Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment

McGowan, Ian; Dezzutti, Charlene S.; Siegel, Aaron; Engstrom, Jarret; Nikiforov, Alexiy; Duffill, Kathryn; Shetler, Cory; Richardson-Harman, Nicola; Abebe, Kaleab Z.; Back, David; Else, Laura; Egan, Deidre; Khoo, Saye; Egan, James E.; Stall, Ronald; Williams, Peter; Rehman, Khaleel K; Adler, Amy; Brand, Rhonda M.; Chen, Beatrice; Achilles, Sharon L.; Cranston, Ross D.

doi:10.1016/s2352-3018(16)30113-8

Cited by 72 publications

(58 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Cabotegravir and rilpivirine (two different dosage forms), injected in separate intramuscular sites, allow drug release predominantly from each injection site. As a result, it takes days to build up plasma drug levels in humans and the T max of each is variable (median 9–69 days [15], 6–11 days [16], depending on the dose). Among other considerations, the delay in reaching therapeutic levels requires an initial dose supplement for these formulations.…”

Section: Discussionmentioning

confidence: 99%

Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma

Kraft¹,

McConnachie²,

Koehn³

et al. 2017

Aids

View full text Add to dashboard Cite

Objective:The aim of the present study was to determine whether a combination of anti-HIV drugs – tenofovir (TFV), lopinavir (LPV) and ritonavir (RTV) – in a lipid-stabilized nanosuspension (called TLC-ART101) could enhance and sustain intracellular drug levels and exposures in lymph node and blood cells above those in plasma.Design:Four macaques were given a single dose of TLC-ART101 subcutaneously. Drug concentrations in plasma and mononuclear cells of the blood (PBMCs) and lymph nodes (LNMCs) were analysed using a validated combination LC-MS/MS assay.Results:For the two active drugs (TFV, LPV), plasma and PBMC intracellular drug levels persisted for over 2 weeks; PBMC drug exposures were three- to four-fold higher than those in plasma. Apparent terminal half-lives (t1/2) of TFV and LPV were 65.3 and 476.9 h in plasma, and 169.1 and 151.2 h in PBMCs. At 24 and 192 h, TFV and LPV drug levels in LNMCs were up to 79-fold higher than those in PBMCs. Analysis of PBMC intracellular TFV and its active metabolite TFV-diphosphate (TFV-DP) indicated that intracellular exposures of total TFV and TFV-DP were markedly higher and persisted longer than in humans and macaques dosed with oral TFV prodrugs, tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF).Conclusions:A simple, scalable three-drug combination, lipid-stabilized nanosuspension exhibited persistent drug levels in cells of lymph nodes and the blood (HIV host cells) and in plasma. With appropriate dose adjustment, TLC-ART101 may be a useful HIV treatment with a potential to impact residual virus in lymph nodes.

show abstract

Section: Discussionmentioning

confidence: 99%

Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma

Kraft¹,

McConnachie²,

Koehn³

et al. 2017

Aids

View full text Add to dashboard Cite

show abstract

“…Clinical trial studies that are still in progress or have been completed using CAB LAP and RPV LA are summarized in the Table. [44, 45, 46]…”

Section: Sustained-release Arv Formulationsmentioning

confidence: 99%

Long-acting slow effective release antiretroviral therapy

Edagwa

McMillan

Sillman

et al. 2017

Expert Opinion on Drug Delivery

View full text Add to dashboard Cite

Introduction Advances in the development of long acting antiretroviral therapy (ART) can revolutionize current treatments for HIV/AIDS. We have coined the term long active slow effective release ART (LASER ART) based on properties of slow drug dissolution, poor water-solubility, excellent bioavailability, limited off target systemic toxicities, and excellent patient treatment adherence. Drug carrier technologies characterized by high payload of antiretroviral drugs (ARVs) in a single carrier are being developed to improve the pharmacokinetics and pharmacodynamics of the nanoformulated ART (nanoART). Additionally, surface modification of slow release antiretroviral carriers with targeting ligands has facilitated receptor-mediated transport across physiological barriers serves to improve therapeutic outcomes. Areas covered This review highlights current developments of reservoir targeted LASER ART delivery platforms that have the potential to improve HIV/AIDS therapeutic outcomes. Such nanoART delivery platforms include decorated multifunctional nano- and micro- particles, prodrugs and polymer conjugates. Therapeutic strategies such as anti-inflammatory and neuroprotective agents and CRISPR/Cas 9 based gene-editing technologies that affect drug depots, boost ART effectiveness and facilitate viral clearance are discussed. Expert opinion The persistence of HIV-1 in its lymphoid, gut and nervous system reservoirs poses a major challenge to viral eradication. Emerging innovative strategies for effective medicines and slow release products to target intracellular pathogens, immune based interventions, genome-editing technologies, compounds that sustain drug depots and combinations of nanoART and image contrast agents have the potential to meet the unmet clinical needs of HIV patients. Such efforts will bring the medicines to sites of active viral replication and accelerate viral clearance.

show abstract

“…We also evaluated their activity against WT subtype C RTs that contained E138A. The pharmacokinetics of the long-acting RPV formulation has been investigated in healthy individuals in two different studies (20,21). In cervicovaginal fluid (CVL), RPV concentrations at day 28 postadministration were 12, 15, and 98 ng/ml (68, 107, and 232 nM, respectively) following injected doses of 300, 600, and 1,200 mg, respectively.…”

mentioning

confidence: 99%

In Vitro Cross-Resistance Profiles of Rilpivirine, Dapivirine, and MIV-150, Nonnucleoside Reverse Transcriptase Inhibitor Microbicides in Clinical Development for the Prevention of HIV-1 Infection

Giacobbi

Sluis‐Cremer

2017

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Rilpivirine (RPV), dapivirine (DPV), and MIV-150 are in development as microbicides. It is not known whether they will block infection of circulating nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant human immunodeficiency virus type 1 (HIV-1) variants. Here, we demonstrate that the activity of DPV and MIV-150 is compromised by many resistant viruses containing single or double substitutions. High DPV genital tract concentrations from DPV ring use may block replication of resistant viruses. However, MIV-150 genital tract concentrations may be insufficient to inhibit many resistant viruses, including those harboring K103N or Y181C.

show abstract

Long-acting rilpivirine as potential pre-exposure prophylaxis for HIV-1 prevention (the MWRI-01 study): an open-label, phase 1, compartmental, pharmacokinetic and pharmacodynamic assessment

Abstract: Bill & Melinda Gates Foundation.

Cited by 72 publications

References 18 publications

Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma

Long-acting combination anti-HIV drug suspension enhances and sustains higher drug levels in lymph node cells than in blood cells and plasma

Long-acting slow effective release antiretroviral therapy

In Vitro Cross-Resistance Profiles of Rilpivirine, Dapivirine, and MIV-150, Nonnucleoside Reverse Transcriptase Inhibitor Microbicides in Clinical Development for the Prevention of HIV-1 Infection

Contact Info

Product

Resources

About