RESUMO
BACKGROUND: Cabotegravir plus rilpivirine (CAB + RPV) is a guideline-recommended long-acting (LA) injectable regimen for the maintenance of human immunodeficiency virus-1 (HIV-1) virologic suppression. This post hoc analysis summarizes CAB + RPV LA results by baseline body mass index (BMI) category among phase 3/3b trial participants. METHODS: Data from CAB + RPV-naive participants receiving every 4 or 8 week dosing in FLAIR, ATLAS, and ATLAS-2M were pooled through week 48. Data beyond week 48 were summarized by study (FLAIR through week 96 and ATLAS-2M through week 152). HIV-1 RNA <50 and ≥50â copies/mL, confirmed virologic failure (CVF; 2 consecutive HIV-1 RNA ≥200â copies/mL), safety and tolerability, and plasma CAB and RPV trough concentrations were evaluated by baseline BMI (<30â kg/m2, lower; ≥30â kg/m2, higher). RESULTS: Among 1245 CAB + RPV LA participants, 213 (17%) had a baseline BMI ≥30â kg/m2. At week 48, 92% versus 93% of participants with lower versus higher BMI had HIV-1 RNA <50â copies/mL, respectively. Including data beyond week 48, 18 participants had CVF; those in the higher BMI group (n = 8) all had at least 1 other baseline factor associated with CVF (archived RPV resistance-associated mutations or HIV-1 subtype A6/A1). Safety and pharmacokinetic profiles were comparable between BMI categories. CONCLUSIONS: CAB + RPV LA was efficacious and well tolerated, regardless of baseline BMI category. CLINICAL TRIALS REGISTRATION: NCT02938520, NCT02951052, and NCT03299049.
Assuntos
Fármacos Anti-HIV , Índice de Massa Corporal , Infecções por HIV , HIV-1 , Piridonas , Rilpivirina , Humanos , Rilpivirina/farmacocinética , Rilpivirina/uso terapêutico , Rilpivirina/administração & dosagem , Rilpivirina/efeitos adversos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Masculino , HIV-1/efeitos dos fármacos , Feminino , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/efeitos adversos , Adulto , Pessoa de Meia-Idade , Piridonas/farmacocinética , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Carga Viral/efeitos dos fármacos , RNA Viral/sangue , Resultado do Tratamento , Quimioterapia Combinada , DicetopiperazinasRESUMO
In a cohort of 72 consecutive virologically-suppressed patients with HIV-1 switching to long-acting cabotegravir and rilpivirine, we observed low cabotegravir trough concentrations 1 and 3 months after the first injection, with a significant association with no oral lead-in at 1 month [odds ratio (OR)â=â6.3 [95% confidence interval (CI) 1.7-29.5], Pâ=â0.01] and three months (ORâ=â5.6 [95% CI 1.3-29.7], Pâ=â0.03), and with high BMI at 1 month (ORâ=â1.3 [95% CI 1.1-1.6], Pâ=â0.007).
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Piridonas , Rilpivirina , Humanos , Piridonas/administração & dosagem , Rilpivirina/administração & dosagem , Rilpivirina/uso terapêutico , Rilpivirina/farmacocinética , Infecções por HIV/tratamento farmacológico , Masculino , Feminino , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , HIV-1/isolamento & purificação , Pessoa de Meia-Idade , Adulto , Substituição de Medicamentos , Administração Oral , Plasma/química , DicetopiperazinasAssuntos
Fármacos Anti-HIV , Dicetopiperazinas , Infecções por HIV , Piridonas , Rilpivirina , Humanos , Rilpivirina/uso terapêutico , Rilpivirina/farmacocinética , Rilpivirina/administração & dosagem , Injeções Intramusculares , Infecções por HIV/tratamento farmacológico , Piridonas/farmacocinética , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , AdultoRESUMO
