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1.
AIDS ; 34(13): 1883-1889, 2020 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-32694416

RESUMEN

OBJECTIVE: For the treatment of HIV-1-related brain disease and for the prevention of the brain becoming a viral reservoir, it is important that antiretroviral agents reach sufficient concentrations in the CNS. To date, human brain pharmacokinetic data are solely derived from lumbar cerebrospinal fluid (CSF) and mostly originate from single samples. DESIGN: We determined concentrations of antiretroviral drugs in serial samples of ventricular CSF and compared these to the concentrations in serum and lumbar CSF of these patients. METHODS: Two treatment-naïve HIV-1-infected patients received external ventricular drainage for obstructive hydrocephalus. Starting with a combination antiretroviral regimen (cART), ventricular CSF, and subsequently lumbar CSF, with parallel serum, was frequently collected. Drug concentrations were determined and CSF-to-serum ratios were calculated. RESULTS: High concentrations, resulting in high CSF-to-serum ratios, were found in the ventricular CSF of the three substances zidovudine, lamivudine and indinavir, whereas this was not observed for stavudine, ritonavir, saquinavir and efavirenz. Concentrations of zidovudine and lamivudine were up to four times greater in CSF from the ventricles than in lumbar CSF of the same patient. The zidovudine concentrations in the ventricular CSF exceeded serum concentrations by a factor of 1.4. CONCLUSION: Unexpectedly high concentrations of some antiretrovirals in the ventricular CSF, the site close to the brain parenchyma where HIV is located, should be considered when the cART regimen is aiming at CNS viral replication.


Asunto(s)
Fármacos Anti-VIH/líquido cefalorraquídeo , Fármacos Anti-VIH/farmacocinética , Infecciones por VIH/tratamiento farmacológico , Lamivudine/líquido cefalorraquídeo , Lamivudine/farmacocinética , Zidovudina/líquido cefalorraquídeo , Zidovudina/farmacocinética , Complejo SIDA Demencia/prevención & control , Adulto , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/uso terapéutico , Quimioterapia Combinada , Infecciones por VIH/metabolismo , VIH-1/genética , Humanos , Lamivudine/sangre , Lamivudine/uso terapéutico , Masculino , ARN Viral/sangre , ARN Viral/líquido cefalorraquídeo , Punción Espinal , Estavudina/administración & dosificación , Estavudina/sangre , Estavudina/líquido cefalorraquídeo , Estavudina/uso terapéutico , Carga Viral , Zidovudina/sangre , Zidovudina/uso terapéutico
2.
Medicine (Baltimore) ; 99(22): e20487, 2020 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-32481459

RESUMEN

Simultaneous therapeutic drug monitoring (TDM) of combination antiretroviral therapy (cART) is critical during pregnancy in order to improve clinical follow-up, monitor viral load, and patient adherence to treatment.A modified simple and fast ultra-high performance liquid chromatography coupled with tandem mass spectrometry and electrospray ionization (UPLC-ESI-MS/MS) method was developed and validated according to national and international guidelines for the simultaneous determination of lamivudine (LMV), zidovudine (ZDV), lopinavir (LPV), and ritonavir (RTV) concentrations in 100-µL plasma sample of Human Immunodeficiency Virus (HIV)-positive pregnant women. Protein precipitation using 0.1% formic acid in cold acetonitrile was used for sample preparation. The chromatographic separation was achieved with a run-time of 3.0 minutes and 3-µL injection on an ethylene bridged hybrid C18 column (2.1 µm × 50 mm, 1.7 µm), under gradient conditions using acetonitrile and formic acid (0.1%).The chromatographic method was used to analyze 10 plasma samples from 8 HIV pregnant women as a clinical patient routinely follow-up by applying TDM criteria.The protonated precursor/product ion transitions for LMV (230.18/112.08), ZDV (268.22/127.10), LPV (629.55/447.35), and RTV (721.50/296.20) were recorded in multiple-reaction-monitoring (MRM) mode. The calibration curve was linear in the range of 50-3,000, 75-4,500, 250-15,000, and 25-1,500-ng/mL for LMV, ZDV, LPV, and RTV, respectively. The range of accuracy was 97.2% to 100.1% and precision 3.4% to 12.7%. The method showed specificity and matrix effect values of < 15%. Minimum absolute recovery percentages (%CV) were 90.5 (5.4), 90.8 (5.0), 95.4 (3.5), and 93.7 (6.9), for LMV, ZDV, LPV, and RTV, respectively. Drug concentrations in patient samples had high inter-individual variability with %CV of 91.98%, 77.54%, 53.80%, and 92.16% for ZDV, LMV, LPV, and RTV, respectively. Two of the 8 patients showed no adherence due to the absence of Protease Inhibitors (PIs) levels in plasma.This technique demonstrated to be effective in therapeutic drug monitoring and is intended to be used in population pharmacokinetics specifically for HIV-positive pregnant women.


