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1.
Artículo en Inglés | MEDLINE | ID: mdl-38823149

RESUMEN

Although antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection to suppress virus in the blood, HIV persists in tissues. HIV persistence in the tissues is due to numerous factors, and one of those factors are antiretroviral (ARV) concentrations. ARV concentrations in tissues must be adequate to suppress HIV at the sites of action. While therapeutic drug monitoring in the plasma is well-known, drug monitoring in the tissues provides local assessments of adequate ARV exposure to prevent localized HIV resistance formation. Towards these efforts, we validated an ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS/MS) method in human tissues (cervical, rectal, and vaginal tissues) for the simultaneous quantification of five ARVs: bictegravir, cabotegravir, dolutegravir, doravirine, and raltegravir. For this assay, protein precipitation with acetonitrile with stable, isotopically-labeled internal standards followed by supernatant pre-concentration was performed. Analyte separation was accomplished using a multistep UPLC gradient mixture of 0.1 % formic acid in water (A) and acetonitrile (B) with a Waters Cortecs T3 (2.1x100 mm) column. The assay was extensively validated as per the United States Food and Drug Administration Bioanalytical Method Validation Guidance over a clinically observed range (0.05-50 ng/mL) with superb linearity (R2 > 0.99 across all ARVs). The assay run time was 8.5 min. This analytical method achieves appropriate performance of trueness (85.5-107.4 %), repeatability, and precision (CV < 15 %). Our method will be employed for the therapeutic monitoring of guideline-recommended ARVs in human tissues for monitoring therapeutic efficacy in HIV treatment and prevention research efforts.


Asunto(s)
Monitoreo de Drogas , Compuestos Heterocíclicos con 3 Anillos , Piperazinas , Piridonas , Espectrometría de Masas en Tándem , Humanos , Espectrometría de Masas en Tándem/métodos , Cromatografía Líquida de Alta Presión/métodos , Monitoreo de Drogas/métodos , Compuestos Heterocíclicos con 3 Anillos/análisis , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Compuestos Heterocíclicos con 3 Anillos/sangre , Reproducibilidad de los Resultados , Piridonas/análisis , Piridonas/sangre , Piperazinas/análisis , Piperazinas/sangre , Límite de Detección , Modelos Lineales , Femenino , Oxazinas/química , Raltegravir Potásico/análisis , Raltegravir Potásico/uso terapéutico , Triazoles/análisis , Triazoles/sangre , Compuestos Heterocíclicos de 4 o más Anillos/análisis , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/sangre , Piridazinas/análisis , Piridazinas/farmacocinética , Antirretrovirales/análisis , Antirretrovirales/farmacocinética , Antirretrovirales/sangre , Antirretrovirales/uso terapéutico , Piridinas/análisis , Piridinas/sangre , Piridinas/farmacocinética , Piridinas/uso terapéutico , Cuello del Útero/química , Infecciones por VIH/tratamiento farmacológico , Amidas , Dicetopiperazinas
2.
J Pharm Biomed Anal ; 240: 115932, 2024 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-38198884

RESUMEN

Antiretroviral therapy (ART) is highly effective for the treatment of HIV-1 infection. ART previously consisted of concomitant administration of many drugs, multiple times per day. Currently, ART generally consists of two- or three-drug regimens once daily as fixed-dose combinations. Drug monitoring may be necessary to ensure adequate concentrations are achieved in the plasma over the dosing interval and prevent further HIV resistance formation. Additionally, nonadherence remains an issue, highlighting the need to ensure sufficient ART exposure. Towards this effort, we developed and validated a highly selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous quantification of a panel of nine antiretrovirals: abacavir, bictegravir, cabotegravir, dolutegravir, doravirine, emtricitabine, lamivudine, raltegravir, and tenofovir in human plasma. Using only 50 µL of plasma, a simple protein precipitation with acetonitrile with internal standards followed by reconstitution in 50 uL (high) or 400 uL (low) was performed. Analyte separation was achieved using a multistep UPLC gradient mixture of (A: 0.1% formic acid in water and B: acetonitrile) and a Waters CORTECS T3 (2.1 ×100 mm) column. The method was comprehensively validated according to the United States Food and Drug Administration Bioanalytical Guidelines over two clinically relevant ranges (1-250 ng/mL and 100-5000 ng/mL) with excellent linearity (R2 > 0.99 for all). The assay run time was 7.5 min. This method achieves acceptable performance of trueness (89.7-104.1%), repeatability, and precision (CV <15%), and allows for simultaneous quantification of guideline-recommended ART regimens. This method can be utilized for the therapeutic monitoring of antiretrovirals in human plasma.


