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Current Opinion in HIV and AIDS Jan 2016Preexposure prophylaxis for HIV prevention is highly effective when taken as prescribed. Adherence to required dosing regimens for protection may pose challenges.... (Review)
Review
PURPOSE OF REVIEW
Preexposure prophylaxis for HIV prevention is highly effective when taken as prescribed. Adherence to required dosing regimens for protection may pose challenges. Long-acting agents for HIV prevention may have the potential to improve adherence via favorable pharmacokinetics supportive of infrequent dosing. This review focuses on the potential benefits and considerations for the study and use of 2 long-acting injectable agents, cabotegravir (GSK1265744LA, CAB LA) and rilpivirine (TMC278LA, RPV LA), for use as chemoprophylaxis for HIV prevention.
RECENT FINDINGS
Oral RPV is United States Food and Drug Administration approved for HIV treatment (in combination with other antiretrovirals). Both CAB LA and RPV LA are currently in phase 2a safety/tolerability/pharmacokinetic studies in anticipation and support of future efficacy evaluation. Both agents have favorable pharmacokinetics, and use is complicated by injection site reactions.
SUMMARY
Long-acting injectable formulations, if safe and well tolerated, may improve pharmacokinetic coverage of exposures to HIV infection. Complexities around safety, tolerability, and starting/stopping protocols require careful consideration.
Topics: Anti-HIV Agents; Chemoprevention; Clinical Trials, Phase II as Topic; Delayed-Action Preparations; Disease Transmission, Infectious; HIV Infections; Humans; Injections; Pre-Exposure Prophylaxis; Rilpivirine; United States
PubMed: 26633643
DOI: 10.1097/COH.0000000000000219 -
Current Opinion in HIV and AIDS Nov 2013Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient... (Review)
Review
PURPOSE OF REVIEW
Long-acting antiretroviral (ARV) drugs may improve adherence to therapy and extend opportunities for therapeutic or prophylactic intervention to underserved patient populations. This review focuses on recent advances in the development of small molecule long-acting injectable ARV agents.
RECENT FINDINGS
The need for combination ART and physicochemical and dosing limitations of current ARV drugs impede attempts to redevelop them as long-acting injectable formulations. However, the intrinsic properties of rilpivirine, a nonnucleoside reverse transcriptase inhibitor, and GSK1265744, an HIV-1 integrase strand transfer inhibitor, have enabled crystalline nanoparticle formulations to progress to clinical trials.
SUMMARY
Investigational long-acting injectable nanoformulations of rilpivirine and GSK1265744 are clinical-stage development candidates. Complementary pharmacologic properties of both agents - different mechanisms of action, resistance profiles, metabolic pathways, lack of drug interactions and low daily oral doses - offer the potential for combination use. Phase I studies of the pharmacokinetics and safety of each long-acting formulation alone and in combination indicate that a monthly dosing regimen is possible for HIV treatment. An ongoing phase IIb trial of oral GSK1265744 and oral rilpivirine is evaluating this two-drug regimen for maintenance of virologic suppression; results will inform future studies using the injectable formulations. Additional preclinical and clinical studies indicate a potential use of each agent for HIV pre-exposure prophylaxis.
Topics: Anti-HIV Agents; Clinical Trials as Topic; Delayed-Action Preparations; HIV Infections; Humans; Injections; Nitriles; Pyridones; Pyrimidines; Rilpivirine
PubMed: 24100877
DOI: 10.1097/COH.0000000000000002 -
Antimicrobial Agents and Chemotherapy Sep 2017Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy...