OBJECTIVE: Large inter-individual variability in the pharmacokinetics of rilpivirine and cabotegravir has been reported in the first weeks after starting long-acting injectable (LAI) therapy. Here, we assessed the distribution of rilpivirine and cabotegravir trough concentrations in people with HIV (PWH) on long-term LAI treatment. METHODS: Adult PWH treated with LAI for at least 32 weeks with an assessment of drug plasma trough concentrations were considered. The proportion of rilpivirine and cabotegravir plasma trough concentrations below four-times the protein-adjusted concentrations required for 90% inhibition of viral replication (4×PA-IC90) was estimated. RESULTS: Sixty-seven PWH were identified. LAI treatment duration was 216â±â80 weeks (range 32-320 weeks). Cabotegravir concentrations were associated with lower inter-individual variability compared with rilpivirine (45% versus 84%; Pâ<â0.05). No differences were found in rilpivirine (160â±â118 versus 189â±â81 ng/mL; Pâ=â0.430) and cabotegravir (1758â±â807 versus 1969â±â802 ng/mL; Pâ=â0.416) trough concentrations in males (nâ=â55) versus females (nâ=â12). A non-significant trend for lower cabotegravir concentrations was found in PWH with a body mass index >30 kg/m2 (nâ=â9) versus non-obese participants (1916â±â905 versus 1606â±â576 ng/mL; Pâ=â0.131). Three out of the 67 PWH had at least one drug concentration <4×PA-IC90: 100% of PWH had undetectable HIV viral load. CONCLUSIONS: At steady state, optimal systemic exposure of cabotegravir and rilpivirine was found in most PWH; cabotegravir trough concentrations were associated with lower inter-individual variability compared with rilpivirine. The study was not powered to assess the contribution of sex and/or body weight on LAI exposure due to the small number of females and obese PWH included.
Assuntos
Fármacos Anti-HIV , Dicetopiperazinas , Infecções por HIV , Piridonas , Rilpivirina , Humanos , Rilpivirina/farmacocinética , Rilpivirina/administração & dosagem , Rilpivirina/uso terapêutico , Rilpivirina/sangue , Masculino , Feminino , Infecções por HIV/tratamento farmacológico , Pessoa de Meia-Idade , Adulto , Piridonas/farmacocinética , Piridonas/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Idoso , Injeções , Carga Viral/efeitos dos fármacosAssuntos
Fármacos Anti-HIV , Dicetopiperazinas , Infecções por HIV , Piridonas , Rilpivirina , Rilpivirina/uso terapêutico , Rilpivirina/farmacocinética , Humanos , Infecções por HIV/tratamento farmacológico , Piridonas/farmacocinética , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Injeções Intramusculares , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagemRESUMO
There is growing interest in the use of long-acting (LA) injectable drugs to improve treatment adherence. However, their long elimination half-life complicates the conduct of clinical trials. Physiologically-based pharmacokinetic (PBPK) modeling is a mathematical tool that allows to simulate unknown clinical scenarios for LA formulations. Thus, this work aimed to develop and verify a mechanistic intramuscular PBPK model. The framework describing the release of a LA drug from the depot was developed by including both the physiology of the injection site and the physicochemical properties of the drug. The framework was coded in Matlab® 2020a and implemented in our existing PBPK model for the verification step using clinical data for LA cabotegravir, rilpivirine, and paliperidone. The model was considered verified when the simulations were within twofold of observed data. Furthermore, a local sensitivity analysis was conducted to assess the impact of various factors relevant for the drug release from the depot on pharmacokinetics. The PBPK model was successfully verified since all predictions were within twofold of observed clinical data. Peak concentration, area under the concentration-time curve, and trough concentration were sensitive to media viscosity, drug solubility, drug density, and diffusion layer thickness. Additionally, inflammation was shown to impact the drug release from the depot. The developed framework correctly described the release and the drug disposition of LA formulations upon intramuscular administration. It can be implemented in PBPK models to address pharmacological questions related to the use of LA formulations.