Asunto(s)
Fármacos Anti-VIH/sangre , Monitoreo de Drogas , Seropositividad para VIH/tratamiento farmacológico , Lamivudine/sangre , Lopinavir/sangre , Ritonavir/sangre , Zidovudina/sangre , Adulto , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Seguridad del Paciente , Embarazo , Espectrometría de Masas en Tándem , Carga Viral
3.
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
4.
Pak J Pharm Sci ; 33(1): 49-52, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32122830

RESUMEN

Shenlin Fuzheng Capsule (SLFZC) is a herbal preparation used for HIV/AIDS in Guangxi, China. This study was designed to evaluate the influence of SLFZC on the pharmacokinetics of highly active antiretroviral therapy (HAART) drugs, zidovudine (3'-azido-3'-deoythymidine, AZT), 2',3'-dideoxy-3'-thiacytidine (3TC) and efavirenz (EFV). Thirty-six male SD rats were divided into three groups. Group A was given a combination of AZT, 3TC and EFV (AZT/3TC/EFV). Group B rats were given AZT/3TC/EFV simultaneously with SLFZC. Group C rats were given AZT/3TC/EFV 2h prior to SLFZC. Blood samples were collected at fixed time intervals. Plasma concentration of each antiretroviral drug was tested for calculation of pharmacokinetic parameters. There was significant difference among groups with respect to t1/2 for AZT (F=3.371, P<0.05), but the Student-Newman-Keuls (SNK) pairwise multiple comparison procedure showed no statistical differences in all pairwise comparisons (P>0.05). There were no significant differences among groups in terms of Cmax, T max, AUC0-12h and CL for AZT, and t1/2, Cmax, Tmax, AUC0-12h and CL for 3TC and EFV, respectively. The results indicate that SLFZC has little impact on pharmacokinetic properties of AZT, 3TC and EFV.


Asunto(s)
Alquinos/farmacocinética , Benzoxazinas/farmacocinética , Ciclopropanos/farmacocinética , Interacciones de Hierba-Droga , Lamivudine/farmacocinética , Zidovudina/farmacocinética , Alquinos/sangre , Animales , Benzoxazinas/sangre , Ciclopropanos/sangre , Lamivudine/sangre , Masculino , Ratas , Zidovudina/sangre
5.
AIDS ; 34(5): 790-793, 2020 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-32167992

RESUMEN

: Associations between markers of liver and renal dysfunction and nucleotide reverse transcriptase inhibitor plasma exposure are ill-defined. As part of a large cohort study (Pharmacokinetic and Clinical Observations in People over Fifty), we analysed associations between alanine aminotransferase and estimated glomerular filtration rate results in people living with HIV on tenofovir disoproxil fumarate, emtricitabine, abacavir and lamivudine. While we found no associations between nucleotide reverse transcriptase inhibitor concentrations and alanine aminotransferase, lower estimated glomerular filtration rate values were associated with greater tenofovir, emtricitabine and lamivudine exposure, whereas abacavir showed no associations.


Asunto(s)
Emtricitabina/sangre , Infecciones por VIH/tratamiento farmacológico , Riñón/metabolismo , Lamivudine/sangre , Hígado/metabolismo , Nucleótidos/sangre , Inhibidores de la Transcriptasa Inversa/sangre , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/sangre , Estudios de Cohortes , Estudios Transversales , Combinación de Medicamentos , Emtricitabina/efectos adversos , Emtricitabina/uso terapéutico , Receptores ErbB/efectos de los fármacos , Infecciones por VIH/complicaciones , Humanos , Lamivudine/efectos adversos , Lamivudine/uso terapéutico , Nucleótidos/efectos adversos , Nucleótidos/uso terapéutico , Inhibidores de la Transcriptasa Inversa/efectos adversos , Inhibidores de la Transcriptasa Inversa/uso terapéutico , Resultado del Tratamiento , Carga Viral
6.
Artículo en Inglés | MEDLINE | ID: mdl-32015045

RESUMEN

Bariatric surgery is increasingly performed in morbidly obese HIV patients. Limited data exist regarding antiretroviral drug exposure after bariatric surgery. We report a case of a morbidly obese HIV patient who underwent sleeve gastrectomy. Abacavir, lamivudine, and dolutegravir therapeutic drug monitoring was performed at several time points pre- and postsurgery. Significantly increased levels were measured, particularly for abacavir, whose levels increased ∼12-fold. Several mechanistic explanations for these findings are discussed.


Asunto(s)
Antirretrovirales/farmacocinética , Antirretrovirales/uso terapéutico , Cirugía Bariátrica , Gastrectomía , Obesidad Mórbida/cirugía , Adulto , Antirretrovirales/sangre , Didesoxinucleósidos/sangre , Didesoxinucleósidos/farmacocinética , Didesoxinucleósidos/uso terapéutico , Monitoreo de Drogas , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/sangre , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Humanos , Lamivudine/sangre , Lamivudine/farmacocinética , Lamivudine/uso terapéutico , Masculino , Oxazinas/sangre , Oxazinas/farmacocinética , Oxazinas/uso terapéutico , Piperazinas/sangre , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Piridonas/sangre , Piridonas/farmacocinética , Piridonas/uso terapéutico
7.
Artículo en Inglés | MEDLINE | ID: mdl-30642925

