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2.
PLoS Med ; 16(9): e1002895, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31539371

RESUMO

BACKGROUND: The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3). METHODS AND FINDINGS: In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum. CONCLUSION: Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy. TRIAL REGISTRATION: clinicaltrials.gov NCT02245022.


Assuntos
Benzoxazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/farmacocinética , HIV/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Feminino , HIV/genética , HIV/crescimento & desenvolvimento , Infecções por HIV/diagnóstico , Infecções por HIV/transmissão , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Recém-Nascido , Troca Materno-Fetal , Leite Humano/metabolismo , Gravidez , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Medição de Risco , África do Sul , Resultado do Tratamento , Uganda , Carga Viral , Adulto Jovem
3.
PLoS One ; 14(8): e0220323, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31408460

RESUMO

OBJECTIVE: To determine the transplacental pharmacokinetics of the HIV integrase inhibitor dolutegravir. STUDY DESIGN: Maternal-to-fetal transfer across the term human placenta was investigated with the ex-vivo dually perfused cotyledon model, in 5 closed-circuit, recirculating experiments. Dolutegravir was added to a maternal perfusate containing antipyrine, a marker to validate the cotyledon's viability, and 2 g/liter of human albumin. RESULTS: After 3h of recirculating perfusion, the mean (± SD) DTG concentrations in the maternal and in the fetal compartments were respectively 2450 ± 286 ng/mL and 715 ± 369 ng/mL, with a fetal-to-maternal ratio of 34% ± 18% and a clearance index (in comparison with antipyrine transfer) of 79% ± 23%. The mean cotyledon accumulation index was 153% ± 25%. CONCLUSION: Fetal transplacental exposure to dolutegravir was considerable as well as accumulation in placental tissue. Whether this may lead to risks for the exposed fetus requires more investigation.


Assuntos
Inibidores de Integrase de HIV/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Troca Materno-Fetal , Placenta/metabolismo , Antipirina/farmacocinética , Feminino , Inibidores de Integrase de HIV/análise , Compostos Heterocíclicos com 3 Anéis/análise , Humanos , Modelos Biológicos , Perfusão , Placenta/química , Gravidez
4.
J Med Case Rep ; 13(1): 224, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31331387

RESUMO

BACKGROUND: Identifying the most appropriate antiretroviral regimen for pregnant women with Human Immunodeficiency Virus (HIV-1) infection can be challenging, mainly due to pregnancy-related physiological alterations which can significantly reduce maternal drug plasma concentration. We would like to report our experience as it consists of an unusual case of low plasmatic concentration of antiretroviral drugs despite regimen intensification in a HIV-positive pregnant woman. It also underlines the need for accurate monitoring and treatment adjustment in pregnant women with Human Immunodeficiency Virus (HIV). CASE PRESENTATION: A 26-year-old Brazilian woman with HIV-1 infection attending our out-patient clinic presented with low plasmatic concentration of antiretroviral drugs and persistent detectable viral load despite regimen intensification during pregnancy. Trough plasma concentrations of dolutegravir and darunavir were measured by validated liquid chromatography-mass spectrometry. At 23 weeks of gestation it showed a lower value than expected in non-pregnant adults, compared to a normal level of plasma concentration measured at 10 weeks after delivery. Our patient and the baby had no regimen-related adverse effects. CONCLUSIONS: Physiological changes during pregnancy can affect pharmacokinetics and reduce a mother's bioavailability of antiretroviral drugs, potentially altering their pharmacological activity. A personalized treatment and a careful follow-up are hence mandatory for this key population.


Assuntos
Darunavir/sangue , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/sangue , Compostos Heterocíclicos com 3 Anéis/sangue , Complicações Infecciosas na Gravidez/tratamento farmacológico , Darunavir/farmacocinética , Feminino , Inibidores de Integrase de HIV/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Gravidez , Carga Viral/efeitos dos fármacos , Adulto Jovem
6.
Int J Antimicrob Agents ; 54(2): 202-206, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31002950

