Pharmacokinetic profile of raltegravir, elvitegravir and dolutegravir in plasma and mucosal secretions in rhesus macaques

Massud, Ivana; Martin, Amy; Dinh, Chuong; Mitchell, James; Jenkins, Leecresia; Heneine, Walid; Pau, Chou‐Pong; Garcı́a-Lerma, J. Gerardo

doi:10.1093/jac/dku556

Cited by 30 publications

(25 citation statements)

References 41 publications

(44 reference statements)

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“…Rhesus macaques administered 50 mg/kg TAF/FTC/EVG/COB orally demonstrated peak TFV levels of 1,326 ng/mL and AUC of 9,934 ng×h/mL (21). The plasma AUC for EVG in macaques (Rhesus, 50 mg/kg) was reported as 4,012 ng×h/mL (22). In contrast, the plasma TFV AUC and EVG AUC in the CD34 + -NSG mice in this study were approximately 2.3 and 9.9-fold higher than AUC observed in macaques with equivalent dosing.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and Elvitegravir Loaded Nanoparticles in Humanized Mice Model

et al. 2017

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Purpose Non-adherence to the antiretroviral (ARV) regimen is a critical factor in determining efficacy of ARV drugs for pre-exposure prophylaxis (PrEP). A long-acting parenteral formulation may be an effective alternative to daily oral dosing. A pharmacokinetic and tissue distribution study of drug-loaded nanoparticle (NP) was performed in female humanized CD34+-NSG mice. Methods Mice received 200 mg/kg each of tenofovir alafenamide (TAF) and elvitegravir (EVG) as free drugs (TAF+EVG solution) or as drug loaded NP (TAF+EVG NP) formulation by subcutaneous (SubQ) administration. Plasma and tissue were collected to determine tenofovir (TFV) and EVG concentrations using LC-MS/MS. Non-compartmental analysis was performed using WinNonlin. Results SubQ administration of TAF+EVG NP formulation resulted in long residence time and exposure for both drugs. The AUC(0–72h) of TFV and EVG was 14.1±2.0, 7.2±1.8 μg×hr/mL from drugs in solution (free) and the AUC(0–14day) for the same drugs was 23.1±4.4, 39.7±6.7 μg×hr/mL from NPs. The observed elimination half-life (t1/2) for TFV of free and NPs were 14.2 h, 5.1 days and for EVG 10.8 h, 3.3 days, respectively. Conclusion This study documents that a TAF+EVG NP provides sustained release, which can overcome patient non-adherence to dosing and may facilitate prediction of appropriate protective drug concentration for HIV prophylaxis.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetic and Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and Elvitegravir Loaded Nanoparticles in Humanized Mice Model

et al. 2017

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“…Systemically TAF penetrates into tissue better than TDF (28). As another component of ARV combination regimen, we chose EVG, an anti-HIV integrase strand transfer inhibitor (29). However, not much literature could be found regarding the concentration-response relationship for EVG.…”

Section: Discussionmentioning

confidence: 99%

Tenofovir alafenamide and elvitegravir loaded nanoparticles for long-acting prevention of HIV-1 vaginal transmission

