RESUMEN
BACKGROUND: The ambitious goal to eliminate new pediatric HIV infections by 2030 requires accelerated prevention strategies in high-risk settings such as South Africa. One approach could be pre-exposure prophylaxis (PrEP) with broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs). The aim of our study is to define the optimal dose(s), the ideal combination(s) of bNAbs in terms of potency and breadth, and timing of subcutaneous (SC) administration(s) to prevent breast milk transmission of HIV. METHODS: Two bNAbs, CAP256V2LS and VRC07-523LS, will be assessed in a sequential and randomized phase I, single-site, single-blind, dose-finding trial. We aim to investigate the 28-day safety and pharmacokinetics (PK) profile of incrementally higher doses of these bNAbs in breastfeeding HIV-1 exposed born without HIV neonates alongside standard of care antiretroviral (ARV) medication to prevent (infants) or treat (mothers) HIV infection. The trial design includes 3 steps and 7 arms (1, 2, 3, 4, 5, 6 and 6b) with 8 infants in each arm. The first step will evaluate the safety and PK profile of the bNAbs when given alone as a single subcutaneous (SC) administration at increasing mg/kg body weight doses within 96 h of birth: arms 1, 2 and 3 at doses of 5, 10, and 20 mg/kg of CAP256V2LS, respectively; arms 4 and 5 at doses of 20 and 30 mg/kg of VRC07-523LS, respectively. Step two will evaluate the safety and PK profile of a combination of the two bNAbs administered SC at fixed doses within 96 h of birth. Step three will evaluate the safety and PK profile of the two bNAbs administered SC in combination at fixed doses, after 3 months. Arms 1 and 6 will follow sequential recruitment, whereas randomization will occur sequentially between arms (a) 2 & 4 and (b) 3 & 5. Before each randomization, a safety pause will allow review of safety data of the preceding arms. DISCUSSION: The results of this trial will guide further studies on bNAbs to prevent breast milk transmission of HIV. PROTOCOL VERSION: Version 4.0 dated 15 March 2024. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR): PACTR202205715278722, 21 April 2022; South African National Clinical Trial Registry (SANCTR): DOH-27-062022-6058.
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Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , VIH-1/inmunología , Recién Nacido , Femenino , Anticuerpos Anti-VIH/administración & dosificación , Lactante , Inyecciones Subcutáneas , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Profilaxis Pre-Exposición/métodos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Sudáfrica , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos ampliamente neutralizantes/administración & dosificación , Lactancia Materna , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Método Simple Ciego , Anticuerpos Neutralizantes/inmunología , Masculino , Ensayos Clínicos Fase I como AsuntoRESUMEN
Fostemsavir is an approved gp120-directed attachment inhibitor and prodrug for the treatment of human immunodeficiency virus type 1 infection in combination with other antiretrovirals (ARVs) in heavily treatment-experienced adults with multi-drug resistance, intolerance, or safety concerns with their current ARV regimen. Initial in vitro studies indicated that temsavir, the active moiety of fostemsavir, and its metabolites, inhibited organic cation transporter (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs) at tested concentration of 100 uM, although risk assessment based on the current Food and Drug Administration in vitro drug-drug interaction (DDI) guidance using the mechanistic static model did not reveal any clinically relevant inhibition on OCTs and MATEs. However, a DDI risk was flagged with EMA static model predictions. Hence, a physiologically based pharmacokinetic (PBPK) model of fostemsavir/temsavir was developed to further assess the DDI risk potential of OCT and MATEs inhibition by temsavir and predict changes in metformin (a sensitive OCT and MATEs substrate) exposure. No clinically relevant impact on metformin concentrations across a wide range of temsavir concentrations was predicted; therefore, no dose adjustment is recommended for metformin when co-administered with fostemsavir.
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Interacciones Farmacológicas , Metformina , Proteínas de Transporte de Catión Orgánico , Transportador 2 de Cátion Orgánico , Organofosfatos , Metformina/farmacocinética , Metformina/administración & dosificación , Humanos , Proteínas de Transporte de Catión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/antagonistas & inhibidores , Transportador 2 de Cátion Orgánico/metabolismo , Organofosfatos/administración & dosificación , Organofosfatos/farmacocinética , Modelos Biológicos , Animales , Transportador 1 de Catión Orgánico/metabolismo , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Factor 1 de Transcripción de Unión a Octámeros/metabolismo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , PiperazinasRESUMEN
An extended action fostemsavir (FTR) lipid nanoparticle (LNP) formulation prevents human immunodeficiency virus type one (HIV-1) infection. This FTR formulation establishes a drug depot in monocyte-derived macrophages that extend the drug's plasma residence time. The LNP's physicochemical properties improve FTR's antiretroviral activities, which are linked to the drug's ability to withstand fluid flow forces and levels of drug cellular internalization. Each is, in measure, dependent on PEGylated lipid composition and flow rate ratios affecting the size, polydispersity, shape, zeta potential, stability, biodistribution, and antiretroviral efficacy. The FTR LNP physicochemical properties enable the drug-particle's extended actions.