Assuntos
Simulação por Computador , Modelos Biológicos , Rilpivirina , Humanos , Injeções Intramusculares , Rilpivirina/farmacocinética , Rilpivirina/administração & dosagem , Palmitato de Paliperidona/farmacocinética , Palmitato de Paliperidona/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Masculino , Adulto , Antirretrovirais/farmacocinética , Antirretrovirais/administração & dosagem , Liberação Controlada de Fármacos , Pessoa de Meia-Idade , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Feminino , Piridonas , DicetopiperazinasRESUMO
BACKGROUND: Obesity is increasingly prevalent among people with human immunodeficiency virus (HIV, PWH). Obesity can reduce drug exposure; however, limited data are available for long-acting (LA) antiretrovirals. We performed in silico trials using physiologically based pharmacokinetic (PBPK) modeling to determine the effect of obesity on the exposure of LA cabotegravir and rilpivirine after the initial injection and after multiple injections. METHODS: Our PBPK model was verified against available clinical data for LA cabotegravir and rilpivirine in normal weight/ overweight (body mass index [BMI] <30â kg/m2) and in obese (BMI >30â kg/m2). Cohorts of virtual individuals were generated to simulate the exposure of LA cabotegravir/rilpivirine up to a BMI of 60â kg/m2. The fold change in LA cabotegravir and rilpivirine exposures (area under the curve [AUC]) and trough concentrations (Cmin) for monthly and bimonthly administration were calculated for various BMI categories relative to normal weight (18.5-25â kg/m2). RESULTS: Obesity was predicted to impact more cabotegravir than rilpivirine with a decrease in cabotegravir AUC and Cmin of >35% for BMI >35â kg/m2 and in rilpivirine AUC and Cmin of >18% for BMI >40â kg/m2 at steady-state. A significant proportion of morbidly obese individuals were predicted to have both cabotegravir and rilpivirine Cmin below the target concentration at steady-state with the bimonthly administration, but this was less frequent with the monthly administration. CONCLUSIONS: Morbidly obese PWH are at risk of presenting suboptimal Cmin for cabotegravir/rilpivirine after the first injection but also at steady-state particularly with the bimonthly administration. Therapeutic drug monitoring is advised to guide dosing interval adjustment.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , Obesidade , Piridonas , Rilpivirina , Humanos , Rilpivirina/farmacocinética , Rilpivirina/administração & dosagem , Rilpivirina/uso terapêutico , Piridonas/farmacocinética , Piridonas/administração & dosagem , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Masculino , Adulto , Feminino , Pessoa de Meia-Idade , Índice de Massa Corporal , Simulação por Computador , DicetopiperazinasRESUMO
BACKGROUND: Long-acting (LA) injectable therapy with cabotegravir (CAB) and rilpivirine (RPV) is currently used as maintenance treatment for human immunodeficiency virus type 1, and has a low risk for virological failure (VF). Although the risk is low, the circumstances and impact of VF in the real-world setting merit further evaluation. METHODS: We performed an in-depth clinical, virological, and pharmacokinetic analysis on the reasons behind and the impact of VF during LA CAB/RPV therapy in 5 cases from the Netherlands. Genotypic resistance testing was performed after the occurrence of VF, and drug plasma (trough) concentrations were measured after VF was established and on any other samples to assess on-treatment drug levels. CAB and RPV drug levels that were below the first quartile of the population cutoff (≤Q1) were considered to be low. RESULTS: Five cases who were eligible for LA CAB/RPV experienced VF despite a low predicted risk at baseline. Genotypic resistance testing revealed extensive selection of nonnucleoside reverse transcriptase inhibitor-associated mutations in all cases, and integrase strand transfer inhibitor mutations in 4 cases. All cases displayed low drug levels of either CAB, RPV, or both during the treatment course, likely contributing to the occurrence of VF. In 3 cases, we were able to identify the potential mechanisms behind these low drug levels. CONCLUSIONS: This is the first in-depth multiple case analysis of VF on LA CAB/RPV therapy in a real-world setting. Our observations stress the need to be aware for (evolving) risk factors and the yield of a comprehensive clinical, virological, and pharmacokinetic approach in case of failure.
