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

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.

Switching to a Dual-Drug Regimen in HIV-Infected Patients Could Be Associated With Macrophage Activation?

“…We suggest this might be due to diminished drug pressure on either tissue or cellular reservoirs. Indeed, it has been shown that INSTI diffusion in lymph nodes, with the exception of Elvitegravir, is generally poor ( 27 ), thus potentially exposing the virus to sub-optimal concentrations of antiretroviral compounds in this reservoir. Besides, the fact that the percentage of patients with VLLV increased after cART simplification could be in favor of an association between immune activation and poorer pharmacological control in reservoirs.…”

Hepatocytic transcriptional signatures predict comparative drug interaction potential of rifamycin antibiotics

“…PHHs were treated with rifampin, rifabutin and rifapentine at 10 µM concentration for 72 h. with the corresponding untreated (negative) and 0.0025% methanol (vehicle) treated controls. We measured intracellular concentrations (ICC) of parent and des-acetyl-metabolites by liquid chromatography tandem mass spectroscopy (LC-MS/MS) as we have previously described [45][46][47][48][49] .…”

Pharmacology of HIV Cure: Site of Action

“…Finally, Dyavar et al . examined LN tissue from mice dosed with dolutegravir and found a penetration ratio (PR) of 0.08, suggesting poor penetration; however, human LN data are not available for this INSTI 45 …”

“…44 Finally, Dyavar et al examined LN tissue from mice dosed with dolutegravir and found a penetration ratio (PR) of 0.08, suggesting poor penetration; however, human LN data are not available for this INSTI. 45 Data regarding concentrations of LRAs in the LNs are minimal. Rosen et al examined panobinostat by mass spectrometry imaging in the LNs of three NHPs chronically infected with SIV and suppressed on ART.…”