RESUMEN

AIDS Clinical Trial Group study A5202 (ClinicalTrials.gov identifier NCT00118898) was a phase 3b, randomized, partially blinded equivalence study of open-label atazanavir/ritonavir or efavirenz, plus either placebo-controlled tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine, in treatment-naive adults living with HIV-1, evaluating efficacy, safety, and tolerability. We report an analysis of the contribution of participant characteristics to the disposition of tenofovir plasma concentrations. Tenofovir concentration data from a total of 817 individuals (88% of the total number of eligible patients randomly assigned to receive treatment in the TDF-containing arms of A5202) were available for analysis. Pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. One- and two-compartment models with first-order absorption and first-order elimination were evaluated. An exponential error model was used for examination of interindividual variability (IIV), and a proportional and mixed-error model was assessed for residual variability. The final structural model contained two compartments with first-order absorption and elimination. IIV was estimated for apparent clearance (CL/F) and the first-order absorption rate constant (ka ), and a proportional residual variability model was selected. The final mean parameter estimates were as follows: ka = 2.87 h-1, CL/F = 37.2 liters/h, apparent volumes of the central and peripheral compartments = 127 and 646 liters, respectively, and apparent intercompartmental clearance = 107 liters/h. In addition to race/ethnicity, creatinine clearance and assignment to atazanavir/ritonavir or efavirenz were significantly associated with CL/F (P < 0.001). In conclusion, race/ethnicity is associated with tenofovir oral CL in HIV-1 positive, treatment-naive adults. This covariate relationship raises questions about the possibility of differences in efficacy and risk of adverse events in different patient populations and suggests that examining preexposure prophylaxis regimens and tenofovir exposure in different race/ethnicity groups be considered.


Asunto(s)
Fármacos Anti-VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/etnología , Inhibidores de la Proteasa del VIH/uso terapéutico , VIH-1 , Tenofovir/sangre , Adulto , Alquinos , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Benzoxazinas/sangre , Benzoxazinas/uso terapéutico , Ciclopropanos , Didesoxinucleósidos/sangre , Didesoxinucleósidos/uso terapéutico , Combinación de Medicamentos , Emtricitabina/sangre , Emtricitabina/uso terapéutico , Femenino , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Lamivudine/sangre , Lamivudine/uso terapéutico , Masculino , Persona de Mediana Edad , Modelos Biológicos , Ritonavir/farmacocinética , Ritonavir/uso terapéutico , Tenofovir/farmacocinética , Tenofovir/uso terapéutico
8.
AIDS Behav ; 23(8): 2072-2078, 2019 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30523490

RESUMEN

There is increasing interest in home based testing and treatment of HIV to expand access to treatment in sub-Saharan Africa. Such programs rely on self-reported HIV history and use of antiretroviral therapy (ART). However, the accuracy of self-reported ART use in community settings is not well described. In this study, we compared self-reported ART (SR-ART) use in a home based survey against biological exposure to ART (BE-ART), in a population study of older adults in South Africa. Health and Aging in Africa: a Longitudinal Study of an INDEPTH community in South Africa (HAALSI) is a cohort of adults aged 40 +. The baseline home-based interview included self-reported HIV status and ART use. All participants also underwent biological testing for HIV antibodies, viral load and exposure to emtricitabine (FTC) or lamivudine (3TC), which are included in all first-line and second-line ART regimens in the public-sector South African HIV program. We calculated the performance characteristics for SR-ART compared to BE-ART and fit multivariable logistic regression models to identify correlates of invalid SR-ART responses. Of 4560 HAALSI participants with a valid HIV test result available, 1048 (23%) were HIV-positive and 734 [70% of people living with HIV (PLWH)] were biologically validated ART users (BE-ART). The sensitivity of SR-ART use was 64% (95% CI 61-68%) and the specificity was 94% (95% CI 91-96%); the positive predictive value (PPV) was 96% (95% CI 94-98%) and negative predictive value (NPV) was 52% (95% CI 48-56%). We found no sociodemographic predictors of accurate SR-ART use. Over one in three individuals with detectable ART in their blood denied current ART use during a home-based interview. These results demonstrate ongoing stigma related to HIV and its treatment, and have important implications for community health worker programs, clinical programs, and research studies planning community-based ART initiation in the region.


Asunto(s)
Terapia Antirretroviral Altamente Activa/estadística & datos numéricos , Infecciones por VIH/diagnóstico , Infecciones por VIH/tratamiento farmacológico , Población Rural , Autoinforme , Estigma Social , Adulto , Anciano , Estudios de Cohortes , Emtricitabina/sangre , Emtricitabina/uso terapéutico , Femenino , Anticuerpos Anti-VIH , Infecciones por VIH/epidemiología , Humanos , Lamivudine/sangre , Lamivudine/uso terapéutico , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Sudáfrica/epidemiología , Encuestas y Cuestionarios , Carga Viral
9.
AIDS Res Hum Retroviruses ; 34(11): 912-915, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30173559