Rilpivirine (TMC278) is a highly potent nonnucleoside reverse transcriptase inhibitor (NNRTI) representing an effective component of combination antiretroviral therapy (cART) in the treatment of HIV-positive patients. Many antiretroviral drugs commonly used in cART are substrates of ATP-binding cassette (ABC) and/or solute carrier (SLC) drug transporters and, therefore, are prone to pharmacokinetic drug-drug interactions (DDIs). The aim of our study was to evaluate rilpivirine interactions with abacavir and lamivudine on selected ABC and SLC transporters and assess its importance for pharmacokinetics Using accumulation assays in MDCK cells overexpressing selected ABC or SLC drug transporters, we revealed rilpivirine as a potent inhibitor of MDR1 and BCRP, but not MRP2, OCT1, OCT2, or MATE1. Subsequent transport experiments across monolayers of MDCKII-MDR1, MDCKII-BCRP, and Caco-2 cells demonstrated that rilpivirine inhibits MDR1- and BCRP-mediated efflux of abacavir and increases its transmembrane transport. experiments in male Wistar rats confirmed inhibition of MDR1/BCRP in the small intestine, leading to a significant increase in oral bioavailability of abacavir. In conclusion, rilpivirine inhibits MDR1 and BCRP transporters and may affect pharmacokinetic behavior of concomitantly administered substrates of these transporters, such as abacavir.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; Biological Transport; Caco-2 Cells; Cell Line; Cell Line, Tumor; Dideoxynucleosides; Dogs; Drug Interactions; Humans; Intestinal Absorption; Lamivudine; Madin Darby Canine Kidney Cells; Male; Membrane Transport Proteins; Rats; Rats, Wistar; Reverse Transcriptase Inhibitors; Rilpivirine
PubMed: 28696229
DOI: 10.1128/AAC.00837-17 -
Biomedicine & Pharmacotherapy =... Nov 2023Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) worldwide and inflammation is key to its progression/resolution. As we...
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease (CLD) worldwide and inflammation is key to its progression/resolution. As we have previously described that rilpivirine (RPV) is hepatoprotective in murine models of CLD, here we determine the molecular mechanisms involved, focusing on its anti-inflammatory and immunomodulating properties. They were evaluated in vitro (human hepatic cell lines of the major hepatic cell types), in vivo (liver samples from a murine nutritional model of NAFLD) and ex vivo (peripheral blood mononuclear cells -PBMC- from patients with CLD). Transcriptomic analysis of liver samples from NAFLD mice showed RPV down-regulated biological processes associated with the inflammatory response (NF-κB/IκB signaling and mitogen-activated protein kinase -MAPK- activity) and leukocyte chemotaxis and migration. We observed a decrease in Adgre1 and Ccr2 expression and in the number of CCR2 + cells in the periportal areas of RPV-treated NAFLD mice. This RPV-induced effect on the CCL2/CCR2 axis was confirmed in vitro. A similar result was also obtained with CXCL10/IP10, one of the main chemokines in the liver. RPV also diminished activation of MAP kinases p38 and JNK. In addition, RPV inhibited the NLRP3 inflammasome pathway in vitro, decreasing NLRP3 protein expression, caspase-1 activation and IL-1β gene expression. RPV was also proven anti-inflammatory in PBMC from patients with CLD treated ex vivo. In conclusion, beyond its well-described role in antiretroviral therapy, RPV manifests anti-inflammatory and immunoregulatory effects, a finding that could be of great relevance for the search of novel targets or repositioning strategies for CLD.
Topics: Humans; Animals; Mice; Non-alcoholic Fatty Liver Disease; Leukocytes, Mononuclear; Rilpivirine; Liver; Anti-Inflammatory Agents; NLR Family, Pyrin Domain-Containing 3 Protein; NF-kappa B
PubMed: 37738799
DOI: 10.1016/j.biopha.2023.115537 -
British Journal of Clinical Pharmacology Dec 2020The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the...
Usefulness of therapeutic drug monitoring of rilpivirine and its relationship with virologic response and resistance in a cohort of naive and pretreated HIV-infected patients.
AIMS
The purpose of this study was to assess the antiviral activity of the rilpivirine/emtricitabine/tenofovir disoproxil fumarate combination and to describe the pharmacokinetics of rilpivirine and its association with resistance in clinical routine.