Asunto(s)
Infecciones por VIH , Espectrometría de Masas en Tándem , Humanos , Cromatografía Líquida de Alta Presión/métodos , Espectrometría de Masas en Tándem/métodos , Cromatografía Liquida , Antirretrovirales , Infecciones por VIH/tratamiento farmacológico , Acetonitrilos , Reproducibilidad de los Resultados , Monitoreo de Drogas/métodos
3.
Acta Pharm Sin B ; 13(11): 4502-4510, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37969744

RESUMEN

Paxlovid is a nirmatrelvir (NMV) and ritonavir (RTV) co-packaged medication used for the treatment of coronavirus disease 2019 (COVID-19). The active component of Paxlovid is NMV and RTV is a pharmacokinetic booster. Our work aimed to investigate the drug/herb-drug interactions associated with Paxlovid and provide mechanism-based guidance for the clinical use of Paxlovid. By using recombinant human cytochrome P450s (CYPs), we confirmed that CYP3A4 and 3A5 are the major enzymes responsible for NMV metabolism. The role of CYP3A in Paxlovid metabolism were further verified in Cyp3a-null mice, which showed that the deficiency of CYP3A significantly suppressed the metabolism of NMV and RTV. Pregnane X receptor (PXR) is a ligand-dependent transcription factor that upregulates CYP3A4/5 expression. We next explored the impact of drug- and herb-mediated PXR activation on Paxlovid metabolism in a transgenic mouse model expressing human PXR and CYP3A4/5. We found that PXR activation increased CYP3A4/5 expression, accelerated NMV metabolism, and reduced the systemic exposure of NMV. In summary, our work demonstrated that PXR activation can cause drug interactions with Paxlovid, suggesting that PXR-activating drugs and herbs should be used cautiously in COVID-19 patients receiving Paxlovid.

4.
Artículo en Inglés | MEDLINE | ID: mdl-37866010

RESUMEN

Although current antiretroviral therapy (ART) effectively suppresses HIV in the blood, regimens may fail due to suboptimal treatment history and non-adherence to ART. In these scenarios, accumulation of viral resistance mutations to ART drug classes may occur. For these treatment-experienced people living with HIV (PLWH), activity against resistant viral strains is required; lack of therapeutic efficacy will result in continued viral replication and progression to acquired immunodeficiency syndrome. New treatment options have emerged. Lenacapavir is a first-in-class long-acting HIV-1 capsid inhibitor approved for the treatment of HIV in treatment-experienced patients. Lenacapavir is approved with an initiation regimen of oral and subcutaneous injection dosing followed by subcutaneous self-injection every 6 months. With infrequent dosing, therapeutic drug monitoring may be necessary to ensure adequate concentrations are consistently achieved in the plasma to assure treatment adherence and prevent further HIV resistance formation. To this end, we developed and validated a highly selective ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to quantify lenacapavir concentrations in human plasma. A simple protein precipitation with acetonitrile followed by supernatant dilution was performed. Lenacapavir and its stable labeled internal standard were separated at 1.90 min using a multi-step UPLC gradient. The assay for lenacapavir quantification was extensively validated according to the United States Food and Drug Administration Bioanalytical Guidelines over a clinically relevant range of 0.1 to 500 ng/mL with excellent linearity (R2 ≥ 0.9960). This analytical method achieves acceptable performance of trueness (89.7-104.1 %), repeatability, and precision (CV < 15 %). We applied this method to quantify a clinical sample and to determine the percent protein-unbound. This method can be utilized for the therapeutic monitoring of lenacapavir in human plasma for monitoring HIV treatment efficacy.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Estados Unidos , Humanos , Cromatografía Líquida de Alta Presión , Espectrometría de Masas en Tándem , Fármacos Anti-VIH/uso terapéutico , Antirretrovirales , Infecciones por VIH/tratamiento farmacológico
5.
Eur J Med Chem ; 259: 115666, 2023 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-37482017