RESUMEN

Clinical trials demonstrated intermittent preventive treatment in pregnancy with mefloquine (MQ) reduced malaria rates among pregnant women, yet an unexpected higher risk of mother-to-child transmission (MTCT) of HIV among HIV-positive women receiving MQ has also been observed. To determine if interactions between antiretroviral drugs (ARVs) and MQ could contribute to the increased MTCT observed in women receiving MQ, we performed a retrospective cross-sectional analysis of ARV plasma concentrations in peripheral blood (maternal plasma) and cord blood (cord plasma) collected at delivery from 186 mothers participating in a randomized clinical trial of MQ (n = 102) compared with placebo (n = 84) in Kenya. Plasma zidovudine (AZT), lamivudine (3TC), and nevirapine (NVP) concentrations were measured by high-performance liquid chromatography-tandem mass spectrometry. Although only 4% (7/186) reported not using these ARVs, AZT, 3TC, and NVP were all below the limit of detection in 44% of maternal plasma and 42% of cord plasma samples, and proportions were similar between the two study arms. Median concentrations of AZT and 3TC were not significantly lower in the MQ arm compared with the placebo arm for maternal plasma and cord plasma (p > .05). However, median NVP concentrations were significantly lower in the MQ study arm compared with the placebo study arm in both maternal plasma (1,597 ng/mL vs. 2,353 ng/mL, Mann-Whitney Rank Sum, p = .023) and cord plasma (2,038 ng/mL vs. 2,434 ng/mL, p = .048). Reduced NVP concentrations in maternal and cord plasma of women receiving MQ suggest MQ may affect NVP metabolism for both mother and infant. These results highlight the need to evaluate potential drug-drug interactions between candidate antimalarials and ARVs for use in pregnant women.


Asunto(s)
Fármacos Anti-VIH/sangre , Antimaláricos/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Malaria/prevención & control , Mefloquina/uso terapéutico , Nevirapina/sangre , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Adulto , Fármacos Anti-VIH/uso terapéutico , Antimaláricos/efectos adversos , Estudios Transversales , Interacciones Farmacológicas , Femenino , Sangre Fetal/metabolismo , Infecciones por VIH/sangre , Infecciones por VIH/transmisión , Humanos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Kenia , Lamivudine/sangre , Lamivudine/uso terapéutico , Mefloquina/efectos adversos , Nevirapina/uso terapéutico , Embarazo , Complicaciones Infecciosas del Embarazo/sangre , Estudios Retrospectivos , Zidovudina/sangre , Zidovudina/uso terapéutico
10.
Biosens Bioelectron ; 111: 82-89, 2018 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-29653420

RESUMEN

Double layered one-by-one imprinted hollow core-shells@ pencil graphite electrode was fabricated for sequential sensing of anti-HIV drugs. For this, two eccentric layers were developed on the surface of vinylated silica nanospheres to obtain double layered one-by-one imprinted solid core-shells. This yielded hollow core-shells on treatment with hydrofluoric acid. The modified hollow core-shells (single layered dual imprinted) evolved competitive diffusion of probe/analyte molecules. However, the corresponding double layered one-by-one imprinted hollow core-shells (outer layer imprinted with Zidovudine, and inner layer with Lamivudine) were found relatively better owing to their bilateral diffusions into molecular cavities, without any competition. The entire work is based on differential pulse anodic stripping voltammetry at double layered one-by-one imprinted hollow core-shells. This resulted in indirect detection of electro inactive targets with limits of detection as low as 0.91 and 0.12 (aqueous sample), 0.94 and 0.13 (blood serum), and 0.99 and 0.20 ng mL-1 (pharmaceutics) for lamivudine and zidovudine, respectively in anti-HIV drug combination.


Asunto(s)
Fármacos Anti-VIH/sangre , Técnicas Electroquímicas/métodos , Lamivudine/sangre , Impresión Molecular/métodos , Polímeros/química , Zidovudina/sangre , Fármacos Anti-VIH/análisis , Técnicas Biosensibles/métodos , Grafito/química , Humanos , Lamivudine/análisis , Límite de Detección , Zidovudina/análisis
11.
J Pharm Sci ; 107(7): 1787-1790, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29548975

RESUMEN

Daily oral antiretroviral therapy regimens produce limited drug exposure in tissues where residual HIV persists and suffer from poor patient adherence and disparate drug kinetics, which all negatively impact outcomes. To address this, we developed a tissue- and cell-targeted long-acting 4-in-1 nanosuspension composed of lopinavir (LPV), ritonavir, tenofovir (TFV), and lamivudine (3TC). In 4 macaques dosed subcutaneously, drug levels over 5 weeks in plasma, lymph node mononuclear cells (LNMCs), and peripheral blood mononuclear cells (PBMCs) were analyzed by liquid chromatography-tandem mass spectrometry. Plasma and PBMC levels of the active drugs (LPV, TFV, and 3TC) were sustained for 5 weeks; PBMC exposures to LPV, ritonavir, and 3TC were 12-, 16-, 42-fold higher than those in plasma. Apparent T1/2z of LPV, TFV, and 3TC were 219.1, 63.1, and 136.3 h in plasma; 1045.7, 105.9, and 127.7 h in PBMCs. At day 8, LPV, TFV, and 3TC levels in LNMCs were 4.1-, 5.0-, and 1.9-fold higher than in those in PBMCs and much higher than in plasma. Therefore, 1 dose of a 4-drug nanosuspension exhibited persistent drug levels in LNMCs, PBMCs, and plasma for 5 weeks. With interspecies scaling and dose adjustment, this 4-in-1 HIV drug-combination could be a long-acting treatment with the potential to target residual virus in tissues and improve patient adherence.