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Morfolinas , Nanopartículas , Organofosfatos , Nanopartículas/química , Humanos , Organofosfatos/farmacología , Organofosfatos/química , Organofosfatos/farmacocinética , Morfolinas/farmacología , Morfolinas/farmacocinética , Morfolinas/química , Animales , VIH-1/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Lípidos/química , Preparaciones de Acción Retardada , Ratones , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/química , Distribución Tisular , Liposomas , PiperazinasRESUMEN
Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly. In multiple previous clinical studies, islatravir was generally well tolerated, with no clear trend in cardiac adverse events. A trial was conducted to evaluate the effect of islatravir on cardiac repolarization. A randomized, double-blind, active- and placebo-controlled phase 1 trial was conducted, in which a single dose of islatravir 0.75 mg, islatravir 240 mg (supratherapeutic dose), moxifloxacin 400 mg (active control), or placebo was administered. Continuous 12-lead electrocardiogram monitoring was performed before dosing through 24 hours after dosing. QT interval measurements were collected, and safety and pharmacokinetics were evaluated. Sixty-three participants were enrolled, and 59 completed the study. Fridericia's QT correction for heart rate was inadequate; therefore, a population-specific correction was applied (QTcP). The placebo-corrected change from baseline in QTcP (ΔΔQTcP) interval at the observed geometric mean maximum plasma concentration associated with islatravir 0.75 mg and islatravir 240 mg was <10 ms at all time points. Assay sensitivity was confirmed because the use of moxifloxacin 400 mg led to a ΔΔQTcP >10 ms. The pharmacokinetic profile of islatravir was consistent with that of previous studies, and islatravir was generally well tolerated. Results from the current trial suggest that single doses of islatravir as high as 240 mg do not lead to QTc interval prolongation.
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Electrocardiografía , Fluoroquinolonas , Moxifloxacino , Humanos , Adulto , Masculino , Electrocardiografía/efectos de los fármacos , Método Doble Ciego , Femenino , Persona de Mediana Edad , Fluoroquinolonas/efectos adversos , Fluoroquinolonas/farmacocinética , Moxifloxacino/efectos adversos , Moxifloxacino/farmacocinética , Frecuencia Cardíaca/efectos de los fármacos , Síndrome de QT Prolongado/inducido químicamente , Adulto Joven , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/uso terapéutico , Compuestos Aza/efectos adversos , Compuestos Aza/farmacocinética , DesoxiadenosinasRESUMEN
In adults requiring protease inhibitor (PI)-based antiretroviral therapy (ART), replacing rifampicin with rifabutin is a preferred option, but there is lack of evidence to guide rifabutin dosing in children, especially with PIs. We aimed to characterize the population pharmacokinetics of rifabutin and 25-O-desacetyl rifabutin (des-rifabutin) in children and optimize its dose. We included children from three age cohorts: (i) <1-year-old cohort and (ii) 1- to 3-year-old cohort, who were ART naïve and received 15- to 20-mg/kg/day rifabutin for 2 weeks followed by lopinavir/ritonavir (LPV/r)-based ART with 5.0- or 2.5 mg/kg/day rifabutin, respectively, while the (iii) >3-year-old cohort was ART-experienced and received 2.5-mg/kg/day rifabutin with LPV/r-based ART. Non-linear mixed-effects modeling was used to interpret the data. Monte Carlo simulations were performed to evaluate the study doses and optimize dosing using harmonized weight bands. Twenty-eight children were included, with a median age of 10 (range 0.67-15.0) years, a median weight of 11 (range 4.5-45) kg, and a median weight-for-age z score of -3.33 (range -5.15 to -1.32). A two-compartment disposition model, scaled allometrically by weight, was developed for rifabutin and des-rifabutin. LPV/r increased rifabutin bioavailability by 158% (95% confidence interval: 93.2%-246.0%) and reduced des-rifabutin clearance by 76.6% (74.4%-78.3%). Severely underweight children showed 26% (17.9%-33.7%) lower bioavailability. Compared to adult exposures, simulations resulted in higher median steady-state rifabutin and des-rifabutin exposures in 6-20 kg during tuberculosis-only treatment with 20 mg/kg/day. During LPV/r co-treatment, the 2.5-mg/kg/day dose achieved similar exposures to adults, while the 5-mg/kg/day dose resulted in higher exposures in children >7 kg. All study doses maintained a median Cmax of <900 µg/L. The suggested weight-band dosing matches adult exposures consistently across weights and simplifies dosing.