RESUMEN

ATP-binding cassette subfamily G member 2 (ABCG2), an efflux transporter, is involved in multiple pathological processes. Ko143 is a potent ABCG2 inhibitor; however, it is quickly metabolized through carboxylesterase 1-mediated hydrolysis of its t-butyl ester moiety. The current work aimed to develop more metabolically stable ABCG2 inhibitors. Novel Ko143 analogs were designed and synthesized by replacing the unstable t-butyl ester moiety in Ko143 with an amide group. The synthesized Ko143 analogs were evaluated for their ABCG2 inhibitory activity, binding mode with ABCG2, cytotoxicity, and metabolic stability. We found that the amide modification of Ko143 led to metabolically stable ABCG2 inhibitors. Among these Ko143 analogs, K2 and K34 are promising candidates with favorable oral pharmacokinetic profiles in mice. In summary, we synthesized novel Ko143 analogs with improved metabolic stability, which can potentially be used as lead compounds for the future development of ABCG2 inhibitors.


Asunto(s)
Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Proteínas de Transporte de Membrana , Animales , Ratones , Transportadoras de Casetes de Unión a ATP/antagonistas & inhibidores , Transporte Biológico , Proteínas de Transporte de Membrana/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/antagonistas & inhibidores
6.
Clin Pharmacol Ther ; 113(4): 896-903, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36622798

RESUMEN

Tenofovir diphosphate (TFVdp; an active metabolite of oral HIV pre-exposure prophylaxis (PrEP)) is measured in dried blood spots (DBS) to estimate adherence. However, TFVdp's long half-life in whole blood may lead to misclassification following a recent change in adherence. PrEP's other metabolite, emtricitabine triphosphate (FTCtp), has a shorter half-life in whole blood but adherence thresholds are undefined. We characterized DBS TFVdp and FTCtp concentrations across many dosing scenarios. Population pharmacokinetic models were fit to TFVdp and FTCtp DBS concentrations from a directly observed therapy study (NCT03218592). Concentrations were simulated for 90 days of daily dosing followed by 90 days of 1 to 7 doses/week and for event-driven PrEP (edPrEP) scenarios. Thresholds of 1,000 and 200 fmol/punch, for TFVdp and FTCtp, respectively, were reflective of taking 4 doses/week (a minimum target for effective PrEP in men). TFVdp was < 1,000 fmol/punch for 17 days after initiating daily PrEP and > 1,000 fmol/punch for 62 days after decreasing to 3 doses/week. Respectively, FTCtp was < 200 fmol/punch for 4 days and > 200 fmol/punch for 6 days. Accuracy of edPrEP adherence classification depended on duration between last sex act and DBS sampling for both measures with misclassification ranging from 9-100%. These data demonstrate adherence misclassification by DBS TFVdp for 2 months following a decline in adherence, elucidating the need for FTCtp to estimate recent adherence. We provide proof of principle that individualized interpretation is needed to support edPrEP adherence monitoring. Our collective approach facilitates clinicians' ability to interpret DBS results and administer patient-centric interventions.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Masculino , Humanos , Tenofovir , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/prevención & control , Cumplimiento de la Medicación
7.
Antimicrob Agents Chemother ; 66(8): e0060922, 2022 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-35856680