RESUMO

BACKGROUND: Tuberculosis (TB) causes 25% of all deaths among individuals infected with human immunodeficiency virus (HIV). Rifampicin (RIF) is a potent inducer of drug metabolizing enzymes and drug transporters, and co-administration with dolutegravir (DTG) reduces DTG exposure; this can be overcome by doubling the DTG dose to 50 mg twice daily. This study investigated the effect of RIF on DTG exposure when dosed at 100 mg once daily, which could provide an easier option than 50 mg twice daily. METHODS: An open label, pharmacokinetic (PK) study was undertaken. Healthy HIV-negative subjects received DTG 50 mg for 7 days (PK1), DTG 100 mg for 7 days (PK2), RIF for 14 days, DTG 50 mg + RIF for 7 days (PK3) and DTG 100 mg + RIF for 7 days (PK4). Steady-state full DTG PK profiles were evaluated. RESULTS: DTG geometric mean ratios (GMRs) of PK3/PK1 of maximum concentration (Cmax), area under curve (AUC24h) and 24-h post-dose concentration (C24h) were 0.65 [90% confidence interval (CI) 0.55-0.75], 0.44 (90% CI 0.37-0.52) and 0.15 (0.13-90% CI 0.17), respectively. GMRs of PK4/PK1 Cmax, AUC24h and C24h were 1.09 (90% CI 0.97-1.21), 0.74 (90% CI 0.64-0.86) and 0.24 (90% CI 0.20-0.28), respectively. Median C24h of DTG 50 mg + RIF and DTG 100 mg + RIF were 251 (range 129-706) ng/mL and 140 (range 73-426) ng/mL, respectively. CONCLUSION: Although there were substantial reductions in DTG C24h when co-administered with RIF, concentrations of both DTG 50 mg and 100 mg once daily with RIF were still above the protein-binding-adjusted IC90 (drug concentration required to inhibit 90% of in-vitro viral replication) of 64 ng/mL. Further studies in HIV-TB co-infected individuals are warranted to confirm these results.


Assuntos
Antibióticos Antituberculose/administração & dosagem , Interações Medicamentosas , Inibidores de Integrase de HIV/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Rifampina/administração & dosagem , Adolescente , Adulto , Antibióticos Antituberculose/farmacocinética , Antibióticos Antituberculose/farmacologia , Feminino , Inibidores de Integrase de HIV/farmacocinética , Inibidores de Integrase de HIV/farmacologia , Voluntários Saudáveis , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Pessoa de Meia-Idade , Rifampina/farmacocinética , Rifampina/farmacologia , Adulto Jovem
7.
Expert Opin Drug Metab Toxicol ; 15(3): 245-252, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30704313

RESUMO

INTRODUCTION: The GEMINI trials have recently shown that a two-drug regimen of dolutegravir plus lamivudine was non-inferior to a three-drug regimen in HIV-infected naïve patients. Accordingly, it is important that physicians be aware and confident about the drug-drug interactions (DDIs) involving dolutegravir, lamivudine, and other medications. Areas covered: Here, we firstly update the available information on the pharmacokinetic features of dolutegravir and lamivudine; subsequently, the articles mainly deals with the predictable DDIs for both antiretroviral drugs, attempting to underline their clinical implications. This review focuses on the DDIs of dolutegravir/lamivudine combined regimen and, therefore, does not provide an exhaustive list of all the potential DDIs involving the two single agents. A MEDLINE Pubmed search for articles published from January 2000 to December 2018 was completed matching the terms dolutegravir or lamivudine with pharmacokinetics, DDIs, and pharmacology. Moreover, additional studies were identified from the reference list of retrieved articles. Expert opinion: The antiretroviral dual regimen of dolutegravir and lamivudine represents an attractive therapeutic option for HIV in terms of DDIs. This is particularly relevant considering that the population with HIV is aging and is increasingly experience age-related comorbidities, increasing pill burden, polypharmacy and the risk of DDIs.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Lamivudina/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Interações Medicamentosas , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Lamivudina/farmacocinética , Lamivudina/farmacologia
8.
J Pharm Biomed Anal ; 168: 163-173, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30807921

RESUMO

Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, is critically involved in cell migration, spreading and proliferation at the early step of various cancers. Small molecule inhibitors of FAK are effective to inhibit its activation in the process of tumor formation in cell. To better understand biotransformation of FAK inhibitors, this work has investigated in vitro phase I metabolism of inhibitors (namely PF-573228, PF-562271 and PF-03814735) by rat liver microsomes model. Using liquid chromatography - quadrupole time of flight mass spectrometry and tandem mass spectrometry (LC/Q-TOF/MS and MS/MS), three metabolites of PF-573228 and PF-562271 were observed and characterized, respectively. These in vitro metabolites were reported for the first time. The structures and fragmentation patterns of these metabolites were elucidated, and phase I metabolic pathways for FAK inhibitors were proposed. The main metabolic pathways of PF-573228 were hydroxylation, dehydrogenation and N-dealkylation. For PF-562271, they were hydroxylation and dehydrogenation. Hydroxylation was observed as the primary metabolism for PF-0381473.