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Infecciones por VIH , Lopinavir , Rifabutina , Ritonavir , Humanos , Rifabutina/farmacocinética , Rifabutina/uso terapéutico , Lopinavir/uso terapéutico , Lopinavir/farmacocinética , Ritonavir/uso terapéutico , Ritonavir/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Preescolar , Masculino , Femenino , Lactante , Tuberculosis/tratamiento farmacológico , Niño , Coinfección/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/uso terapéutico , Inhibidores de la Proteasa del VIH/farmacocinética , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéuticoRESUMEN
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.
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Fármacos Anti-VIH , Índice de Masa Corporal , Infecciones por VIH , VIH-1 , Piridonas , Rilpivirina , Humanos , Rilpivirina/farmacocinética , Rilpivirina/uso terapéutico , Rilpivirina/administración & dosificación , Rilpivirina/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Masculino , VIH-1/efectos de los fármacos , Femenino , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/efectos adversos , Adulto , Persona de Mediana Edad , Piridonas/farmacocinética , Piridonas/administración & dosificación , Piridonas/efectos adversos , Carga Viral/efectos de los fármacos , ARN Viral/sangre , Resultado del Tratamiento , Quimioterapia Combinada , DicetopiperazinasRESUMEN
BACKGROUND: Renally adjusted lamivudine dosages are effective. However, some of the kidney failure patients managed with lamivudine-containing regimens are failing to suppress HIV in peritoneal dialysis (CAPD) effluent. The steady-state lamivudine pharmacokinetics among these patients was evaluated. METHODS: This overnight open-label pharmacokinetic study enrolled participants living with HIV and managed with CAPD. Lamivudine levels in blood serum and CAPD effluent samples were quantified using liquid chromatography coupled with a mass spectrometer. Pharmacokinetic measures were obtained through non-compartmental analysis. RESULTS: Twenty-eight participants were recruited with a median antiretroviral (ARV) drug duration of 8 (IQR,4.5-10.5) years and a CAPD duration of 13.3 (IQR,3.3-31.9) months. 14.3% (4/28) had detectable unsuppressed HIV-1 viral load in CAPD effluents. The majority (78,6%,22/28) of participants received a 50 mg dose, while 10.7% (3/28), and another 10.7% (3/28) received 75 mg and 300 mg dosages, respectively. Among those treated with 75 and 300 mg, 66.7% (2/3) and 33.3% (1/3) had detectable HIV-VL in CAPD, respectively. The peritoneal membrane characteristics and CAPD system strengths were variable across the entire study population. Lamivudine exposure was increased in blood serum (50 mg-AUC0-24 h, 651.3 ng/mL; 75 mg-AUC0-24 h, 677.84 ng/mL; 300 mg-AUC0-24 h, 3135.89 ng/mL) compared to CAPD effluents (50 mg-AUC0-24 h, 384.91 ng/mL; 75 mg-AUC0-24 h, 383.24 ng/mL; 300 mg-AUC0-24 h, 2001.60 ng/mL) among the entire study population. The Cmax (50 mg, 41.5 ng/mL; 75 mg, 53.2 ng/mL; 300 mg, 199.1 ng/mL) and Cmin (50 mg, 17.8 ng/mL; 75 mg, 16.4 ng/mL; 300 mg, 76.4 ng/mL) measured in serum were within the therapeutic levels. CONCLUSIONS: Steady-state lamivudine pharmacokinetic measures were variable among the entire study population. However, the total lamivudine exposure was within the therapeutic levels.