RESUMEN

Although current antiretroviral therapy (ART) has increased life expectancy, a cure for human immunodeficiency virus (HIV) remains elusive due to the persistence of the virus in tissue reservoirs. In the present study, we sought to elucidate the relationship between antiretrovirals (ARVs) and viral expression in the spleen. We performed mass spectrometry imaging (MSI) of 6 different ARVs, RNAscope in situ hybridization of viral RNA, and immunohistochemistry of three different fibrosis markers in the spleens of 8 uninfected and 10 reverse transcriptase simian-human immunodeficiency virus (RT-SHIV)-infected rhesus macaques (infected for 6 weeks) that had been dosed for 10 days with combination ART. Using MATLAB, computational quantitative imaging analysis was performed to evaluate the spatial and pharmacological relationships between the 6 ARVs, viral RNA, and fibrotic deposition. In these spleens, >50% of the spleen tissue area was not covered by any detectable ARV response (any concentration above the limits of detection for individual ARVs). The median spatial ARV coverage across all tissues was driven by maraviroc followed by efavirenz. Yet >50% of RNA-positive cells were not exposed to any detectable ARV. Quantifiable maraviroc and efavirenz colocalization with RNA-positive cells was usually greater than the in vitro concentration inhibiting 50% replication (IC50). Fibrosis markers covered more than 50% of the spleen tissue area and had negative relationships with cumulative ARV coverages. Our findings suggest that a heterogeneous ARV spatial distribution must be considered when evaluating viral persistence in lymphoid tissue reservoirs.


Asunto(s)
Infecciones por VIH , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Fibrosis , VIH/genética , Infecciones por VIH/tratamiento farmacológico , Transcriptasa Inversa del VIH/genética , Humanos , Macaca mulatta/genética , Macaca mulatta/metabolismo , Maraviroc/uso terapéutico , ARN Viral/genética , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/metabolismo , Bazo/metabolismo , Carga Viral
8.
J Am Coll Clin Pharm ; 4(6): 743-753, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-34355135

RESUMEN

Accrediting bodies for Doctor of Pharmacy (Pharm.D.) and postgraduate residency training programs recognize the importance of research and scholarship training. However, specific guidance on how research and scholarship fundamentals should be delivered to trainees have not been provided. As a result, competing priorities often create barriers for trainees to develop research and scholarship skills and limit the trainees' ability to conduct and participate in high-quality, meaningful research experiences. The purpose of this "how-to" guide is to assist pharmacy school faculty and pharmacy residency program directors with strategies to overcome programmatic, trainee, and project barriers to providing a high-quality training experience in research and scholarship. Programmatic topics addressed include institutional support and program oversight, expertise and number of research mentors, incentives for mentor engagement, and competing priorities that diminish time for research activities. Trainee topics include lack of trainee interest in the assigned project, trainee departure prior to project completion, lack of knowledge of the publication process, and time constraints to work on the project. Project topics addressed include time needed to initiate a project, training on methodology relevant to a project, selection of projects that lack rigor, depth, or feasibility, and resource constraints to disseminate project results. A summary of specific recommended actions is provided to effectively overcome these common barriers encountered in research and scholarship training programs.

9.
Clin Pharmacol Ther ; 109(4): 841-855, 2021 04.
Artículo en Inglés | MEDLINE | ID: mdl-33540481

RESUMEN

Despite significant advances in HIV treatment over the past 30 years, critical barriers to an HIV cure persist. The HIV reservoir, defined at both the cellular and anatomical level, constitutes the main barrier to cure. While the mechanisms underlying the reservoir are not yet well understood, one theory to explain persistence at the anatomical level is that subtherapeutic exposure to antiretroviral therapy (ART) within certain tissue compartments permits ongoing replication. Characterizing ART pharmacology throughout the body is important in the context of these potential pharmacologic sanctuaries and for maximizing the probability of success with forthcoming cure strategies that rely on latency reversal and require ART to prevent reseeding the reservoir. In this review, we provide a comprehensive overview of ART and latency reversal agent distribution at the site of action for HIV cure (i.e., anatomical sites commonly associated with HIV persistence, such as lymphoid organs and the central nervous system). We also discuss methodologic approaches that provide insight into HIV cure pharmacology, including experimental design and advances within the computational, pharmaceutical, and analytical chemistry fields. The information discussed in this review will assist in streamlining the development of investigational cure strategies by providing a roadmap to ensure therapeutic exposure within the site of action for HIV cure.