Assuntos
Fármacos Anti-HIV , Farmacorresistência Viral , Infecções por HIV , HIV-1 , Piridonas , Rilpivirina , Falha de Tratamento , Humanos , Rilpivirina/uso terapêutico , Rilpivirina/farmacocinética , Rilpivirina/administração & dosagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Piridonas/farmacocinética , Piridonas/uso terapêutico , Piridonas/administração & dosagem , Masculino , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , HIV-1/efeitos dos fármacos , HIV-1/genética , Pessoa de Meia-Idade , Adulto , Feminino , Países Baixos , Carga Viral/efeitos dos fármacos , Genótipo , DicetopiperazinasRESUMO
Cabotegravir + rilpivirine administered via intramuscular gluteal injections is the first complete long-acting (LA) regimen approved for maintaining HIV-1 virologic suppression. The vastus lateralis (lateral) thigh muscle could be a potential alternative site of administration in circumstances such as injection site fatigue, intolerability, or contraindication for gluteal administration. Cabotegravir and rilpivirine pharmacokinetics and participant tolerability were evaluated following single intramuscular injections to the lateral thigh. Healthy adult participants received 4 weeks of daily oral cabotegravir (30 mg) and rilpivirine (25 mg), followed by a 10- to 14-day washout and single 3 mL intramuscular injections of cabotegravir LA 600 mg and rilpivirine LA 900 mg to the lateral thigh. Safety, tolerability, and pharmacokinetics were evaluated through 52 weeks post injection. Pharmacokinetic parameters were estimated using non-compartmental analysis. Fifteen participants (female at birth, n = 6) enrolled. Median age was 33 years. Median weight was 93.6 kg. Median body mass index was 31.4 kg/m2. One participant withdrew due to pregnancy after oral dosing before receiving an injection. Plasma concentrations at Weeks 4 and 8 were 15.4- and 5.3-fold above the protein-adjusted 90% inhibitory concentration for cabotegravir and 4.7- and 2.4-fold for rilpivirine, respectively. The most common injection site reactions were pain [28/28 (100%)], induration [15/28 (54%)], and swelling [12/28 (42%)]; 94% were Grade 1 or 2. Cabotegravir and rilpivirine plasma pharmacokinetic profiles observed in this study support further evaluation of thigh administration in target populations of people living with HIV-1. Tolerability of cabotegravir + rilpivirine LA intramuscular lateral thigh injections was similar to gluteal administration.
Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Adulto , Recém-Nascido , Humanos , Feminino , Rilpivirina/farmacocinética , Injeções Intramusculares , Fármacos Anti-HIV/farmacocinética , Músculo Quadríceps , Coxa da Perna , Infecções por HIV/tratamento farmacológico , Piridonas/farmacocinética , Antirretrovirais/uso terapêuticoRESUMO
BACKGROUND: This study aimed to evaluate the concentrations of rilpivirine (RLP) and doravirine (DOR) after 3 days-off using simulations from population pharmacokinetics models. METHODS: The authors conducted a series of 500 sets of 10,000 Monte Carlo simulations to examine the steady-state conditions for 2 common dosage levels: 25 mg/d for RLP and 100 mg/d for DOR. These simulations were conducted under 2 scenarios: 1 without drug cessation and another after a 3-day break. The validity of the implementation was established through a comparison of median trough concentrations (C24h) with previously reported data. Subsequently, the proportion of simulated patients with C24h and C72h after 3 days-off (C72h/3do) that exceeded the inhibitory concentration 50 (IC50), 5.2 mcg/L for DOR and 20.5 mcg/L for RLP respectively, was calculated. The inhibitory quotient (IQ) was also computed, which was 6 times IC50 for DOR and 4.5 times IC50 for RLP. Finally, nomograms were constructed to estimate the probability of having C72h/3do > IC50 or > IQ for different ranges of C24h. RESULTS: Simulated C24h median ± SD for RLP were 61.8 ± 0.4 mcg/L and for DOR 397 ± 0 mcg/L. For RLP, 99.3 ± 0.1% exceeded IC50 at C24h, 16.4 ± 0.4% at C72h/3do, and none surpassed the IQ threshold. In contrast, DOR had 100% ± 0% above IC50 at C24h, 93.6 ± 0.2% at C72h/3do, and 58.6 ± 0.5% exceeded the IQ. CONCLUSIONS: These findings suggest that treatment with DOR may offer a more forgiving therapeutic profile than RLP, given the larger proportion of patients achieving effective drug exposure with DOR. However, it is important to acknowledge a significant limitation of this study, namely, the assumption that drug concentration is a perfect surrogate for drug effectiveness.
