination of TAF-derived tenofovir appeared faster than its blood plasma elimination. These findings provide valuable insight for further mechanistic study of cellular entry and drug metabolism in the male genital tract.

引用

页码：821 / 830

页数：10

共 31 条

[1] The role of latency reversal agents in the cure of HIV: A review of current data [J].

Bashiri, Kiandokht ;

Rezaei, Nima ;

Nasi, Milena ;

Cossarizza, Andrea .

IMMUNOLOGY LETTERS, 2018, 196 :135-139

[2] Ways to fit a PK model with some data below the quantification limit [J].

Beal, SL .

JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS, 2001, 28 (05) :481-504

[3] Handling Data Below the Limit of Quantification in Mixed Effect Models [J].

Bergstrand, Martin ;

Karlsson, Mats O. .

AAPS JOURNAL, 2009, 11 (02) :371-380

[4] Single- and Multiple-Dose Pharmacokinetics of Darunavir Plus Ritonavir and Etravirine in Semen and Rectal Tissue of HIV-Negative Men [J].

Brown, Kevin C. ;

Patterson, Kristine B. ;

Jennings, Steven H. ;

Malone, Stephanie A. ;

Shaheen, Nicholas J. ;

Prince, Heather M. Asher ;

Spacek, Melissa ;

Cohen, Myron S. ;

Kashuba, Angela D. M. .

JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES, 2012, 61 (02) :138-144

[5] Population Pharmacokinetics of Tenofovir and Tenofovir-Diphosphate in Healthy Women [J].

Burns, Rebecca N. ;

Hendrix, Craig W. ;

Chaturvedula, Ayyappa .

JOURNAL OF CLINICAL PHARMACOLOGY, 2015, 55 (06) :629-638

[6] HIV reservoirs: what, where and how to target them [J].

Churchill, Melissa J. ;

Deeks, Steven G. ;

Margolis, David M. ;

Siliciano, Robert F. ;

Swanstrom, Ronald .

NATURE REVIEWS MICROBIOLOGY, 2016, 14 (01) :55-60

[7] A Translational Pharmacology Approach to Predicting Outcomes of Preexposure Prophylaxis Against HIV in Men and Women Using Tenofovir Disoproxil Fumarate With or Without Emtricitabine [J].

Cottrell, Mackenzie L. ;

Yang, Kuo H. ;

Prince, Heather M. A. ;

Sykes, Craig ;

White, Nicole ;

Malone, Stephanie ;

Dellon, Evan S. ;

Madanick, Ryan D. ;

Shaheen, Nicholas J. ;

Hudgens, Michael G. ;

Wulff, Jacob ;

Patterson, Kristine B. ;

Nelson, Julie A. E. ;

Kashuba, Angela D. M. .

JOURNAL OF INFECTIOUS DISEASES, 2016, 214 (01) :55-64

[8] Pharmacokinetics and Safety of Tenofovir Alafenamide in HIV-Uninfected Subjects with Severe Renal Impairment [J].

Custodio, Joseph M. ;

Fordyce, Marshall ;

Garner, William ;

Vimal, Mona ;

Ling, Kah Hiing J. ;

Kearney, Brian P. ;

Ramanathan, Srinivasan .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2016, 60 (09) :5135-5140

[9] Differential extracellular, but similar intracellular, disposition of two tenofovir formulations in the male genital tract [J].

Dumond, Julie B. ;

Greene, Stephen A. ;

Prince, Heather M. A. ;

Chen, Jingxian ;

Maas, Brian M. ;

Sykes, Craig ;

Schauer, Amanda P. ;

Blake, Kimberly H. ;

Nelsons, Julie A. E. ;

Gay, Cynthia L. ;

Kashuba, Angela D. M. ;

Cohen, Myron S. .

ANTIVIRAL THERAPY, 2019, 24 (01) :45-50

[10] Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: the male and female genital tract [J].

Else, Laura J. ;

Taylor, Stephen ;

Back, David J. ;

Khoo, Saye H. .

ANTIVIRAL THERAPY, 2011, 16 (08) :1149-1167

← 1 2 3 4 →