Asunto(s)
Antirretrovirales/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Antirretrovirales/uso terapéutico , Sistema Nervioso Central/efectos de los fármacos , Sistema Nervioso Central/fisiología , Sistema Nervioso Central/virología , Cálculo de Dosificación de Drogas , Farmacorresistencia Viral/fisiología , Quimioterapia Combinada , Edición Génica/métodos , VIH-1/fisiología , Humanos , Estructuras Linfoides Terciarias/tratamiento farmacológico , Estructuras Linfoides Terciarias/fisiopatología , Carga Viral/fisiología , Latencia del Virus/efectos de los fármacos , Latencia del Virus/fisiología
10.
AIDS Res Hum Retroviruses ; 37(10): 725-735, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-33499746

RESUMEN

The persistence of HIV in the spleen, despite combination antiretroviral therapy, is not well understood. Sustained immune dysregulation and delayed immune recovery, in addition to immune cell exhaustion, may contribute to persistence of infection in the spleen. Eliminating HIV from this secondary lymphoid organ will require a thorough understanding of antiretroviral (ARV) pharmacology in the spleen, which has been minimally investigated. Low ARV exposure within the spleen may hinder the achievement of a functional or sterilizing cure if cells are not protected from HIV infection. In this study, we provide an overview of the anatomy and physiology of the spleen, review the evidence of the spleen as a site for persistence of HIV, discuss the consequences of persistence of HIV in the spleen, address challenges to eradicating HIV in the spleen, and examine opportunities for future curative efforts.


Asunto(s)
Infecciones por VIH , Antirretrovirales/uso terapéutico , VIH , Infecciones por VIH/tratamiento farmacológico , Humanos , Bazo , Latencia del Virus
11.
AIDS ; 34(13): 1923-1931, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32773474

RESUMEN

OBJECTIVES: The aim of this study was to evaluate penetration of antiretrovirals into compartments and efficacy of a dual, NRTI-sparing regimen in acute HIV infection (AHI). DESIGN: Single-arm, open-label pilot study of participants with AHI initiating ritonavir-boosted darunavir 800 mg once daily and etravirine 400 mg once daily or 200 mg twice daily within 30 days of AHI diagnosis. METHODS: Efficacy was defined as HIV RNA less than 200 copies/ml by week 24. Optional sub-studies included pharmacokinetics analysis from genital fluids (weeks 0-4, 12, 48), cerebrospinal fluid (CSF) (weeks 2-4, 24 and 48) and endoscopic biopsies (weeks 4-12 and 36-48). Neuropsychological performance was assessed at weeks 0, 24 and 48. RESULTS: Fifteen AHI participants were enrolled. Twelve (80%) participants achieved HIV RNA less than 200 copies/ml by week 24. Among 12 participants retained through week 48, nine (75%) remained suppressed to less than 50 copies/ml. The median time from ART initiation to suppression less than 200 and less than 50 copies/ml was 59 and 86 days, respectively. The penetration ratios for etravirine and darunavir in gut associated lymphoid tissue were 19.2 and 3.05, respectively. Most AHI participants achieving viral suppression experienced neurocognitive improvement. Of the three participants without overall improvement in neurocognitive functioning as measured by impairment ratings (more than two tests below 1 SD), two had virologic failure. CONCLUSION: NRTI-sparing ART started during AHI resulted in rapid viral suppression similar to NRTI-based regimens. More novel and compact two-drug treatments for AHI should be considered. Early institution of ART during AHI appears to improve overall neurocognitive function and may reduce the risk of subsequent neurocognitive impairment. CLINICALTRIALS.GOV:: NCT00855413.


Asunto(s)
Fármacos Anti-VIH/uso terapéutico , Terapia Antirretroviral Altamente Activa , Darunavir/farmacocinética , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Ritonavir/farmacocinética , Adulto , Recuento de Linfocito CD4 , Darunavir/uso terapéutico , Farmacorresistencia Viral , Quimioterapia Combinada , Femenino , VIH/genética , Humanos , Masculino , Persona de Mediana Edad , Proyectos Piloto , Ritonavir/uso terapéutico , Resultado del Tratamiento , Carga Viral/efectos de los fármacos
12.
Antimicrob Agents Chemother ; 64(10)2020 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-32661005