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Infecciones por VIH , VIH-1 , Fallo Renal Crónico , Lamivudine , Diálisis Peritoneal , Humanos , Lamivudine/farmacocinética , Lamivudine/uso terapéutico , Lamivudine/administración & dosificación , Masculino , Persona de Mediana Edad , Femenino , VIH-1/efectos de los fármacos , Fallo Renal Crónico/terapia , Adulto , Infecciones por VIH/tratamiento farmacológico , ARN Viral/sangre , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/administración & dosificación , Carga ViralRESUMEN
Human immunodeficiency virus (HIV) continues to pose a serious threat to global health. Oral preexposure prophylaxis (PrEP), considered highly effective for HIV prevention, is the utilisation of antiretroviral (ARV) drugs before HIV exposure in high-risk uninfected individuals. However, ARV drugs are associated with poor patient compliance and pill fatigue due to their daily oral dosing. Therefore, an alternative strategy for drug delivery is required. In this work, two dissolving microneedle patches (MNs) containing either bictegravir (BIC) or tenofovir alafenamide (TAF) solid drug nanoparticles (SDNs) were developed for systemic delivery of a novel ARV regimen for potential HIV prevention. According to ex vivo skin deposition studies, approximately 11% and 50% of BIC and TAF was delivered using dissolving MNs, respectively. Pharmacokinetic studies in Sprague Dawley rats demonstrated that BIC MNs achieved a long-acting release profile, maintaining the relative plasma concentration above the 95% inhibitory concentration (IC95) for 3 weeks. For TAF MNs, a rapid release of drug and metabolism of TAF into TFV were obtained from the plasma samples. This work has shown that the proposed transdermal drug delivery platform could be potentially used as an alternative method to systemically deliver ARV drugs for HIV PrEP.
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Administración Cutánea , Alanina , Fármacos Anti-VIH , Infecciones por VIH , Agujas , Profilaxis Pre-Exposición , Ratas Sprague-Dawley , Tenofovir , Animales , Tenofovir/administración & dosificación , Tenofovir/farmacocinética , Tenofovir/análogos & derivados , Alanina/farmacocinética , Alanina/administración & dosificación , Alanina/química , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Profilaxis Pre-Exposición/métodos , Infecciones por VIH/prevención & control , Masculino , Adenina/administración & dosificación , Adenina/farmacocinética , Adenina/análogos & derivados , Adenina/química , Ratas , Nanopartículas/administración & dosificación , Nanopartículas/química , Liberación de Fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Compuestos Heterocíclicos de 4 o más Anillos/química , Piridonas/administración & dosificación , Piridonas/farmacocinética , Sistemas de Liberación de Medicamentos , Piperazinas/farmacocinética , Piperazinas/administración & dosificación , Piperazinas/química , Ciclopropanos/administración & dosificación , Ciclopropanos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Amidas/administración & dosificación , Amidas/farmacocinética , Amidas/químicaRESUMEN
The latent reservoir of human immunodeficiency virus (HIV) is a major obstacle in the treatment of acquired immune deficiency syndrome (AIDS). The "shock and kill" strategy has emerged as a promising approach for clearing HIV latent reservoirs. However, current latency-reversing agents (LRAs) have limitations in effectively and safely activating the latent virus and reducing the HIV latent reservoirs in clinical practice. Previously, EK-16A was extracted from Euphorbia kansui, which had the effect of interfering with the HIV-1 latent reservoir and inhibiting HIV-1 entry. Nevertheless, there is no suitable and efficient EK-16A oral formulation for in vivo delivery and clinical use. In this study, an oral EK-16A self-nanoemulsifying drug delivery system (EK-16A-SNEDDS) was proposed to "shock" the HIV-1 latent reservoir. This system aims to enhance the bioavailability and delivery of EK-16A to various organs. The composition of EK-16A-SNEDDS was optimized through self-emulsifying grading and ternary phase diagram tests. Cell models, pharmacokinetic experiments, and pharmacodynamics in HIV-1 latent cell transplant animal models suggested that EK-16A-SNEDDS could be absorbed by the gastrointestinal tract and enter the blood circulation after oral administration, thereby reaching various organs to activate latent HIV-1. The prepared EK-16A-SNEDDS demonstrated safety and efficacy, exhibited high clinical experimental potential, and may be a promising oral preparation for eliminating HIV-1 latent reservoirs.