Asunto(s)
Fármacos Anti-VIH/administración & dosificación , Sistemas de Liberación de Medicamentos , Lamivudine/administración & dosificación , Lopinavir/administración & dosificación , Ritonavir/administración & dosificación , Tenofovir/administración & dosificación , Animales , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacocinética , Portadores de Fármacos/química , Quimioterapia Combinada , Infecciones por VIH/tratamiento farmacológico , Inyecciones Subcutáneas , Lamivudine/sangre , Lamivudine/farmacocinética , Leucocitos Mononucleares/metabolismo , Lopinavir/sangre , Lopinavir/farmacocinética , Ganglios Linfáticos/metabolismo , Macaca nemestrina , Masculino , Nanopartículas/química , Ritonavir/sangre , Ritonavir/farmacocinética , Tenofovir/sangre , Tenofovir/farmacocinética
12.
J Pharm Biomed Anal ; 153: 248-259, 2018 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-29518644

RESUMEN

Nucleoside reverse transcriptase inhibitors (NRTIs) require intracellular phosphorylation to active triphosphate (TP) nucleotide metabolites before they can inhibit the HIV reverse transcriptase. However, monitoring these pharmacologically active TP metabolites is challenging due to their instability and their low concentrations at the pg/ml levels in blood and tissues. The combination of lamivudine (3TC) and abacavir (ABC) is one of the first lines for HIV therapy. Therefore, a sensitive, selective, accurate, and precise LC-MS/MS method was developed and validated for the simultaneous quantification of 3TC- and ABC-TP metabolites in mouse blood and tissues. Calibration curves were linear over the range of 10-100,000 pg/ml for 3TC-TP and 4-40,000 pg/ml for carbovir-TP (CBV-TP; phosphorylated metabolite of ABC). This corresponds to 2.1-21,322 fmol/106 cells for 3TC-TP and 0.8-8000 fmol/106 cells for CBV-TP. Accuracy and precision were less than 15% for all quality control sample (QCs), and absolute extraction recovery of were >65% for 3TC-TP and >90% for CBV-TP. The method was optimized to ensure stability of TP samples and standards during sample collection, preparation, analysis, and storage conditions. This method has enhanced sensitivity and requires smaller amounts of blood and tissue samples compared to previous LC-MS/MS methods for 3TC- and CBV-TP quantification. The developed method was successfully applied to characterize the pharmacokinetic profile of TP metabolites in mouse peripheral blood mononuclear cells (PBMCs), spleen, lymph nodes, and liver cells. In addition, another direct, simple, and high-throughput method for the quantification of TP standards was developed and used for the analysis of stability samples.


Asunto(s)
Didesoxinucleósidos/sangre , Lamivudine/sangre , Polifosfatos/sangre , Animales , Fármacos Anti-VIH/sangre , Cromatografía Liquida/métodos , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Inhibidores de la Transcriptasa Inversa/sangre , Espectrometría de Masas en Tándem/métodos
13.
Antivir Ther ; 23(6): 549-552, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29533918

RESUMEN

Triumeq is a single-tablet regimen for patients with HIV infection comprising dolutegravir, abacavir and lamivudine. Overdoses with Triumeq have not been reported previously. We present a case of a 26-year-old man who presented to our hospital after intentionally ingesting 30 tablets of Triumeq. An intoxication with Triumeq can lead to several side effects. An overdose of abacavir and lamivudine can cause mitochondrial toxicity and lactic acidosis. An intoxication with dolutegravir appears to be relatively harmless. As Triumeq will be used on a regular basis as treatment for patients with HIV-1 infection, these intoxications are expected to be encountered more often.


Asunto(s)
Fármacos Anti-VIH/farmacocinética , Didesoxinucleósidos/farmacocinética , Sobredosis de Droga/terapia , Infecciones por VIH/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Lamivudine/farmacocinética , Intento de Suicidio/prevención & control , Adulto , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/sangre , Área Bajo la Curva , Disponibilidad Biológica , Didesoxinucleósidos/efectos adversos , Didesoxinucleósidos/sangre , Combinación de Medicamentos , Sobredosis de Droga/sangre , Sobredosis de Droga/psicología , Sobredosis de Droga/virología , Fluidoterapia/métodos , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , Semivida , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/sangre , Humanos , Lamivudine/efectos adversos , Lamivudine/sangre , Masculino , Intento de Suicidio/psicología , Comprimidos
14.
J Pharm Biomed Anal ; 149: 40-45, 2018 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-29100029

RESUMEN

The ability to monitor adherence to antiretroviral therapy is critical for the interpretation of outcomes from clinical studies of HIV, and for optimizing patient care. The antiretrovirals tenofovir (TFV), emtricitabine (FTC), and lamivudine (3TC) are commonly included in drug regimens for HIV prevention and treatment. The active form of the drugs tenofovir diphosphate (TFVdp), emtricitabine triphosphate (FTCtp), and lamivudine triphosphate (3TCtp) are found intracellularly in erythrocytes and peripheral blood mononuclear cells (PBMCs). The ability to collect and analyze dried blood spot (DBS) samples is an attractive alternative to PBMC sampling in many resource limited settings. We developed and validated an assay to quantify all three intracellular metabolites over the range of 100-25000 fmol/sample. This assay utilizes a simple protein precipitation/liquid-liquid extraction of a single 3-mm DBS punch (from a Whatman 903 Protein Saver card) with isotopically labeled 13C5-TFVdp included as the internal standard. Following extraction, samples are analyzed by anion exchange chromatography on a Thermo Biobasic AX 5µm column with detection by electrospray ionization in the positive mode on a AB Sciex API-5000 triple quadrupole mass spectrometer with a total run time of 8min. The assay was linear over the entire range (R2>0.996). The assay was accurate (inter-assay%bias within ±3.0%) and precise (inter-assay % CV≤9.8%). The assay was also reproducible from multiple punches within a spot as well as punches from separate blood spots. Stability was established at room temperature for 3days, and at -80°C for up to 63days. Clinical samples were analyzed from subjects on Truvada®, Stribild®, Descovy®, and Triumeq® regimens and intracellular metabolites were detected in all samples as expected, indicating the assay performs well for all current formulations of TFV, FTC, and 3TC.