METHODS
A retrospective multicentre cohort study was performed in both naive and pretreated HIV patients receiving the once-daily rilpivirine/emtricitabine/tenofovir disoproxil fumarate regimen. Immuno-virologic and resistance data, and rilpivirine plasma trough concentrations were collected over the follow-up. Statistical analyses were performed to evaluate the relationship between rilpivirine pharmacokinetics and virological response. Receiver operating characteristic (ROC) curve analysis was performed to determine the best target rilpivirine trough concentration.
RESULTS
Overall, 379 patients were included. After a median follow-up of 28 months, 26% of patients discontinued mainly due to toxicity and the virological success rate was 65.7%. Virological failure occurred in 5% of patients. A significant proportion of patients with HIV-RNA > 40 copies/mL displayed rilpivirine plasma trough concentrations below the currently used 50 ng/mL efficacy threshold at both M6 (28%) and M12 (31%), in agreement with a significant lower median rilpivirine plasma trough concentration compared with patients virologically suppressed. Half of the patients with virologic failure who acquired rilpivirine resistance mutations had at least one suboptimal rilpivirine trough concentration. The optimal target for rilpivirine trough concentration was 70 ng/mL (sensitivity 75.4%; specificity 61.5%).
CONCLUSIONS
This study shows the impact of rilpivirine plasma trough concentration on both virological response and the emergence of rilpivirine mutations. Moreover, our results suggest that a higher target of rilpivirine trough concentration could be proposed in clinical practice.
Topics: Adult; Aged; Anti-HIV Agents; Cohort Studies; Drug Monitoring; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Male; Middle Aged; Retrospective Studies; Rilpivirine; Tenofovir; Viral Load; Young Adult
PubMed: 32374049
DOI: 10.1111/bcp.14344 -
AIDS (London, England) May 2023Baseline rilpivirine drug resistance mutations (DRMs) are a risk factor for virological failure in patients treated with long-acting cabotegravir and rilpivirine...
Baseline rilpivirine drug resistance mutations (DRMs) are a risk factor for virological failure in patients treated with long-acting cabotegravir and rilpivirine (CAB/RPV LA). We investigated rilpivirine cross-resistance in treatment-naive and experienced patients in South Africa. One in 10 treatment-naive patients and 74.5% of patients failing treatment presented with rilpivirine DRMs. Our data suggest targeted genotyping may be required for patients initiating CAB/RPV LA, which significantly complicates the currently used public health approach.
Topics: Humans; Rilpivirine; Anti-HIV Agents; Developing Countries; HIV Infections; HIV-1; Pyridones; Anti-Retroviral Agents
PubMed: 36779485
DOI: 10.1097/QAD.0000000000003505 -
P & T : a Peer-reviewed Journal For... Apr 2016Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) for combination HIV-1 therapy; dapsone gel, 7.5% (Aczone) for acne vulgaris; extended-release tofacitinib...
Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) for combination HIV-1 therapy; dapsone gel, 7.5% (Aczone) for acne vulgaris; extended-release tofacitinib (Xeljanz XR) for rheumatoid arthritis; and brivaracetam (Briviact) for epilepsy.
PubMed: 27069339
DOI: No ID Found -
Clinical Pharmacokinetics Feb 2018Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce...
BACKGROUND AND OBJECTIVES
Long-acting injectable antiretrovirals represent a pharmacological alternative to oral formulations and an innovative clinical option to address adherence and reduce drug costs. Clinical studies in children and adolescents are characterised by ethical and logistic barriers complicating the identification of dose optimisation. Physiologically-based pharmacokinetic modelling represents a valuable tool to inform dose finding prior to clinical trials. The objective of this study was to simulate potential dosing strategies for existing long-acting injectable depot formulations of cabotegravir and rilpivirine in children and adolescents (aged 3-18 years) using physiologically-based pharmacokinetic modelling.