Assuntos
Fármacos Anti-HIV , Simulação por Computador , Método de Monte Carlo , Piridonas , Rilpivirina , Triazóis , Humanos , Rilpivirina/farmacocinética , Fármacos Anti-HIV/farmacocinética , Piridonas/farmacocinética , Triazóis/farmacocinética , Triazóis/sangue , Infecções por HIV/tratamento farmacológico , Modelos BiológicosRESUMO
Background: Delivery of long-acting nanoformulated antiretroviral drugs (ARVs) to human immunodeficiency virus type one cell and tissue reservoirs underlies next generation antiretroviral therapeutics. Nanotheranostics, comprised of trackable nanoparticle adjuncts, can facilitate ARV delivery through real-time drug tracking made possible through bioimaging platforms. Methods: To model HIV-1 therapeutic delivery, europium sulfide (EuS) nanoprobes were developed, characterized and then deployed to cells, tissues, and rodents. Tests were performed with nanoformulated rilpivirine (NRPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used clinically to suppress or prevent HIV-1 infection. First, CD4+ T cells and monocyte-derived macrophages were EuS-treated with and without endocytic blockers to identify nanoprobe uptake into cells. Second, Balb/c mice were co-dosed with NRPV and EuS or lutetium177-doped EuS (177LuEuS) theranostic nanoparticles to assess NRPV biodistribution via mass spectrometry. Third, single photon emission computed tomography (SPECT-CT) and magnetic resonance imaging (MRI) bioimaging were used to determine nanotheranostic and NRPV anatomic redistribution over time. Results: EuS nanoprobes and NRPV entered cells through dynamin-dependent pathways. SPECT-CT and MRI identified biodistribution patterns within the reticuloendothelial system for EuS that was coordinate with NRPV trafficking. Conclusions: EuS nanoprobes parallel the uptake and biodistribution of NRPV. These data support their use in modeling NRPV delivery to improve treatment strategies.
Assuntos
Fármacos Anti-HIV , Portadores de Fármacos , Európio , Infecções por HIV , HIV-1/metabolismo , Imageamento por Ressonância Magnética , Nanopartículas , Rilpivirina , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Sulfetos , Animais , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Linhagem Celular , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Európio/química , Európio/farmacocinética , Európio/farmacologia , Infecções por HIV/diagnóstico por imagem , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Nanopartículas/uso terapêutico , Rilpivirina/química , Rilpivirina/farmacocinética , Rilpivirina/farmacologia , Sulfetos/química , Sulfetos/farmacocinética , Sulfetos/farmacologiaRESUMO
The widespread use of highly active antiretroviral treatments has dramatically changed the prognosis of people living with HIV (PLWH). However, such treatments have to be taken lifelong raising issues regarding the maintenance of both therapeutic effectiveness and long-term tolerability. Recently approved or investigational antiretroviral drugs present considerable advantages, allowing once daily oral dosage along with activity against resistant variants (eg, bictegravir and doravirine) and also parenteral intramuscular administration that facilitates treatment adherence (eg, long-acting injectable formulations such as cabotegravir and rilpivirine). Still, there remains a risk of insufficient or exaggerated circulating exposure due to absorption issues, abnormal elimination, drug-drug interactions, and others. In this context, a multiplex ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) bioassay has been developed for the monitoring of plasma levels of bictegravir, cabotegravir, doravirine, and rilpivirine in PLWH. A simple and convenient protein precipitation was performed followed by direct injection of the supernatant into the UHPLC-MS/MS system. The four analytes were eluted in less than 3 minutes using a reversed-phase chromatography method coupled with triple quadrupole mass spectrometry detection. This bioassay was fully validated following international guidelines and achieved good performances in terms of trueness (94.7%-107.5%), repeatability (2.6%-11%), and intermediate precision (3.0%-11.2%) over the clinically relevant concentration ranges (from 30 to 9000 ng/mL for bictegravir, cabotegravir, and doravirine and from 10 to 1800 ng/mL for rilpivirine). This sensitive, accurate, and rapid UHPLC-MS/MS assay is currently applied in our laboratory for routine therapeutic drug monitoring of the oral drugs bictegravir and doravirine and is also intended to be applied for the monitoring of cabotegravir/rilpivirine levels in plasma from PLWH receiving once monthly or every 2-month intramuscular injection of these long-acting antiretroviral drugs.