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Emulsiones , VIH-1 , Latencia del Virus , VIH-1/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Animales , Administración Oral , Humanos , Activación Viral/efectos de los fármacos , Euphorbia/química , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Disponibilidad Biológica , Sistema de Administración de Fármacos con Nanopartículas , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/farmacocinética , Masculino , Sistemas de Liberación de Medicamentos/métodos , RatonesRESUMEN
INTRODUCTION: The treatment of HIV infection has been revolutionized in recent years thanks to the advent of dual antiretroviral regimens, administered orally or as long-acting injectable formulations. Here, we provide an update on the usefulness of therapeutic drug monitoring (TDM) of antiretroviral drugs to optimize the management of people with HIV (PWH) in the current scenario. AREAS COVERED: A MEDLINE PubMed search for articles published between January 2014 and January 2024 was completed matching the terms HIV, antiretrovirals and TDM. Moreover, additional studies were identified from the reference list of retrieved articles. EXPERT OPINION: Available antiretroviral treatments achieve a response rate of 90%-95%, making the routine TDM of antiretroviral drugs of limited clinical value. However, there are still some important applications of TDM in selected clinical conditions, such as assessing patient compliance or suspected drug-drug interactions (DDIs). Indeed, we are increasingly having to deal with polypharmacy and DDIs in the context of an aging patient with comorbidities that may potentially alter the pharmacokinetics of antiretroviral drugs. Finally, the role of pharmacogenetics, which is closely related to TDM, in influencing both the disposition of antiretrovirals and the course of DDIs should also be considered.
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Fármacos Anti-VIH , Interacciones Farmacológicas , Monitoreo de Drogas , Infecciones por VIH , Humanos , Monitoreo de Drogas/métodos , Infecciones por VIH/tratamiento farmacológico , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Farmacogenética , Cumplimiento de la Medicación , PolifarmaciaRESUMEN
Different from most antiretroviral drugs that act as passive defenders to inhibit HIV-1 replication inside the host cell, virus inactivators can attack and inactivate HIV-1 virions without relying on their replication cycle. Herein, we describe the discovery of a hydrocarbon double-stapled helix peptide, termed D26. D26 is based on the HIV-1 gp41 protein lentiviral lytic peptide-3 motif (LLP3) sequence, which can efficiently inhibit HIV-1 infection and inactivate cell-free HIV-1 virions. It was noted that D26 was highly resistant to proteolytic degradation and exhibited a remarkably extended in vivo elimination half-life. Additionally, relative to its linear, nonstapled version, D26 exhibited much higher exposure in sanctuary sites for HIV-1. Amazingly, this lead compound also demonstrated detectable oral absorption. Thus, it can be concluded that D26 is a promising candidate for further development as a long-acting, orally applicable HIV-1 inactivator for the treatment of HIV-1 infection.
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Fármacos Anti-VIH , Disponibilidad Biológica , Proteína gp41 de Envoltorio del VIH , VIH-1 , Péptidos , VIH-1/efectos de los fármacos , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacocinética , Humanos , Animales , Administración Oral , Proteína gp41 de Envoltorio del VIH/metabolismo , Proteína gp41 de Envoltorio del VIH/química , Péptidos/química , Péptidos/farmacología , Péptidos/farmacocinética , Descubrimiento de Drogas , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , SemividaRESUMEN
BACKGROUND: Efavirenz (EFV) is a drug used to treat HIV. Low plasma concentrations of EFV result in suboptimal viral suppression, whereas high concentrations can cause adverse neuropsychiatric side reactions. Some studies have identified a correlation between the plasma concentrations of EFV metabolites and neurotoxicity. To our knowledge, no studies have investigated the metabolism of EFV in young children and its effect on treatment outcomes. Therefore, the aim of this study was to develop and validate a method for quantifying EFV and its metabolites in human plasma derived from children. METHODS: Sample preparation was performed using protein precipitation of 100 µL plasma. Thereafter, an aliquot of the supernatant was used to quantify EFV, 7-hydroxyefavirenz (7-OH-EFV), 8-hydroxyefavirenz (8-OH-EFV), and a newly discovered metabolite ("EFAdeg") associated with 8-OH-EFV. A second aliquot of the supernatant was hydrolyzed using ß-glucuronidase/arylsulfatase and used with the first aliquot to quantify phase II metabolites. The analyses were performed using a Dionex Ultimate 3000RS LC-system coupled with a Q Exactive Orbitrap mass spectrometer. RESULTS: The method has a measuring range of 100-50,000 ng/mL (EFV, 8-OH-EFV), 125-25,000 ng/mL (7-OH-EFV), and 200-10,000 ng/mL ("EFAdeg"). All criteria of the European Medicines Agency guidelines regarding precision, accuracy, and selectivity were met. Of note, carryover must be considered for 8-OH-EFV. Overall, the validated method was successfully applied to plasma samples obtained from children and confirmed the presence of the newly discovered metabolite, "EFAdeg." CONCLUSIONS: An LC-HRMS/MS method for the quantification of EFV and its phase I and II metabolites was developed and validated. This method is suitable for analyzing plasma samples from children. Furthermore, studies using this method identified an additional metabolite that may influence the concentration of 8-OH-EFV in patient samples.
