Assessing the lymphoid tissue bioavailability of antiretrovirals in human primary lymphoid endothelial cells and in mice

Shetty Ravi Dyavar, Nagsen Gautam, Anthony T Podany, Lee C. Winchester, Jonathan A. Weinhold, Timothy M. Mykris, Kayla M. Campbell, Yazen Alnouti, Courtney V Fletcher

Research output: Contribution to journalArticle

Abstract

BACKGROUND: The secondary lymphoid tissues (LTs), lymph nodes (LNs) and gut-associated lymphoid tissue (GALT) are considered reservoirs for HIV. Antiretrovirals (ARVs) have lower penetration into LT. In vitro models predictive of ARV LT penetration have not been established. OBJECTIVES: To develop an in vitro model of LT bioavailability using human lymphoid endothelial cells (HLECs) and investigate its predictability with in vivo pharmacokinetic (PK) studies in mice. METHODS: ARV bioavailability in HLECs was evaluated at the maximum plasma concentration (Cmax) observed in HIV-infected patients. ARVs were: abacavir, atazanavir, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, maraviroc, raltegravir, rilpivirine, ritonavir, tenofovir disoproxil fumarate and the PK booster cobicistat. The LT PK of representative drugs showing high (efavirenz), intermediate (dolutegravir) and low (emtricitabine) HLEC bioavailability was investigated in BALB/c mice given 50/10/30 mg/kg efavirenz/dolutegravir/emtricitabine orally, daily for 3 days. The concordance of in vitro and in vivo ARV bioavailability was examined. RESULTS: ARVs showed high (>67th percentile; rilpivirine, efavirenz, elvitegravir and cobicistat), intermediate (67th-33rd percentile; ritonavir, tenofovir disoproxil fumarate, dolutegravir and maraviroc) and low (<33rd percentile; atazanavir, darunavir, raltegravir, emtricitabine and abacavir) HLEC bioavailability. The hierarchy of efavirenz, dolutegravir and emtricitabine bioavailability in LN, gut and brain tissues of mice was: efavirenz>dolutegravir>emtricitabine. CONCLUSIONS: ARVs displayed distinct HLEC penetration patterns. PK studies of representative ARVs in LT of mice were concordant with HLEC bioavailability. These findings support further development of this approach and its translational predictability in humans.

Original languageEnglish (US)
Pages (from-to)2974-2978
Number of pages5
JournalThe Journal of antimicrobial chemotherapy
Volume74
Issue number10
DOIs
StatePublished - Oct 1 2019

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efavirenz
Lymphoid Tissue
Biological Availability
Endothelial Cells
Lymphocytes
Rilpivirine
Tenofovir
Pharmacokinetics
Ritonavir
HIV
Lymph Nodes
dolutegravir
Emtricitabine
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Microbiology (medical)
  • Pharmacology (medical)
  • Infectious Diseases

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Assessing the lymphoid tissue bioavailability of antiretrovirals in human primary lymphoid endothelial cells and in mice. / Dyavar, Shetty Ravi; Gautam, Nagsen; Podany, Anthony T; Winchester, Lee C.; Weinhold, Jonathan A.; Mykris, Timothy M.; Campbell, Kayla M.; Alnouti, Yazen; Fletcher, Courtney V.

In: The Journal of antimicrobial chemotherapy, Vol. 74, No. 10, 01.10.2019, p. 2974-2978.

Research output: Contribution to journalArticle

Dyavar, Shetty Ravi ; Gautam, Nagsen ; Podany, Anthony T ; Winchester, Lee C. ; Weinhold, Jonathan A. ; Mykris, Timothy M. ; Campbell, Kayla M. ; Alnouti, Yazen ; Fletcher, Courtney V. / Assessing the lymphoid tissue bioavailability of antiretrovirals in human primary lymphoid endothelial cells and in mice. In: The Journal of antimicrobial chemotherapy. 2019 ; Vol. 74, No. 10. pp. 2974-2978.
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AU - Gautam, Nagsen

AU - Podany, Anthony T

AU - Winchester, Lee C.

AU - Weinhold, Jonathan A.

AU - Mykris, Timothy M.

AU - Campbell, Kayla M.

AU - Alnouti, Yazen

AU - Fletcher, Courtney V

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N2 - BACKGROUND: The secondary lymphoid tissues (LTs), lymph nodes (LNs) and gut-associated lymphoid tissue (GALT) are considered reservoirs for HIV. Antiretrovirals (ARVs) have lower penetration into LT. In vitro models predictive of ARV LT penetration have not been established. OBJECTIVES: To develop an in vitro model of LT bioavailability using human lymphoid endothelial cells (HLECs) and investigate its predictability with in vivo pharmacokinetic (PK) studies in mice. METHODS: ARV bioavailability in HLECs was evaluated at the maximum plasma concentration (Cmax) observed in HIV-infected patients. ARVs were: abacavir, atazanavir, darunavir, dolutegravir, efavirenz, elvitegravir, emtricitabine, maraviroc, raltegravir, rilpivirine, ritonavir, tenofovir disoproxil fumarate and the PK booster cobicistat. The LT PK of representative drugs showing high (efavirenz), intermediate (dolutegravir) and low (emtricitabine) HLEC bioavailability was investigated in BALB/c mice given 50/10/30 mg/kg efavirenz/dolutegravir/emtricitabine orally, daily for 3 days. The concordance of in vitro and in vivo ARV bioavailability was examined. RESULTS: ARVs showed high (>67th percentile; rilpivirine, efavirenz, elvitegravir and cobicistat), intermediate (67th-33rd percentile; ritonavir, tenofovir disoproxil fumarate, dolutegravir and maraviroc) and low (<33rd percentile; atazanavir, darunavir, raltegravir, emtricitabine and abacavir) HLEC bioavailability. The hierarchy of efavirenz, dolutegravir and emtricitabine bioavailability in LN, gut and brain tissues of mice was: efavirenz>dolutegravir>emtricitabine. CONCLUSIONS: ARVs displayed distinct HLEC penetration patterns. PK studies of representative ARVs in LT of mice were concordant with HLEC bioavailability. These findings support further development of this approach and its translational predictability in humans.

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