Asunto(s)
Fármacos Anti-VIH/sangre , Cromatografía Líquida de Alta Presión/métodos , Infecciones por VIH/tratamiento farmacológico , Cumplimiento de la Medicación , Espectrometría de Masas en Tándem/métodos , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/uso terapéutico , Cromatografía Líquida de Alta Presión/instrumentación , Pruebas con Sangre Seca/métodos , Quimioterapia Combinada/métodos , Emtricitabina/sangre , Emtricitabina/farmacocinética , Humanos , Lamivudine/sangre , Lamivudine/farmacocinética , Lamivudine/uso terapéutico , Leucocitos Mononucleares/metabolismo , Extracción Líquido-Líquido/métodos , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray/instrumentación , Espectrometría de Masa por Ionización de Electrospray/métodos , Espectrometría de Masas en Tándem/instrumentación , Tenofovir/sangre , Tenofovir/farmacocinética , Tenofovir/uso terapéutico
15.
Artículo en Inglés | MEDLINE | ID: mdl-28651173

RESUMEN

OBJECTIVES: To present the validation and clinical application of a LC-MS/MS method for the quantification of lamivudine (3TC), emtricitabine (FTC) and tenofovir (TFV) in dried blood spots (DBS) and dried breast milk spots (DBMS). METHODS: DBS and DBMS were prepared from 50 and 30µL of drug-spiked whole blood and human breast milk, respectively. Following extraction with acetonitrile and water, chromatographic separation utilised a Synergi polar column with a gradient mobile phase program consisting of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. Detection and quantification was performed using a TSQ Quantum Ultra triple quadrupole mass spectrometer. The analytical method was used to evaluate NRTI drug levels in HIV-positive nursing mothers-infant pairs. RESULTS: The assay was validated over the concentration range of 16.6-5000ng/mL for 3TC, FTC and TFV in DBS and DBMS except for TFV in DBMS where linearity was established from 4.2-1250ng/mL. Intra and inter-day precision (%CV) ranged from 3.5-8.7 and accuracy was within 15% for all analytes in both matrices. The mean recovery in DBS was >61% and in DBMS >43% for all three analytes. Matrix effect was insignificant. Median AUC0-8 values in maternal DBS and DBMS, respectively, were 4683 (4165-6057) and 6050 (5217-6417)ngh/mL for 3TC, 3312 (2259-4312) and 4853 (4124-6691)ngh/mL for FTC and 1559 (930-1915) and 56 (45-80)ngh/mL for TFV. 3TC and FTC were quantifiable (>16.6ng/mL) in DBS from 2/6 and 1/6 infants respectively whereas TFV was undetectable in all infants. CONCLUSIONS: DBS and DBMS sampling for bioanalysis of 3TC, FTC and TFV is straightforward, robust, accurate and precise, and ideal for use in low-resource settings.


Asunto(s)
Fármacos Anti-VIH/análisis , Pruebas con Sangre Seca/métodos , Emtricitabina/análisis , Lamivudine/análisis , Leche Humana/química , Tenofovir/análisis , Adulto , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/química , Área Bajo la Curva , Cromatografía Liquida/métodos , Estudios de Cohortes , Emtricitabina/sangre , Emtricitabina/química , Femenino , Humanos , Lactante , Lamivudine/sangre , Lamivudine/química , Modelos Lineales , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masas en Tándem/métodos , Tenofovir/sangre , Tenofovir/química , Adulto Joven
16.
J Crit Care ; 40: 113-118, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28384599

RESUMEN

INTRODUCTION: To our knowledge, there is no published data on the pharmacokinetic (PK) profile of antiretroviral (ART) drugs on patients undergoing extracorporeal membrane oxygenation (ECMO) therapy. We present PK analyses of Ritonavir, Darunavir, Lamivudine and Tenofovir in a patient with HIV who required veno-venous ECMO (VV ECMO). METHODS: Plasma concentrations for Ritonavir, Darunavir, Tenofovir and Lamivudine were obtained while the patient was on ECMO following pre-emptive dose adjustments. Published population PK models were used to simulate plasma concentration profiles for the drugs. The population prediction and the observed plasma concentrations were then overlaid with the expected drug profiles using the individual Bayesian post-hoc parameter estimates. RESULTS: Following dose adjustments, the PK profiles of Ritonavir, Darunavir and Tenofovir fell within the expected range and appeared similar to the population prediction, although slightly different for Ritonavir. The observed data for Lamivudine and its PK profile were completely different from the data available in the literature. CONCLUSIONS: To our knowledge, this is the first study reporting the PK profile of ART drugs during ECMO therapy. Based on our results, dose adjustment of ART drugs while on VV ECMO may be advisable. Further study of the PK profile of Lamivudine is required.