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Alquinos , Benzoxazinas , Ciclopropanos , Espectrometría de Masas en Tándem , Humanos , Benzoxazinas/sangre , Benzoxazinas/farmacocinética , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Niño , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacocinética , Preescolar , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/sangre , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy. METHODS: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported. RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12). CONCLUSIONS: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.
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Dispositivos Anticonceptivos Femeninos , Levonorgestrel , Pirimidinas , Hemorragia Uterina , Humanos , Femenino , Levonorgestrel/farmacocinética , Levonorgestrel/administración & dosificación , Levonorgestrel/efectos adversos , Adulto , Pirimidinas/farmacocinética , Pirimidinas/efectos adversos , Pirimidinas/administración & dosificación , Dispositivos Anticonceptivos Femeninos/efectos adversos , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/administración & dosificación , Adulto Joven , Persona de Mediana Edad , Infecciones por VIH/tratamiento farmacológicoRESUMEN
In the pursuit of achieving better therapeutic outcomes in the treatment of HIV, innovative drug delivery strategies have been extensively explored. Mannose receptors, which are primarily found on macrophages and dendritic cells, offer promising targets for drug delivery due to their involvement in HIV pathogenesis. This review article comprehensively evaluates recent drug delivery system advancements targeting the mannose receptor. We have systematically described recent developments in creating and utilizing drug delivery platforms, including nanoparticles, liposomes, micelles, noisomes, dendrimers, and other nanocarrier systems targeted at the mannose receptor. These strategies aim to enhance drug delivery specificity, bioavailability, and therapeutic efficacy while decreasing off-target effects and systemic toxicity. Furthermore, the article delves into how mannose receptors and HIV interact, highlighting the potential for exploiting this interaction to enhance drug delivery to infected cells. The review covers essential topics, such as the rational design of nanocarriers for mannose receptor recognition, the impact of physicochemical properties on drug delivery performance, and how targeted delivery affects the pharmacokinetics and pharmacodynamics of anti-HIV agents. The challenges of these novel strategies, including immunogenicity, stability, and scalability, and future research directions in this rapidly growing area are discussed. The knowledge synthesis presented in this review underscores the potential of mannose receptor-based targeted drug delivery as a promising avenue for advancing HIV treatment. By leveraging the unique properties of mannose receptors, researchers can design drug delivery systems that cater to individual needs, overcome existing limitations, and create more effective and patient-friendly treatments in the ongoing fight against HIV/AIDS.
Asunto(s)
Fármacos Anti-VIH , Sistemas de Liberación de Medicamentos , Infecciones por VIH , Lectinas Tipo C , Receptor de Manosa , Lectinas de Unión a Manosa , Receptores de Superficie Celular , Humanos , Lectinas Tipo C/metabolismo , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/farmacocinética , Receptores de Superficie Celular/metabolismo , Infecciones por VIH/tratamiento farmacológico , Lectinas de Unión a Manosa/metabolismo , Animales , NanopartículasRESUMEN
HIV infection has been a severe global health burden, with millions living with the virus and continuing new infections each year. Antiretroviral therapy can effectively suppress HIV replication but requires strict lifelong adherence to daily oral medication regimens, which presents a significant challenge. Long-acting formulations of antiretroviral drugs administered infrequently have emerged as a promising strategy to improve treatment outcomes and adherence to HIV therapy and prevention. Long-acting injectable (LAI) formulations are designed to gradually release drugs over extended periods of weeks or months following a single injection. Critical advantages of LAIs over conventional oral dosage forms include less frequent dosing requirements, enhanced patient privacy, reduced stigma associated with daily pill regimens, and optimised pharmacokinetic/pharmacodynamic profiles. Several LAI antiretroviral products have recently gained regulatory approval, such as the integrase strand transfer inhibitor cabotegravir for HIV preexposure prophylaxis and the Cabotegravir/Rilpivirine combination for HIV treatment. A leading approach for developing long-acting antiretroviral depots involves encapsulating drug compounds in polymeric microspheres composed of biocompatible, biodegradable materials like poly (lactic-co-glycolic acid). These injectable depot formulations enable high drug loading with customisable extended-release kinetics controlled by the polymeric matrix. Compared to daily oral therapies, LAI antiretroviral formulations leveraging biodegradable polymeric microspheres offer notable benefits, including prolonged therapeutic effects, reduced dosing frequency for improved adherence, and the potential to kerb the initial HIV transmission event. The present manuscript aims to review the pathogenesis of the virus and its progression and propose therapeutic targets and long-acting drug delivery strategies that hold substantial promise for enhancing outcomes in HIV treatment and prevention.
