Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles

AbstractTreatment and prevention of human immunodeficiency virus type one (HIV-1) infection was transformed through widespread use of antiretroviral therapy (ART). However, ART has limitations in requiring life-long daily adherence. Such limitations have led to the creation of long-acting (LA) ART. While nucleoside reverse transcriptase inhibitors (NRTI) remain the ART backbone, to the best of our knowledge, none have been converted into LA agents. To these ends, we transformed tenofovir (TFV) into LA surfactant stabilized aqueous prodrug nanocrystals (referred to as NM1TFV and NM2TFV), enhancing intracellular drug uptake and retention. A single intramuscular injection of NM1TFV, NM2TFV, or a nanoformulated tenofovir alafenamide (NTAF) at 75 mg/kg TFV equivalents to Sprague Dawley rats sustains active TFV-diphosphate (TFV-DP) levels ≥ four times the 90% effective dose for two months. NM1TFV, NM2TFV and NTAF elicit TFV-DP levels of 11,276, 1,651, and 397 fmol/g in rectal tissue, respectively. These results are a significant step towards a LA TFV ProTide.

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Corrigendum to “Nanoencapsulation introduces long-acting phenomenon to tenofovir alafenamide and emtricitabine drug combination: A comparative pre-exposure prophylaxis efficacy study against HIV-1 vaginal transmission” [Journal of Controlled Release 294 (2019) 216–225]

Journal of Controlled Release ◽

10.1016/j.jconrel.2019.05.002 ◽

2019 ◽

Vol 304 ◽

pp. 101

Author(s):

Subhra Mandal ◽

Guobin Kang ◽

Pavan Kumar Prathipati ◽

You Zhou ◽

Wenjin Fan ◽

...

Keyword(s):

Controlled Release ◽

Drug Combination ◽

Efficacy Study ◽

Vaginal Transmission ◽

Tenofovir Alafenamide ◽

Long Acting ◽

Exposure Prophylaxis ◽

Hiv 1

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Pharmacokinetics of Long-Acting Tenofovir Alafenamide (GS-7340) Subdermal Implant for HIV Prophylaxis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00656-15 ◽

2015 ◽

Vol 59 (7) ◽

pp. 3913-3919 ◽

Cited By ~ 96

Author(s):

Manjula Gunawardana ◽

Mariana Remedios-Chan ◽

Christine S. Miller ◽

Rob Fanter ◽

Flora Yang ◽

...

Keyword(s):

Sustained Release ◽

Vulnerable Populations ◽

Mononuclear Cells ◽

Systemic Exposure ◽

Systemic Delivery ◽

Tenofovir Alafenamide ◽

Long Acting ◽

Pharmacologically Active ◽

Hiv 1 ◽

Subdermal Implant

ABSTRACTOral or topical daily administration of antiretroviral (ARV) drugs to HIV-1-negative individuals in vulnerable populations is a promising strategy for HIV-1 prevention. Adherence to the dosing regimen has emerged as a critical factor determining efficacy outcomes of clinical trials. Because adherence to therapy is inversely related to the dosing period, sustained release or long-acting ARV formulations hold significant promise for increasing the effectiveness of HIV-1 preexposure prophylaxis (PrEP) by reducing dosing frequency. A novel, subdermal implant delivering the potent prodrug tenofovir alafenamide (TAF) with controlled, sustained, zero-order (linear) release characteristics is described. A candidate device delivering TAF at 0.92 mg day−1in vitrowas evaluated in beagle dogs over 40 days for pharmacokinetics and preliminary safety. No adverse events related to treatment with the test article were noted during the course of the study, and no significant, unusual abnormalities were observed. The implant maintained a low systemic exposure to TAF (median, 0.85 ng ml−1; interquartile range [IQR], 0.60 to 1.50 ng ml−1) and tenofovir (TFV; median, 15.0 ng ml−1; IQR, 8.8 to 23.3 ng ml−1), the product ofin vivoTAF hydrolysis. High concentrations (median, 512 fmol/106cells over the first 35 days) of the pharmacologically active metabolite, TFV diphosphate, were observed in peripheral blood mononuclear cells at levels over 30 times higher than those associated with HIV-1 PrEP efficacy in humans. Our report on the first sustained-release nucleoside reverse transcriptase inhibitor (NRTI) for systemic delivery demonstrates a successful proof of principle and holds significant promise as a candidate for HIV-1 prophylaxis in vulnerable populations.

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Multispecies Evaluation of a Long-Acting Tenofovir Alafenamide Subdermal Implant for HIV Prophylaxis

Frontiers in Pharmacology ◽

10.3389/fphar.2020.569373 ◽

2020 ◽

Vol 11 ◽

Author(s):

Manjula Gunawardana ◽

Mariana Remedios-Chan ◽

Debbie Sanchez ◽

Simon Webster ◽

Patricia Galvan ◽

...