RESUMEN

Adequate antiretroviral (ARV) concentrations in lymphoid tissues are critical for optimal antiretroviral therapy (ART). While the spleen contains 25% of the body's lymphocytes, there are minimal data on ARV penetration in this organ. This study quantified total and protein-unbound splenic ARV concentrations and determined whether drug transporters, sex, or infection status were modifiers of these concentrations in animal models and humans. Two humanized mice models (hu-HSC-Rag [n = 36; 18 HIV-positive (HIV+) and 18 HIV-negative (HIV-)] and bone marrow-liver-thymus [n = 13; 7 HIV+ and 6 HIV-]) and one nonhuman primate (NHP) model (rhesus macaque [n = 18; 10 SHIV+ and 8 SHIV-]) were dosed to steady state with ARV combinations. HIV+ human spleens (n = 14) from the National NeuroAIDS Tissue Consortium were analyzed postmortem (up to 24 h postdose). ARV concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), drug transporter concentrations were measured with LC-MS proteomics, and protein binding in NHP spleens was determined by rapid equilibrium dialysis. Mice generally had the lowest splenic concentrations of the three species. Protein binding in splenic tissue was 6 to 96%, compared to 76 to 99% in blood plasma. NHPs had quantifiable Mrp4, Bcrp, and Ent1 concentrations, and humans had quantifiable ENT1 concentrations. None significantly correlated with tissue ARV concentrations. There was also no observable influence of infection status or sex. With these dosing strategies, NHP splenic penetration most closely resembled that of humans. These data can inform tissue pharmacokinetic scaling to humans to target HIV reservoirs by identifying important species-related differences.


Asunto(s)
Fármacos Anti-VIH , Infecciones por VIH , Preparaciones Farmacéuticas , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Animales , Fármacos Anti-VIH/uso terapéutico , Cromatografía Liquida , Infecciones por VIH/tratamiento farmacológico , Humanos , Macaca mulatta , Ratones , Modelos Animales , Proteínas de Neoplasias , Bazo , Espectrometría de Masas en Tándem
13.
Antivir Ther ; 25(2): 115-119, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32341207

RESUMEN

BACKGROUND: Pharmacokinetic (PK) changes can affect antiretroviral (ARV) systemic exposure for critically ill patients living with HIV (CI-PLWH). Studies to guide ARV adjustments in this population are limited. METHODS: A PK analysis was conducted in a 44-year-old CI-PLWH who presented for a heart and lung transplant on veno-arterial extracorporeal membrane oxygenation (VA ECMO). Home ARV therapy (ART) of co-formulated abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) was continued. ARV serum concentrations were obtained during and after VA ECMO. Two blood levels were drawn at 1 h, for maximum serum concentration (Cmax) and a serum trough (Ct). ARVs were given as a single tablet crushed via nasogastric tube. RESULTS: Area under the concentration-time curve (AUC0-t) was calculated using non-compartmental analysis. Cmax and AUC0-t were higher during VA ECMO compared with post-decannulation. The Cmax of ABC was >2.5-fold higher than the mean in the reference. Cmax and Ct post VA ECMO were within range of referenced literature for all ARVs. Cmax and AUC0-t of DTG post VA ECMO was approximately four- to fivefold lower than referenced literature. HIV virological suppression was maintained throughout the hospitalization. CONCLUSIONS: ART adjustments would not be required for this patient. Additional studies are needed to assess effects of VA ECMO and crushed tube administration of ARVs in CI-PLWH.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Didesoxinucleósidos/farmacocinética , Oxigenación por Membrana Extracorpórea/efectos adversos , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Lamivudine/farmacocinética , Oxazinas/farmacocinética , Piperazinas/farmacocinética , Piridonas/farmacocinética , Adulto , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Didesoxinucleósidos/administración & dosificación , Didesoxinucleósidos/sangre , Didesoxinucleósidos/uso terapéutico , Combinación de Medicamentos , Femenino , Infecciones por VIH/complicaciones , Trasplante de Corazón-Pulmón/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/administración & dosificación , Compuestos Heterocíclicos con 3 Anillos/sangre , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Intubación Gastrointestinal , Lamivudine/administración & dosificación , Lamivudine/sangre , Lamivudine/uso terapéutico , Oxazinas/administración & dosificación , Oxazinas/sangre , Oxazinas/uso terapéutico , Piperazinas/administración & dosificación , Piperazinas/sangre , Piperazinas/uso terapéutico , Piridonas/administración & dosificación , Piridonas/sangre , Piridonas/uso terapéutico
14.
Artículo en Inglés | MEDLINE | ID: mdl-31611355