Assuntos
Antirretrovirais/sangue , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/métodos , Infecções por HIV/tratamento farmacológico , Espectrometria de Massas em Tandem/métodos , Amidas , Antirretrovirais/farmacocinética , Antirretrovirais/uso terapêutico , Compostos Heterocíclicos com 3 Anéis , Compostos Heterocíclicos de 4 ou mais Anéis/sangue , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Limite de Detecção , Modelos Lineares , Piperazinas , Piridonas/sangue , Piridonas/farmacocinética , Piridonas/uso terapêutico , Padrões de Referência , Reprodutibilidade dos Testes , Rilpivirina/sangue , Rilpivirina/farmacocinética , Rilpivirina/uso terapêutico , Triazóis/sangue , Triazóis/farmacocinética , Triazóis/uso terapêuticoRESUMO
Introduction: Antiretroviral treatment (ART) has led to improved control of HIV infection, giving the opportunity of exploring therapeutic alternatives as new long-acting (LA) regimens, that might improve the quality of life of people living with HIV (PLWH).Areas covered: This article overviews the pharmacokinetic and pharmacodynamic properties of LA cabotegravir and rilpivirine (CR), two nanoformulated drugs of intramuscular administration and focuses on assessing its role on the treatment of HIV infection.Expert opinion: In addition to the advantage of treatment simplification, which could be especially beneficial for population subgroups with significant HIV-related stigma, it also reduces the number of drugs, and probably, the risk of treatment-related toxicity. The similar efficacy when compared to oral triple therapies in clinical trials and the high satisfaction rates among both professionals and patients make LA CR a suitable alternative for the control of HIV infection in the modern era.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Piridonas/administração & dosagem , Rilpivirina/administração & dosagem , Animais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Preparações de Ação Retardada , Humanos , Nanopartículas , Satisfação do Paciente , Piridonas/farmacocinética , Piridonas/farmacologia , Qualidade de Vida , Rilpivirina/farmacocinética , Rilpivirina/farmacologia , Estigma SocialRESUMO
Human immunodeficiency virus theranostics facilitates the development of long acting (LA) antiretroviral drugs (ARVs) by defining drug-particle cell depots. Optimal drug formulations are made possible based on precise particle composition, structure, shape and size. Through the creation of rod-shaped particles of defined sizes reflective of native LA drugs, theranostic probes can be deployed to measure particle-cell and tissue biodistribution, antiretroviral activities and drug retention. Methods: Herein, we created multimodal rilpivirine (RPV) 177lutetium labeled bismuth sulfide nanorods (177LuBSNRs) then evaluated their structure, morphology, configuration, chemical composition, biological responses and adverse reactions. Particle biodistribution was analyzed by single photon emission computed tomography (SPECT/CT) and laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) imaging. Results: Nanoformulated RPV and BSNRs-RPV particles showed comparable physicochemical and cell biological properties. Drug-particle pharmacokinetics (PK) and biodistribution in lymphoid tissue macrophages proved equivalent, one with the other. Rapid particle uptake and tissue distribution were observed, without adverse reactions, in primary blood-derived and tissue macrophages. The latter was seen within the marginal zones of spleen. Conclusions: These data, taken together, support the use of 177LuBSNRs as theranostic probes as a rapid assessment tool for PK LA ARV measurements.
Assuntos
Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Lutécio/farmacocinética , Macrófagos/metabolismo , Nanopartículas/administração & dosagem , Radioisótopos/farmacocinética , Rilpivirina/farmacocinética , Nanomedicina Teranóstica/métodos , Animais , Células Cultivadas , Sistemas de Liberação de Medicamentos/métodos , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/isolamento & purificação , HIV-1/metabolismo , Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Compostos Radiofarmacêuticos/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Rilpivirina/farmacologia , Distribuição TecidualRESUMO
INTRODUCTION: Existing HIV therapy using oral antiretrovirals (ARVs) can result in pill fatigue and sub-optimal adherence. Microneedle array patches (MAPs) offer non-invasive, blood-free and painless drug delivery, and may improve patient adherence. The objective of this study was to develop a novel physiologically-based pharmacokinetic (PBPK) model to simulate the systemic pharmacokinetics of cabotegravir and rilpivirine MAPs using the intradermal route. METHODS: The developed PBPK models were qualified against observed pharmacokinetic data after intramuscular (IM) and intradermal administration of long-acting nanoformulated rilpivirine to rats, and for IM administration of both drugs to healthy adults. Qualified models were then utilised to estimate suitable MAP characteristics (e.g. nanoformulation dose and release rates) and inform dosing strategies to maintain plasma concentrations above target trough concentrations for the designated dosing interval. RESULTS: PBPK models