Keyword(s):

Animal Models ◽

Active Agent ◽

The Body ◽

Dermal Tissue ◽

Metabolite Concentrations ◽

Tenofovir Alafenamide ◽

Long Acting ◽

Exposure Prophylaxis ◽

Hiv 1 ◽

Subdermal Implant

New HIV-1 infection rates far outpace the targets set by global health organizations, despite important progress in curbing the progression of the epidemic. Long-acting (LA) formulations delivering antiretroviral (ARV) agents for HIV-1 pre-exposure prophylaxis (PrEP) hold significant promise, potentially facilitating adherence due to reduced dosing frequency compared to oral regimens. We have developed a subdermal implant delivering the potent ARV drug tenofovir alafenamide that could provide protection from HIV-1 infection for 6 months, or longer. Implants from the same lot were investigated in mice and sheep for local safety and pharmacokinetics (PKs). Ours is the first report using these animal models to evaluate subdermal implants for HIV-1 PrEP. The devices appeared safe, and the plasma PKs as well as the drug and metabolite concentrations in dermal tissue adjacent to the implants were studied and contrasted in two models spanning the extremes of the body weight spectrum. Drug and drug metabolite concentrations in dermal tissue are key in assessing local exposure and any toxicity related to the active agent. Based on our analysis, both animal models were shown to hold significant promise in LA product development.

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Dynamics of the Decay of Human Immunodeficiency Virus (HIV) RNA and Distribution of Bictegravir in the Genital Tract and Rectum in Antiretroviral-naive Adults Living With HIV–1 Treated With Bictegravir/Emtricitabine/Tenofovir Alafenamide (Spanish HIV/AIDS Research Network, PreEC/RIS 58)

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1416 ◽

2020 ◽

Author(s):

Arkaitz Imaz ◽

Juan M Tiraboschi ◽

Jordi Niubó ◽

Javier Martinez-Picado ◽

Mackenzie L Cottrell ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Research Network ◽

People Living With Hiv ◽

Limit Of Quantification ◽

Immunodeficiency Virus ◽

Liquid Chromatography Tandem Mass ◽

Half Maximal Effective Concentration ◽

Tenofovir Alafenamide ◽

Living With Hiv ◽

Hiv 1

Abstract Background The pharmacokinetics of bictegravir (BIC) and its association with the decay of human immunodeficiency virus (HIV)–1 RNA in genital fluids and the rectum have not yet been addressed. Methods We conducted a prospective, multicenter study of antiretroviral-naive people living with HIV-1 and initiating BIC/emtricitabine (FTC)/tenofovir alafenamide (TAF). HIV-1 RNA was measured (limit of quantification, 40 copies/mL) in blood plasma (BP), seminal plasma (SP), rectal fluid (RF), and cervicovaginal fluid (CVF) at baseline; Days 3, 7, 14, and 28; and Weeks 12 and 24. Total and protein-unbound BIC concentrations at 24 hours postdose (C24h) were quantified in BP, SP, CVF and rectal tissue (RT) on Day 28 and Week 12 using a validated liquid chromatography-tandem mass spectrometry assay. Results The study population comprised 15 males and 8 females. In SP, RF, and CVF, the baseline HIV-1 RNA was >40 copies/mL in 12/15, 13/15, and 4/8 individuals, respectively, with medians of 3.54 (2.41–3.79), 4.19 (2.98–4.70), and 2.56 (1.61–3.56) log10 copies/mL, respectively. The initial decay slope was significantly lower in SP than in RF and BP. The time to undetectable HIV-1 RNA was significantly shorter in SP and RF than in BP. All women achieved undetectable HIV-1 RNA in CVF at Day 14. The median total BIC concentrations in SP, RT, and CVF were 65.5 (20.1–923) ng/mL, 74.1 (6.0–478.5) ng/g, and 61.6 (14.4–1760.2) ng/mL, respectively, representing 2.7%, 2.6%, and 2.8% of the BP concentration, respectively, while the protein-unbound fractions were 51.1%, 44.6%, and 42.6%, respectively. Conclusions BIC/FTC/TAF led to rapid decay of HIV-1 RNA in genital and rectal fluids. Protein-unbound BIC concentrations in SP, RT, and CVF highly exceeded the half-maximal effective concentration (EC50) value (1.1 ng/mL). Clinical Trials Registration EudraCT 2018-002310-12.