Asunto(s)
Oxigenación por Membrana Extracorpórea , Infecciones por VIH/sangre , Inhibidores de la Proteasa del VIH/farmacocinética , Teorema de Bayes , Darunavir/sangre , Darunavir/farmacocinética , Relación Dosis-Respuesta a Droga , Infecciones por VIH/tratamiento farmacológico , Inhibidores de la Proteasa del VIH/sangre , Humanos , Lamivudine/sangre , Lamivudine/farmacocinética , Masculino , Persona de Mediana Edad , Ritonavir/sangre , Ritonavir/farmacocinética , Tenofovir/sangre , Tenofovir/farmacocinética
17.
Antivir Ther ; 22(4): 353-356, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28008867

RESUMEN

BACKGROUND: Studies in healthy volunteers have shown that the recently approved HIV integrase inhibitor dolutegravir has limited drug-to-drug interaction profile. Here we carried out a pharmacokinetic survey in HIV-infected patients given dolutegravir as part of their antiretroviral therapy. METHODS: Dolutegravir plasma trough concentrations were measured in 78 HIV-infected patients given the drug in combination with a protease inhibitor, a non-nucleoside reverse transcriptase inhibitor or abacavir/lamivudine. Drug concentrations were assessed by high performance liquid chromatography method with UV-detection. RESULTS: All patients were given dolutegravir at 50 mg once daily, with median trough drug concentrations of 1,096 (664-2,356) ng/ml (interindividual coefficient of variation: 85.3%). Patients given dolutegravir with atazanavir had significantly higher drug concentrations compared with those given darunavir, rilpivirine or abacavir/lamivudine (2,399 [1,929-4,070] versus 738 [552-1,048], 603 [432-1,373] or 1,045 [856-1,115] ng/ml; P<0.001 for all comparisons). By multivariate analyses, only companion antiretroviral drug resulted in significant association with dolutegravir plasma trough concentrations (P=0.012). CONCLUSIONS: Atazanavir coadministration significantly inhibited dolutegravir metabolism, ultimately resulting in a two- to fourfold increase in drug disposition compared with other antiretroviral drugs. This boosting effect of atazanavir could be used to optimize dolutegravir dosing in particular clinical settings.


Asunto(s)
Fármacos Anti-VIH/sangre , Sulfato de Atazanavir/sangre , Darunavir/sangre , Didesoxinucleósidos/sangre , Infecciones por VIH/tratamiento farmacológico , Inhibidores de Integrasa VIH/sangre , Compuestos Heterocíclicos con 3 Anillos/sangre , Lamivudine/sangre , Rilpivirina/sangre , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Sulfato de Atazanavir/farmacocinética , Sulfato de Atazanavir/farmacología , Disponibilidad Biológica , Recuento de Linfocito CD4 , Darunavir/farmacocinética , Darunavir/farmacología , Didesoxinucleósidos/farmacocinética , Didesoxinucleósidos/farmacología , Esquema de Medicación , Combinación de Medicamentos , Cálculo de Dosificación de Drogas , Interacciones Farmacológicas , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Inhibidores de Integrasa VIH/farmacocinética , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/fisiología , Compuestos Heterocíclicos con 3 Anillos/farmacocinética , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Lamivudine/farmacocinética , Lamivudine/farmacología , Masculino , Persona de Mediana Edad , Oxazinas , Piperazinas , Piridonas , Estudios Retrospectivos , Rilpivirina/farmacocinética , Rilpivirina/farmacología , Carga Viral/efectos de los fármacos
18.
Eur J Pharm Sci ; 94: 72-83, 2016 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-26796142

RESUMEN

A major aim of Systems Pharmacology is to understand clinically relevant mechanisms of action (MOA) of drugs and to use this knowledge in order to optimize therapy. To enable this mission it is necessary to obtain knowledge on how in vitro testable insights translate into clinical efficacy. Mathematical modeling and data integration are essential components to achieve this goal. Two modeling philosophies are prevalent, each of which in isolation is not sufficient to achieve the above described: In a 'top-down' approach, a minimal pharmacokinetic-pharmacodynamic (PK-PD) model is derived from- and fitted to available clinical data. This model may lack interpretability in terms of mechanisms and may only be predictive for scenarios already covered by the data used to derive it. A 'bottom-up' approach builds on mechanistic insights derived from in vitro/ex vivo experiments, which can be conducted under controlled conditions, but may not be fully representative for the in vivo/clinical situation. In this work, we employ both approaches side-by-side to predict the clinical potency (IC50 values) of the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine, emtricitabine and tenofovir. In the 'top-down' approach, this requires to establish the dynamic link between the intracellularly active NRTI-triphosphates (which exert the effect) and plasma prodrug PK and to subsequently link this composite PK model to viral kinetics. The 'bottom-up' approach assesses inhibition of reverse transcriptase-mediated viral DNA polymerization by the intracellular, active NRTI-triphosphates, which has to be brought into the context of target cell infection. By using entirely disparate sets of data to derive and parameterize the respective models, our approach serves as a means to assess the clinical relevance of the 'bottom-up' approach. We obtain very good qualitative and quantitative agreement between 'top-down' vs. 'bottom-up' predicted IC50 values, arguing for the validity of the 'bottom-up' approach. We noted, however, that the 'top-down' approach is strongly dependent on the sparse and noisy intracellular pharmacokinetic data. All in all, our work provides confidence that we can translate in vitro parameters into measures of clinical efficacy using the 'bottom-up' approach. This may allow to infer the potency of various NRTIs in inhibiting e.g. mutant viruses, to distinguish sources of interaction of NRTI combinations and to assess the efficacy of different NRTIs for repurposing, e.g. for pre-exposure prophylaxis.