RESUMEN

For HIV cure strategies like "kick and kill" to succeed, antiretroviral (ARV) drugs must reach effective concentrations in putative viral reservoirs. We characterize penetration of six ARVs in three preclinical animal models and humans. We found that standard dosing strategies in preclinical species closely mimicked tissue concentrations in humans for some, but not all, ARVs. These results have implications for interpreting HIV treatment, prevention, or cure interventions between preclinical and clinical models.


Asunto(s)
Antirretrovirales/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Animales , Fármacos Anti-VIH/uso terapéutico , Sulfato de Atazanavir/uso terapéutico , Emtricitabina/uso terapéutico , Femenino , Humanos , Técnicas In Vitro , Maraviroc/uso terapéutico , Ratones , Raltegravir Potásico/uso terapéutico , Tenofovir/uso terapéutico
15.
Clin Pharmacol Ther ; 105(6): 1362-1377, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30739315

RESUMEN

Despite development of modern antiretrovirals with lower drug interaction potential than their predecessors, drug interaction challenges remain. Standard treatment regimens still require multiple antiretrovirals that may cause, or may be the target of, drug interactions. Additionally, people living with HIV are living longer and often present with comorbid conditions that require concomitant long-term drug therapy. Also, treatment of infectious diseases in resource-limited settings can result in significant interactions. In this review, we describe absorption, distribution, metabolism, and excretion pathways as they relate to relevant drug interactions with antiretrovirals along with the potential clinical consequences of these interactions. We highlight clinical data that illustrate pertinent interactions and provide tools to assist in predicting drug interactions in the absence of clinical data. Given these tools and thoughtful consideration of drug combinations, drug therapy in people living with HIV can be safely and effectively managed throughout their lifetime.


Asunto(s)
Fármacos Anti-VIH/metabolismo , Antirretrovirales/metabolismo , Interacciones Farmacológicas/fisiología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/metabolismo , Fármacos Anti-VIH/efectos adversos , Antirretrovirales/efectos adversos , Antihipertensivos/efectos adversos , Antihipertensivos/metabolismo , Antineoplásicos/efectos adversos , Antineoplásicos/metabolismo , Humanos
16.
Pharmacotherapy ; 37(10): 1298-1308, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28730660

RESUMEN

During the past decade, the incidence and severity of Clostridium difficile infection (CDI) have significantly increased, leading to a rise in CDI-associated hospitalizations, health care costs, and mortality. Although treatment options exist for CDI, recurrence is frequent following treatment. Furthermore, patients with at least one CDI recurrence are at an increased risk of developing additional recurrences. A novel approach to the prevention of recurrent CDI is the use of monoclonal antibodies directed against the toxins responsible for CDI as an adjunct to antibiotic treatment. Bezlotoxumab, a human monoclonal antibody that binds and neutralizes C. difficile toxin B, is the first therapeutic agent to receive United States Food and Drug Administration approval for the prevention of CDI recurrence. Clinical studies have demonstrated superior efficacy of bezlotoxumab in adults receiving antibiotic therapy for CDI compared with antibiotic therapy alone for the prevention of CDI recurrence. Bezlotoxumab was well tolerated in clinical trials, with the most common adverse effects being nausea, vomiting, fatigue, pyrexia, headache, and diarrhea. The demonstrated efficacy, safety, and characteristics of bezlotoxumab present an advance in prevention of CDI recurrence.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Proteínas Bacterianas/antagonistas & inhibidores , Toxinas Bacterianas/antagonistas & inhibidores , Clostridioides difficile/efectos de los fármacos , Infecciones por Clostridium/prevención & control , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos ampliamente neutralizantes , Ensayos Clínicos Fase III como Asunto , Infecciones por Clostridium/epidemiología , Semivida , Humanos , Infusiones Intravenosas , Recurrencia , Prevención Secundaria , Resultado del Tratamiento
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