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Cholinergic vasodilation of intracerebral arterioles in rats

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1987.253.5.h1253 ◽

1987 ◽

Vol 253 (5) ◽

pp. H1253-H1260 ◽

Cited By ~ 4

Author(s):

R. G. Dacey ◽

J. E. Bassett

Keyword(s):

Vessel Diameter ◽

Sprague Dawley ◽

Cholinergic Mechanisms ◽

Smooth Muscle Contractility ◽

Cholinergic Mechanism ◽

In Situ Data ◽

Prostaglandin F2 Alpha ◽

Sprague Dawley Rats ◽

Long Acting

Much morphological and physiological evidence indicates that cholinergic mechanisms play a significant role in the control of cerebral blood flow. Despite in situ data suggesting that an intrinsic cholinergic mechanism produces vasodilation in the intracerebral microcirculation, there is no direct information on the effect of acetylcholine (ACh) on intracerebral arterioles. We investigated cholinergic mechanisms in isolated perfused intracerebral arterioles from pentobarbital sodium-anesthetized Sprague-Dawley rats. In arterioles with resting diameters of 46.8 +/- 6.6 microns (mean +/- SE) ACh produced no significant dilation at pH 7.30. At pH 7.60, however, a significant dose-dependent dilation to a maximum of 119.0 +/- 1.0% of control diameter was observed. Carbachol, a long-acting cholinergic agonist, similarly failed to dilate vessels at pH 7.30 but significantly dilated vessels at pH 7.60. Prostaglandin F2 alpha produced a maximum contraction to 68.3 +/- 2.7% of control diameter (n = 8). ACh at concentrations of 10(-4) and 2 X 10(-4) M induced a significant dilation of this prostaglandin-induced contraction. In vessels similarly preconstricted with serotonin, 10(-4) M ACh produced significant dilation. Atropine, having no effect on vessel diameter when administered alone, blocked cholinergic vasodilation of intracerebral arterioles at pH 7.60. Attempts at endothelial removal, although successful in eliminating endothelial cells from the preparation, significantly impaired smooth muscle contractility. ACh has no significant effect on the spontaneous cerebrovascular tone in this preparation, but in vessels preconstricted by a variety of means it produced vasodilation mediated by atropine sensitive receptors.

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Patient-reported outcomes for HIV: the future of long-acting injectables and antiretroviral therapy evaluations

Future Virology ◽

10.2217/fvl-2020-0322 ◽

2021 ◽

Author(s):

Richard Leong ◽

Leon Owusu ◽

Jerrica Tang ◽

Neeraj John ◽

Kira E Voyer ◽

...

Keyword(s):

Antiretroviral Therapy ◽

Treatment Satisfaction ◽

Patient Reported Outcomes ◽

Potential Role ◽

Drug Regimen ◽

Patient Reported ◽

Immunodeficiency Virus ◽

Long Acting ◽

Hiv 1 ◽

Human Immunodeficiency Virus 1

Patient-reported outcomes (PROs) are an increasingly important aspect of patient care, as they offer a perspective from the patient themselves in the treatment and management of a particular disease state. They have a potential role in helping clinicians select an appropriate drug regimen in human immunodeficiency virus-1 (HIV-1)-infected individuals, as well as those with HIV/hepatitis C (HCV) co-infection. They can also provide insight for individuals receiving long-acting (LA) injectable antiretroviral therapy (ART). Studies found from PROs that participants on an LA injectable ART regimen reported greater preference and treatment satisfaction compared with those on an oral ART regimen. Some additional studies have also used PROs to evaluate the switch to single-tablet regimens and compare different ART in treating HIV-1. Current PROs and how they can be improved for LA injectables were also discussed.

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Stochastic modeling for dynamics of HIV-1 infection using cellular automata: A review

Journal of Bioinformatics and Computational Biology ◽

10.1142/s021972001630001x ◽

2016 ◽

Vol 14 (01) ◽

pp. 1630001 ◽

Cited By ~ 4

Author(s):

Monamorn Precharattana

Keyword(s):

Human Immunodeficiency Virus ◽

Cellular Automata ◽

Immune Cells ◽

Lymphoid Tissue ◽

Discrete Models ◽

Future Studies ◽

Immunodeficiency Virus ◽

Significant Step ◽

Hiv 1

Recently, the description of immune response by discrete models has emerged to play an important role to study the problems in the area of human immunodeficiency virus type 1 (HIV-1) infection, leading to AIDS. As infection of target immune cells by HIV-1 mainly takes place in the lymphoid tissue, cellular automata (CA) models thus represent a significant step in understanding when the infected population is dispersed. Motivated by these, the studies of the dynamics of HIV-1 infection using CA in memory have been presented to recognize how CA have been developed for HIV-1 dynamics, which issues have been studied already and which issues still are objectives in future studies.

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