Asunto(s)
Fármacos Anti-VIH , Preparaciones de Acción Retardada , Infecciones por VIH , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacocinética , Inyecciones , Cumplimiento de la Medicación , Composición de Medicamentos , Piridonas , DicetopiperazinasRESUMEN
GSK2838232 (GSK8232) is a second-generation maturation inhibitor (MI) developed for the treatment of HIV with excellent broad-spectrum virological profiles. The compound has demonstrated promising clinical results as an orally administered agent. Additionally, the compound's physical and pharmacological properties present opportunities for exploitation as long-acting parenteral formulations. Despite unique design constraints including solubility and dose of GSK8232, we report on three effective tunable drug delivery strategies: active pharmaceutical ingredient (API) suspensions, ionic liquids, and subdermal implants. Promising sustained drug release profiles were achieved in rats with each approach. Additionally, we were able to tune drug release rates through a combination of passive and active strategies, broadening applicability of these formulation approaches beyond GSK8232. Taken together, this report is an important first step to advance long-acting formulation development for critical HIV medicines that do not fit the traditional profile of suitable long-acting candidates.
Asunto(s)
Liberación de Fármacos , Animales , Ratas , Interacciones Hidrofóbicas e Hidrofílicas , Preparaciones de Acción Retardada , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Líquidos Iónicos/química , Ratas Sprague-Dawley , Masculino , Solubilidad , Infecciones por VIH/tratamiento farmacológico , Antirretrovirales/administración & dosificación , Antirretrovirales/químicaRESUMEN
INTRODUCTION: To prevent mother-to-child transmission (PMTCT) of the human immunodeficiency virus (HIV) during pregnancy, the appropriate dosing regimens of antiretroviral (ARV) drugs need to be determined. Reliable data about pharmacokinetic (PK) characteristics of ARVs from randomized clinical trials (RCTs) are lacking, and post-marketing observational studies may offer valuable, but sometimes insufficient data, especially in pregnant people living with HIV (PLWHIV). This review article is focused PK and toxicological considerations affecting ARV dosing in pregnant PLWHIV. AREAS COVERED: In our search, we included studies focused on PKs of ARVs in pregnancy available on PubMed, abstracts from recent global conferences and data from modeling studies. There are no significant changes in PKs of nucleoside/nucleotide reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors throughout pregnancy. In contrast, the PKs of PIs and INSTIs are more variable, especially in the second and third trimesters. EXPERT OPINION: Pregnant women are left out of RCTs. To the greatest extent possible, future research should include pregnant persons in RCTs, including PK studies, strictly considering maternal and fetal safety. Alternative innovative approaches/models need to be developed to obtain reliable data about rational pharmacotherapy of ARVs in the effective PMTCT of HIV, with maximum safety.
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Fármacos Anti-VIH , Infecciones por VIH , Transmisión Vertical de Enfermedad Infecciosa , Complicaciones Infecciosas del Embarazo , Ensayos Clínicos Controlados Aleatorios como Asunto , Humanos , Embarazo , Infecciones por VIH/tratamiento farmacológico , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Femenino , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Relación Dosis-Respuesta a DrogaRESUMEN
BACKGROUND: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations. METHODS: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia. RESULTS: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses. CONCLUSIONS: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV.