Mandal

Prathipati

Kang

et al. 2017

Aids

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Objective This report presents tenofovir alafenamide (TAF) and elvitegravir (EVG) fabricated into nanoparticles (NPs) for subcutaneous (SubQ) delivery as prevention strategy. Design Prospective prevention study in hu-BLT mice. Methods Using an oil-in-water emulsion solvent evaporation technique, TAF+EVG drugs were entrapped together into NPs containing poly(lactic-co-glycolic acid) (PLGA). In vitro prophylaxis studies (IC90) compared NPs to drugs in solution. Humanized-BLT (n=5/group) mice were given 200 mg/kg SubQ, and vaginally challenged with HIV-1 (5×105 TCID50) 4 and 14 days (d) post-NP administration (PI). Control mice (n=5) were challenged at 4 d. Weekly plasma viral load (pVL) was performed using RT-PCR. Hu-BLT mice were sacrificed and lymph nodes were harvested for HIV-1 viral RNA detection by in situ hybridization (ISH). In parallel, CD34+ humanized mice (3/time point) compared tenofovir (TFV) and EVG drug levels in vaginal tissues from NPs and solution. TFV and EVG were analyzed from tissue using LC-MS/MS. Results TAF+EVG NPs were < 200 nm in size. In-vitro prophylaxis indicates TAF+EVG NPs IC90 was 0.002 μg/mL and TAF+EVG solution was 0.78 μg/mL. TAF+EVG NPs demonstrated detectable drugs for 14 days and 72 h for solution, respectively. All Hu-BLT control mice became infected within 14 d after HIV-1 challenge. In contrast, hu-BLT mice that received NPs and challenged at 4 d PI, 100% were uninfected, and 60% challenged at 14 d PI were uninfected (p = 0.007; Mantel-Cox test). ISH confirmed these results. Conclusions This proof-of-concept study demonstrated sustained protection for TAF+EVG NPs in a hu-BLT mouse model of HIV vaginal transmission.

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“…Given that several of these transporters have been shown to efflux numerous antiretrovirals, the species used in investigations of ART disposition into tissues, whether for prevention or eradication, is a critically important variable. RAL, for example, has been shown to reach rectal concentrations that are 35-fold greater than plasma in macaques[25]. We have also recently shown that RAL distributes readily throughout the macaque rectum, but that distribution in humanized mouse rectum is lacking[26].…”

Section: Discussionmentioning

confidence: 99%

Multimodal analysis of drug transporter expression in gastrointestinal tissue

Thompson

Fallon²,

Mathews³

et al. 2017

Aids

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Objectives Drug transporters affect ART tissue disposition, but quantitative measures of drug transporter protein expression across pre-clinical species are not available. Our objective was to use proteomics to obtain absolute transporter concentrations and assess agreement with corresponding gene and immunometric protein data. Design In order to make interspecies comparisons, two humanized mouse (hu-HSC-Rag (n=41); BLT (n=13)) and one primate (rhesus macaque, (NHP, n=12)) models were dosed to steady-state with combination ART. Ileum and rectum were collected at necropsy and snap frozen for analysis. Methods Tissues were analyzed for gene (qPCR) and protein (LC-MS proteomics and Western blot) expression and localization (immunohistochemistry) of ART efflux and uptake transporters. Drug concentrations were measured by LC-MS/MS. Multivariable regression was used to determine the ability of transporter data to predict tissue ART penetration. Results Analytical methods did not agree, with different trends observed for gene and protein expression. For example, qPCR analysis showed a 2-fold increase in permeability glycoprotein (Pgp) expression in NHPs versus mice, however proteomics showed a 200-fold difference in the opposite direction. Proteomics results were supported by IHC staining showing extensive efflux transporter localization on the luminal surface of these tissues. ART tissue concentration was variable between species, and multivariable regression showed poor predictive power of transporter data. Conclusions Lack of agreement between analytical techniques suggests that resources should be focused on generating downstream measures of protein expression to predict drug exposure. Taken together, these data inform the use of pre-clinical models for studying ART distribution and the design of targeted therapies for HIV eradication.

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Pharmacokinetic profile of raltegravir, elvitegravir and dolutegravir in plasma and mucosal secretions in rhesus macaques

Cited by 30 publications

References 41 publications

Pharmacokinetic and Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and Elvitegravir Loaded Nanoparticles in Humanized Mice Model

Pharmacokinetic and Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and Elvitegravir Loaded Nanoparticles in Humanized Mice Model

Tenofovir alafenamide and elvitegravir loaded nanoparticles for long-acting prevention of HIV-1 vaginal transmission

Multimodal analysis of drug transporter expression in gastrointestinal tissue

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