METHODS
Whole-body physiologically-based pharmacokinetic models were developed to represent the anatomical, physiological and molecular processes and age-related changes in children and adolescents through allometric equations. Models were validated for long-acting injectable intramuscular cabotegravir and rilpivirine in adults. Subsequently, the anatomy and physiology of children and adolescents were validated against available literature. The optimal doses of monthly administration of cabotegravir and rilpivirine were identified in children and adolescents, to achieve trough concentrations over the target concentrations derived in a recent efficacy trial of the same formulations.
RESULTS
Pharmacokinetic data generated through the physiologically-based pharmacokinetic simulations were similar to observed clinical data in adults. Optimal doses of long-acting injectable antiretrovirals cabotegravir and rilpivirine were predicted using the release rate observed for existing clinical formulations, for different weight groups of children and adolescents. The intramuscular loading dose and maintenance dose of cabotegravir ranged from 200 to 600 mg and from 100 to 250 mg, respectively, and for rilpivirine it ranged from 250 to 550 mg and from 150 to 500 mg, respectively, across various weight groups of children ranging from 15 to 70 kg.
CONCLUSIONS
The reported findings represent a rational platform for the identification of suitable dosing strategies and can inform prospective clinical investigation of long-acting injectable formulations in children and adolescents.
Topics: Adolescent; Age Factors; Anti-HIV Agents; Body Weight; Child; Child, Preschool; Computer Simulation; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Liberation; Humans; Models, Biological; Pyridones; Rilpivirine
PubMed: 28540638
DOI: 10.1007/s40262-017-0557-x -
Drugs Apr 2020Long-acting antiretroviral therapy holds the promise of new options for human immunodeficiency virus (HIV) treatment beyond the current paradigm of daily oral pills. Of... (Review)
Review
Long-acting antiretroviral therapy holds the promise of new options for human immunodeficiency virus (HIV) treatment beyond the current paradigm of daily oral pills. Of particular interest is their potential role in addressing challenges with adherence to oral therapy and treatment fatigue. Similar to other conditions where long-acting formulations have proven effective such as contraception and mental health, long-acting antiretroviral therapy could provide additional treatment choices to people with HIV. This review provides an outline of the current landscape of long-acting antiretroviral therapy for HIV treatment, both approved and under development, including cabotegravir, rilpivirine, leronlimab, islatravir, albuvirtide, GS-6207, and broadly neutralizaing antibodies. However, there are a number of research gaps for long-acting antiretroviral therapy including issues regarding resistance and understudied populations, and this review highlights some of the challenges that will need to be addressed for clinical implementation of these novel treatment modalities.
Topics: Anti-Retroviral Agents; Drug Resistance, Viral; HIV Infections; Humans
PubMed: 32180205
DOI: 10.1007/s40265-020-01284-1 -
Clinical Pharmacokinetics 2009More than 20 individual and fixed-dose combinations of antiretrovirals are approved for the treatment of human immunodeficiency virus (HIV) infection. However, owing to... (Review)
Review
More than 20 individual and fixed-dose combinations of antiretrovirals are approved for the treatment of human immunodeficiency virus (HIV) infection. However, owing to the ongoing limitations of drug resistance and adverse effects, new treatment options are still required. A number of promising new agents in existing or new drug classes are in development or have recently been approved by the US FDA. Since these agents will be used in combination with other new and existing antiretrovirals, understanding the potential for drug interactions between these compounds is critical to their appropriate use. This article summarizes the drug interaction potential of new and investigational protease inhibitors (darunavir), non-nucleoside reverse transcriptase inhibitors (etravirine and rilpivirine), chemokine receptor antagonists (maraviroc, vicriviroc and INCB 9471), integrase inhibitors (raltegravir and elvitegravir) and maturation inhibitors (bevirimat).
Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Drug Interactions; Drug Therapy, Combination; Drugs, Investigational; HIV Integrase Inhibitors; HIV Protease Inhibitors; Humans; Molecular Structure; Receptors, Chemokine; Reverse Transcriptase Inhibitors; Succinates; Triterpenes
PubMed: 19492868
DOI: 10.2165/00003088-200948040-00001