simulated q4-weekly loading and maintenance doses of 360â¯mg and 180â¯mg for long-acting formulated cabotegravir between the release rates of 1â¯×â¯10-3-3â¯×â¯10-3h-1 and 1â¯×â¯10-3-1.5â¯×â¯10-3h-1 respectively, for a 70â¯kg adult. Estimated patch size was 60â¯cm2 for a 360â¯mg dose of cabotegravir. For q4-weekly dosing, rilpivirine required a 1080â¯mg loading dose and a 540â¯mg maintenance dose with release rates of 1.5â¯×â¯10-3-2.5â¯×â¯10-3h-1 and 5â¯×â¯10-4-1â¯×â¯10-3h-1, respectively. Weekly dosing was also evaluated to assess the potential application from a smaller patch size. The ability to self-administer via a patch that is only left in place for a short duration makes longer durations less important than for some other long-acting approaches. Weekly cabotegravir required 60â¯mg between release rates 7â¯×â¯10-3-9â¯×â¯10-3h-1 and rilpivirine required 270â¯mg and 180â¯mg respectively between release rates of 7â¯×â¯10-3-9â¯×â¯10-3h-1. DISCUSSION: This model estimated optimal dose and release rates for cabotegravir and rilpivirine MAPs. Our approach provides a computational platform to support rational development of intradermal administration strategies to tackle problems associated with chronic oral ARV administration.
Assuntos
Antirretrovirais/administração & dosagem , Antirretrovirais/farmacocinética , Adolescente , Adulto , Animais , Sistemas de Liberação de Medicamentos/métodos , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Injeções Intradérmicas/métodos , Masculino , Pessoa de Meia-Idade , Agulhas , Ratos , Rilpivirina/administração & dosagem , Rilpivirina/farmacocinética , Adulto JovemRESUMO
Antiretroviral therapy requires lifelong daily dosing to attain viral suppression, restore immune function, and improve quality of life. As a treatment alternative, long-acting (LA) antiretrovirals can sustain therapeutic drug concentrations in blood for prolonged time periods. The success of recent clinical trials for LA parenteral cabotegravir and rilpivirine highlight the emergence of these new therapeutic options. Further optimization can improve dosing frequency, lower injection volumes, and facilitate drug-tissue distributions. To this end, we report the synthesis of a library of RPV prodrugs designed to sustain drug plasma concentrations and improved tissue biodistribution. The lead prodrug M3RPV was nanoformulated into the stable LA injectable NM3RPV. NM3RPV treatment led to RPV plasma concentrations above the protein-adjusted 90% inhibitory concentration for 25â¯weeks with substantial tissue depots after a single intramuscular injection in BALB/cJ mice. NM3RPV elicited 13- and 26-fold increases in the RPV apparent half-life and mean residence time compared to native drug formulation. Taken together, proof-of-concept is provided that nanoformulated RPV prodrugs can extend the apparent drug half-life and improve tissue biodistribution. These results warrant further development for human use.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Nanopartículas/administração & dosagem , Pró-Fármacos/administração & dosagem , Rilpivirina/administração & dosagem , Animais , Fármacos Anti-HIV/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , HIV-1/efeitos dos fármacos , Humanos , Macaca mulatta , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Pró-Fármacos/farmacocinética , Rilpivirina/farmacocinética , Distribuição TecidualRESUMO
BACKGROUND: Rilpivirine is widely prescribed in people living with HIV. Although trough plasma concentrations have been associated with virological response, the drug pharmacodynamics remain incompletely characterized. OBJECTIVES: To develop the first pharmacodynamic model of rilpivirine in order to establish the rilpivirine concentration-response relationship for future treatment optimization. METHODS: A retrospective observational study was conducted in patients receiving the once-daily rilpivirine/tenofovir disoproxil fumarate/emtricitabine regimen. Individual rilpivirine trough plasma concentrations over time were predicted using a previous pharmacokinetic model. An established susceptible, infected, recovered model was used to describe HIV dynamics without assuming disease steady-state. Population analysis was performed with MONOLIX 2018 software. Simulations of the viral load evolution as a function of time and rilpivirine trough plasma concentration were performed. RESULTS: Overall, 60 naive and 39 pre-treated patients were included with a follow-up ranging from 2 to 37 months. The final model adequately described the data and the pharmacodynamic parameters were estimated with a good precision. The population typical value of rilpivirine EC50 was estimated at 65 ng/mL. A higher infection rate constant of CD4 cells for HIV-1 was obtained in pre-treated patients. Consequently, the time to obtain virological suppression was longer in pre-treated than in naive patients. CONCLUSIONS: The concentration-response relationship of rilpivirine was satisfactorily described for the first time using an original population pharmacodynamic model. Simulations performed using the final model showed that the currently used 50 ng/mL rilpivirine trough plasma concentration efficacy target might need revision upwards, particularly in pre-treated patients.
Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Modelos Teóricos , Rilpivirina/farmacocinética , Adulto , Idoso , Algoritmos , Fármacos Anti-HIV/uso terapêutico , Contagem de Linfócito CD4 , Simulação por Computador , Gerenciamento Clínico , Monitoramento de Medicamentos , Feminino , Infecções por HIV/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Rilpivirina/uso terapêutico , Carga Viral , Adulto JovemRESUMO
The MWRI-01 study characterized the safety, acceptability, pharmacokinetic (PK), and pharmacodynamic (PD) profile of rilpivirine (RPV) long acting (LA) in a model of preexposure prophylaxis (PrEP). Prospective, open-label Phase 1 study. The safety and acceptability of three repeated doses of RPV LA were monitored. Blood, tissue (rectal, cervical, and vaginal), and biological fluids (vaginal and endocervical) were collected at baseline and at 1- to 2-month intervals throughout the study for PK and PD assessment. Eight women and four men received three intramuscular doses of 1,200 mg of RPV LA given 8 weeks apart. There were a total of 195 adverse events (AEs) reported, of which 138 (70.8%) were Grade 1 and 55 (28.2%) were Grade 2. The most common AE was injection site pain. Geometric mean (90% confidence interval) plasma RPV concentrations at 56 days after the first and third doses were 39 (33-45) ng/mL (female)/29 (17-40) ng/mL (male) and 59 (45-62) ng/mL (female)/40 (30-51) ng/mL (male), respectively. Exposure to RPV LA was associated with significant inhibition of HIV-1BaL viral replication in the ex vivo rectal explant model (p < .0001) that persisted for up to 4 months after the third dose of RPV LA. In contrast, no viral suppression was seen in cervicovaginal tissue. Multiple dose administration of RPV LA was safe and well tolerated, and was associated with prolonged suppression of viral replication in rectal explant tissue.
Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Infecções por HIV/prevenção & controle , Profilaxia Pré-Exposição , Rilpivirina/administração & dosagem , Rilpivirina/farmacocinética , Adulto , Fármacos Anti-HIV/efeitos adversos , Colo do Útero/virologia , Esquema de Medicação , Feminino , Soronegatividade para HIV , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Humanos , Injeções Intramusculares , Masculino , Estudos Prospectivos , Reto/virologia , Rilpivirina/efeitos adversos , Vagina/virologia , Replicação Viral/efeitos dos fármacos , Adulto JovemRESUMO
As the HIV epidemic continues to contribute to global morbidity and mortality, the prevalence of HIV-associated neurological disorders (HAND) also continues to be a major concern in infected individuals, despite the widespread use of combination antiretroviral therapy. Therefore, current antiretroviral drugs should be able to reach therapeutic levels in the brain for the treatment of HAND. The brain distribution of the next-generation non-nucleoside reverse transcriptase inhibitor, rilpivirine (RPV) was investigated in healthy female Sprague-Dawley (SD) rats. The presented study involves the use of liquid chromatography-tandem mass spectrometry (LC-MS/MS) to estimate the concentrations of RPV in plasma and brain homogenate samples. The use of matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) provided regional spatial distribution of RPV in brain tissue sections. The localization of RPV was found to be relatively high in the hypothalamus, thalamus and corpus callosum, brain regions known to be associated with neurodegeneration during HAND (including the cerebral cortex). This study has shown that RPV has an excellent blood-brain barrier penetrability. Thus, in combination with other antiretroviral drugs, better central nervous system (CNS) protection against HAND can possibly be achieved.