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Carbamazepina , Darunavir , Interacciones Farmacológicas , Infecciones por VIH , Humanos , Darunavir/uso terapéutico , Darunavir/farmacocinética , Masculino , Persona de Mediana Edad , Carbamazepina/uso terapéutico , Carbamazepina/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Neuralgia del Trigémino/tratamiento farmacológico , Ritonavir/uso terapéutico , Ritonavir/administración & dosificación , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/uso terapéutico , Anticonvulsivantes/administración & dosificación , Piridonas/farmacocinética , Piridonas/uso terapéutico , Piridonas/sangre , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Piperazinas/uso terapéutico , Piperazinas/farmacocinética , Oxazinas/uso terapéutico , Oxazinas/farmacocinética , Relación Dosis-Respuesta a Droga , Fármacos Anti-VIH/uso terapéutico , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Monitoreo de Drogas/métodosRESUMEN
BACKGROUND: Poor adherence to ART and pre-exposure prophylaxis (PrEP) can impact patient and public health. Point-of-care testing (POCT) may aid monitoring and adherence interventions. OBJECTIVES: We report the pharmacokinetics of tenofovir [dosed as tenofovir disoproxil (TDF) and tenofovir alafenamide (TAF)], emtricitabine (FTC), lamivudine (3TC) and dolutegravir (DTG) in plasma and urine following drug cessation to evaluate adherence targets in urine for POCT. METHODS: Subjects were randomized (1:1) to receive DTG/FTC/TAF or DTG/3TC/TDF for 15â days. Plasma and spot urine were collected on Day 15 (0-336â h post final dose). Drug concentrations were quantified using LC-MS, and non-linear mixed-effects models applied to determine drug disposition between matrices and relationship with relevant plasma [dolutegravir protein-adjusted 90% inhibitory concentration (PA-IC90â=â64â ng/mL) and minimum effective concentration (MECâ=â324â ng/mL)] and urinary thresholds [tenofovir disoproxil fumarate 1500â ng/mL]. RESULTS: Of 30 individuals enrolled, 29 were included (72% female at birth, 90% Caucasian). Median (range) predicted time to plasma dolutegravir PA-IC90 and MEC were 83.5 (41.0-152) and 49.0â h (23.7-78.9), corresponding to geometric mean (90%) urine concentrations of 5.42 (4.37-6.46) and 27.4â ng/mL (22.1-32.7). Tenofovir in urine reached 1500â ng/mL by 101â h (58.6-205) with an equivalent plasma concentration of 6.20â ng/mL (4.21-8.18). CONCLUSIONS: These data support use of a urinary tenofovir threshold of <1500â ng/mL (tenofovir disoproxil fumarate-based regimens) as a marker of three or more missed doses for a POCT platform. However, due to low dolutegravir concentrations in urine, POCT would be limited to a readout of recent dolutegravir intake (one missed dose).
Asunto(s)
Fármacos Anti-VIH , Emtricitabina , Infecciones por VIH , Compuestos Heterocíclicos con 3 Anillos , Lamivudine , Oxazinas , Piperazinas , Pruebas en el Punto de Atención , Piridonas , Tenofovir , Humanos , Piridonas/orina , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/orina , Compuestos Heterocíclicos con 3 Anillos/sangre , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Masculino , Emtricitabina/orina , Emtricitabina/farmacocinética , Emtricitabina/uso terapéutico , Emtricitabina/sangre , Adulto , Piperazinas/orina , Piperazinas/sangre , Lamivudine/orina , Lamivudine/farmacocinética , Lamivudine/sangre , Femenino , Infecciones por VIH/tratamiento farmacológico , Tenofovir/orina , Tenofovir/farmacocinética , Tenofovir/uso terapéutico , Tenofovir/sangre , Fármacos Anti-VIH/orina , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Persona de Mediana Edad , Profilaxis Pre-Exposición/métodos , Adulto Joven , Plasma/química , Cumplimiento de la MedicaciónRESUMEN
OBJECTIVE: Preliminary evidence shows that concomitant administration of valproic acid can reduce the exposure to dolutegravir with limited clinical impacts. Here, we describe a male living with HIV who experienced a drastic reduction in dolutegravir trough concentrations a few weeks after starting valproic acid treatment as identified by therapeutic drug monitoring. Concomitantly, pharmacists recommended a supplementation of magnesium to improve insomnia. CASE REPORT: A 62-year-old man with HIV on antiretroviral therapy with dolutegravir and lamivudine recently added valproic acid to clonazepam and sertraline to treat severe sleep disturbances. An 84% reduction in dolutegravir trough concentrations was observed compared with the previous outpatient visit (418 versus 2714 ng/mL), with values close to the minimum effective drug concentration (300 ng/mL). Considering this, we strongly discourage the use of magnesium. CONCLUSIONS: We are confident that our findings can contribute to a better understanding of the clinical problems that infectious disease physicians encounter in their daily management of people with HIV and how therapeutic drug monitoring may add value in this context. This case also highlights the importance of multidisciplinary services for the optimal management of polypharmacy in people with HIV.