Assuntos
Cromatografia Líquida/métodos , Proteína-Tirosina Quinases de Adesão Focal/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Remoção de Radical Alquila , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Hidroxilação , Indóis/farmacocinética , Microssomos Hepáticos/metabolismo , Pirimidinas/farmacocinética , Quinolonas/farmacocinética , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacocinética , Sulfonas/farmacocinética
9.
Artigo em Inglês | MEDLINE | ID: mdl-30420479

RESUMO

Across sub-Saharan Africa, patients with HIV on antiretrovirals often get malaria and need cotreatment with artemisinin-containing therapies. We undertook two pharmacokinetic studies in healthy volunteers, using standard adult doses of artemether-lumefantrine or artesunate-amodiaquine given with 50 mg once daily dolutegravir (DTG) to investigate the drug-drug interaction between artemether-lumefantrine or artesunate-amodiaquine and dolutegravir. The dolutegravir/artemether-lumefantrine interaction was evaluated in a two-way crossover study and measured artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine over 264 h. The dolutegravir/artesunate-amodiaquine interaction was investigated using a parallel study design due to long half-life of the amodiaquine metabolite, desethylamodiaquine and measured artesunate, amodiaquine, and desethylamodiaquine over 624 h. Noncompartmental analysis was performed, and geometric mean ratios and 90% confidence intervals were generated for evaluation of both interactions. Dolutegravir did not significantly change the maximum concentration in plasma, the time to maximum concentration, and the area under the concentration-time curve (AUC) for artemether, dihydroartemisinin, lumefantrine, and desbutyl-lumefantrine, nor did it significantly alter the AUC for artesunate, dihydroartemisinin, amodiaquine, and desethylamodiaquine. Coadministration of dolutegravir with artemether-lumefantrine resulted in a 37% decrease in DTG trough concentrations. Coadministration of dolutegravir with artesunate-amodiaquine resulted in 42 and 24% approximate decreases in the DTG trough concentrations and the AUC, respectively. The significant decreases in DTG trough concentrations with artemether-lumefantrine and artesunate-amodiaquine and dolutegravir exposure with artesunate-amodiaquine are unlikely to be of clinical significance since the DTG trough concentrations were above dolutegravir target concentrations of 300 ng/ml. Study drugs were well tolerated with no serious adverse events. Standard doses of artemether-lumefantrine and artesunate-amodiaquine should be used in patients receiving dolutegravir. (This study has been registered at ClinicalTrials.gov under identifier NCT02242799.).


Assuntos
Antimaláricos/uso terapêutico , Artemeter/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Adulto , Amodiaquina/farmacocinética , Amodiaquina/uso terapêutico , Artemeter/farmacocinética , Artesunato/farmacocinética , Artesunato/uso terapêutico , Aleitamento Materno , Estudos Cross-Over , Interações Medicamentosas , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Lumefantrina/farmacocinética , Lumefantrina/uso terapêutico , Masculino
10.
J Antimicrob Chemother ; 74(1): 149-156, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30272231

RESUMO

Background: Dolutegravir combined with darunavir/cobicistat is a promising NRTI-sparing and/or salvage strategy for the treatment of HIV-1 infection. Methods: This Phase I, open-label, 57 day, crossover, pharmacokinetic (PK) study, enrolled healthy volunteers aged 18-65 years, who were randomized to one of two groups. Group 1 received dolutegravir (50 mg) once daily for 14 days followed by a 7 day washout, then a 14 day dolutegravir/darunavir/cobicistat (DTG/DRV/COBI) once-daily co-administration period followed by a 7 day washout and finally a 14 day period of darunavir/cobicistat (800/150 mg) once daily. Group 2 followed the same sequence starting with darunavir/cobicistat and concluding with dolutegravir. Each group underwent intensive PK sampling over 24 h on day 14 of each drug period and DTG/DRV/COBI concentrations were measured using validated LC-MS/MS methods. Results: Twenty participants completed all PK phases. Thirteen were female and median age and BMI were 33.5 years and 27 kg/m2. Dolutegravir geometric mean ratios (GMR, DTG/DRV/COBI versus dolutegravir alone) and 90% CI for Cmax, AUC0-24 and C24 were 1.01 (0.92-1.11), 0.95 (0.87-1.04) and 0.9 (0.8-1.0), respectively. Darunavir GMR (DRV/COBI/DTG versus darunavir/cobicistat alone) and 90% CI for Cmax, AUC0-24 and C24 were 0.90 (0.83-0.98), 0.93 (0.86-1.00) and 0.93 (0.78-1.11), respectively. No grade 3 or 4 adverse events or laboratory abnormalities were observed. Conclusions: Concentrations of dolutegravir and darunavir, when boosted with cobicistat, decreased by <10% during co-administration, suggesting this combination can be prescribed safely in the treatment of HIV-1, with no adjustment to current guideline-recommended dosages.