Asunto(s)
Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacología , VIH-1/metabolismo , Leucocitos Mononucleares/metabolismo , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/farmacología , Fármacos Anti-VIH/uso terapéutico , Relación Dosis-Respuesta a Droga , Emtricitabina/sangre , Emtricitabina/farmacología , Emtricitabina/uso terapéutico , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Humanos , Lamivudine/sangre , Lamivudine/farmacología , Lamivudine/uso terapéutico , Leucocitos Mononucleares/efectos de los fármacos , Tenofovir/sangre , Tenofovir/farmacología , Tenofovir/uso terapéutico , Resultado del Tratamiento
19.
Clin Exp Obstet Gynecol ; 42(4): 523-8, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26411225

RESUMEN

PURPOSE: To investigate the morphological and biochemical effects of lamivudine associated with ritonavir on maternal and fetal livers and kidneys throughout the pregnancy of albino rats. MATERIALS AND METHODS: Forty pregnant rats were divided into four numerically equal groups: control (C), experiment 1 (E1), experiment 2 (E2), and experiment 3 (E3). Only distilled water was given to the control group, while groups E1, E2, and E3 received, respectively, 5, 15 and 45 mg/kg of lamivudine associated with 20, 60, and 180 mg/kg of ritonavir, per day, throughout the pregnancy. On the 20th day of the pregnancy, the histological structure of the maternal and fetal livers and kidneys was analyzed by means of optical microscopy, along with the blood concentrations of AST, ALT, urea, and matrix creatinine. The numerical variables were analyzed using the Kruskal-Wallis test and Dunn's multiple comparison test. RESULTS: The histological alterations occurred in both the maternal livers and the maternal kidneys, particularly in group E3, which received the greatest therapeutic dosage (nine times). The blood levels ofALT in group E3 were significantly lower than in the other groups (p = 0.0037). The urea and creatinine levels in the blood were significantly lower in group E1 (p = 0.0420 andp = 0.0108, respectively). CONCLUSIONS: rhe association of lamivudine and ritonavir affected the histological structure of the kidneys of the matrices of group E3. There was a significant decrease in the blood values of urea e creatinine in group El.


Asunto(s)
Antirretrovirales/farmacología , Riñón/efectos de los fármacos , Lamivudine/farmacología , Hígado/efectos de los fármacos , Ritonavir/farmacología , Síndrome de Inmunodeficiencia Adquirida/tratamiento farmacológico , Animales , Antirretrovirales/sangre , Antirretrovirales/toxicidad , Evaluación Preclínica de Medicamentos , Femenino , Riñón/embriología , Riñón/patología , Lamivudine/sangre , Lamivudine/toxicidad , Hígado/embriología , Hígado/patología , Embarazo , Complicaciones Infecciosas del Embarazo/tratamiento farmacológico , Ratas , Ratas Wistar , Ritonavir/sangre , Ritonavir/toxicidad
20.
J Pharm Biomed Anal ; 114: 127-32, 2015 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-26037161

RESUMEN

Hepatitis B infection affects two billion people worldwide and 350 million of these are chronically infected. Chronic hepatitis B virus is one of the most important cause of mortality and morbidity worldwide. If it is left untreated, about one-third of affected people will develop progressive and possibly fatal liver disease, like hepatic cirrhosis and primary hepatocellular carcinoma. Currently, five nucleos(t)ide analogs are approved for the treatment of chronic HBV infection. They are: lamivudine, adefovir dipivoxil, telbivudine, entecavir and tenofovir disoproxil fumarate. In this work, we developed and validated an UPLC-Tandem mass spectrometry assay method capable of monitoring lamivudine, telbivudine, tenofovir and entecavir plasma concentrations. Both standards and quality controls (high, medium and low) were prepared in human plasma. Each sample was added with internal standard (5'amino-5'deoxy-thymidine) and then drugs were extracted through a protein precipitation protocol with acetonitrile+0.1% formic acid and then dried. The extracts were resuspended in water and then injected into the chromatographic system. The chromatographic separation was performed on an Acquity UPLC HSS T3 1.8 µm 2.1 × 150 mm column, with a gradient of water and acetonitrile, both added with formic acid (0.05%). Accuracy, intra-day and inter-day precision at quality controls levels fitted all FDA guidelines for all analytes, while matrix effects and recoveries resulted stable between samples for each analyte. Finally, we tested this method by monitoring plasma concentrations in 30 HBV+ patients with good results. This simple analytical method could represent a useful tool for the management of anti-HBV therapy.


Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Guanina/análogos & derivados , Hepatitis B Crónica/sangre , Hepatitis B Crónica/tratamiento farmacológico , Lamivudine/sangre , Espectrometría de Masas en Tándem/métodos , Tenofovir/sangre , Timidina/análogos & derivados , Antivirales/sangre , Calibración , Técnicas de Química Analítica , Cromatografía , Guanina/sangre , Humanos , Límite de Detección , Nucleósidos/química , Reproducibilidad de los Resultados , Telbivudina , Timidina/sangre
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