Assuntos
Fármacos Anti-HIV/farmacocinética , Cobicistat/farmacocinética , Darunavir/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Cobicistat/administração & dosagem , Cobicistat/efeitos adversos , Estudos Cross-Over , Darunavir/administração & dosagem , Darunavir/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Voluntários Saudáveis , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Artigo em Inglês | MEDLINE | ID: mdl-30572204

RESUMO

Dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine are antiretroviral drugs used as part of combined antiretroviral treatment for HIV-infection. For quantification of these drugs in human K2EDTA plasma samples an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) bioanalytical method was developed and validated. Stable isotope labeled internal standards were used for each analyte. Simple protein precipitation with methanol was implemented to prepare plasma samples of at least 50 µL. The method was validated for dolutegravir, elvitegravir, raltegravir, nevirapine and etravirine over the ranges 9.7-9700, 52-10,470, 9.7-9730, 73-14,680 and 15-3010 ng/mL, respectively. Within-run and between-run accuracy and precision were within ±15% of the nominal concentration for quality controls at high, medium and low concentrations, and within ±20% at the lower limit of quantification for all analytes. Recovery was ≥76% and reproducible. Long-term stability of patient plasma samples was demonstrated for at least 12 months at -40 °C (4 months for etravirine). Currently, this robust method with a run time of 10 min is used in clinical research and for therapeutic drug monitoring of these frequently used antiretroviral drugs.


Assuntos
Antirretrovirais/sangue , Cromatografia Líquida de Alta Pressão/métodos , Compostos Heterocíclicos com 1 Anel/sangue , Compostos Heterocíclicos com 3 Anéis/sangue , Quinolonas/sangue , Antirretrovirais/química , Antirretrovirais/farmacocinética , Estabilidade de Medicamentos , Compostos Heterocíclicos com 1 Anel/química , Compostos Heterocíclicos com 1 Anel/farmacocinética , Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Limite de Detecção , Modelos Lineares , Quinolonas/química , Quinolonas/farmacocinética , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos
12.
Clin Infect Dis ; 68(1): 87-95, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29771285

RESUMO

Background: Demographic data show an increasingly aging human immunodeficiency virus (HIV) population worldwide. Recent concerns over dolutegravir-related neuropsychiatric toxicity have emerged, particularly amongst older people living with HIV (PLWH). We describe the pharmacokinetics (PK) of dolutegravir (DTG) 50 mg once daily in PLWH aged 60 and older. Additionally, to address calls for prospective neuropsychiatric toxicodynamic data, we evaluated changes in sleep quality and cognitive functioning in this population after switching to abacavir (ABC)/lamivudine (3TC)/DTG over 6 months. Methods: PLWH ≥60 years with HIV-viral load <50 copies/mL on any non-DTG-based antiretroviral combination were switched to ABC/3TC/DTG. On day 28, 24-hour PK sampling was undertaken. Steady-state PK parameters were compared to a published historical control population aged ≤50 years. We administered 6 validated sleep questionnaires and neurocognitive (Cogstate) testing pre-switch and over 180 days. Results: In total, 43 participants enrolled, and 40 completed the PK phase. Overall, 5 discontinued (2 due to sleep-related adverse events, 4.6%). DTG maximum concentration (Cmax) was significantly higher in patients ≥60 years old versus controls (geometric mean 4246 ng/mL versus 3402 ng/mL, P = .005). In those who completed day 180 (n = 38), sleep impairment (Pittsburgh Sleep Quality Index) was marginally higher at day 28 (P = .02), but not at days 90 or 180. Insomnia, daytime functioning, and fatigue test scores did not change statistically over time. Conclusions: DTG Cmax was significantly higher in older PLWH. Our data provides clinicians with key information on the safety of prescribing DTG in older PLWH.


Assuntos
Transtornos Cognitivos/induzido quimicamente , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/farmacocinética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Transtornos do Sono-Vigília/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
13.
J Clin Virol ; 109: 45-49, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30471517

RESUMO

BACKGROUND AND OBJECTIVES: We aimed to investigate to what extent a first-line DTG-based ART regimen reduces HIV-RNA in semen compared to plasma. STUDY DESIGN: In this prospective, observational study, ART-naïve, HIV-infected males starting their first ART regimen with DTG plus TDF/FTC or ABC/3TC were enrolled. Paired blood (BP) and seminal plasma (SP) samples were collected at baseline (T0) and at week-2/4/12/24 after ART initiation. Sexually transmitted infections (STI) were ruled out before enrolment. RESULTS: Median baseline HIV-RNA levels were lower in SP compared to BP (657 versus 38.200 copies/ml, p < 0.001), three subjects had undetectable semen HIV-RNA. After 12 weeks of treatment, HIV-RNA was below the quantification limit in both BP and SP of 11 pts (61.1%). Discordant results were obtained in 6 subjects (33.3%), showing quantifiable HIV-RNA in blood only (2 cases) and in semen only (4 cases). Finally, one subject had a positive HIV-RNA in SP/BP. At W24, only in 2/16 subjects (12.5%) HIV-RNA was detectable in semen, while in the others it was negative on SP/BP. No concurrent STI was found in subjects with detectable VL in semen. CONCLUSIONS: DTG demonstrated effectiveness in reducing VL with different kinetics in blood and semen, despite seminal viral suppression after 6 months of ART was not obtained in the totality of subjects.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , RNA Viral/sangue , Sêmen/virologia , Adolescente , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Infecções por HIV/virologia , Inibidores de Integrase de HIV/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Viral/metabolismo , Sêmen/metabolismo , Carga Viral/efeitos dos fármacos , Adulto Jovem
14.
Nat Commun ; 9(1): 4156, 2018 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-30297889

RESUMO

Non-adherence to medication is an important health care problem, especially in the treatment of chronic conditions. Injectable long-acting (LA) formulations of antiretrovirals (ARVs) represent a viable alternative to improve adherence to HIV/AIDS treatment and prevention. However, the LA-ARV formulations currently in clinical trials cannot be removed after administration even if adverse events occur. Here we show an ultra-LA removable system that delivers drug for up to 9 months and can be safely removed to stop drug delivery. We use two pre-clinical models for HIV transmission and treatment, non-human primates (NHP) and humanized BLT (bone marrow/liver/thymus) mice and show a single dose of subcutaneously administered ultra-LA dolutegravir effectively delivers the drug in both models and show suppression of viremia and protection from multiple high-dose vaginal HIV challenges in BLT mice. This approach represents a potentially effective strategy for the ultra-LA drug delivery with multiple possible therapeutic applications.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , HIV-1/efeitos dos fármacos , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Modelos Animais de Doenças , Infecções por HIV/virologia , HIV-1/genética , HIV-1/fisiologia , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Macaca mulatta , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Fatores de Tempo , Distribuição Tecidual , Replicação Viral/efeitos dos fármacos , Replicação Viral/genética
15.
Mol Pharm ; 15(11): 5387-5396, 2018 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-30339013

RESUMO

Treatment failure remains a main challenge in the management of high-risk multiple myeloma (MM) even with the expanding repertoire of new drugs. Combinatorial therapy is considered an encouraging strategy that can overcome the compensatory mechanisms and undesirable off-target effects that limit the benefits of many prospective agents. Preliminary results of a current phase I trial have indicated that the new BET bromodomain inhibitor OTX015 has favorable activity and tolerability. However, OTX015 is not efficacious enough as a monotherapy. Here, we provide evidence that synergistic drug combinations with OTX015 were generally more specific to particular cellular contexts than single agent activities. In addition, pairing OTX015 with three classes of drugs dramatically enhanced the antitumor activity in mouse models of disseminated human myeloma. Our studies further underscored that the BET inhibitor OTX015 sensitized MM cells by interrupting several pathways and genes critical for MM cell proliferation and drug response, which provided the rationale for multiple myeloma therapy with OTX015 combined with conventional chemotherapeutic drugs. Thus, the context specificity of synergistic combinations not only provide profound insights into therapeutically relevant selectivity but also improve control of complex biological systems.


Assuntos
Acetanilidas/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Mieloma Múltiplo/tratamento farmacológico , Acetanilidas/uso terapêutico , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Camundongos , Mieloma Múltiplo/patologia , Estudos Prospectivos , Proteínas/antagonistas & inibidores , Ensaios Antitumorais Modelo de Xenoenxerto
16.
J Acquir Immune Defic Syndr ; 79(5): 631-638, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30239425

RESUMO

BACKGROUND: The fixed-dose combination (FDC) tablet formulation of abacavir/dolutegravir/lamivudine is indicated for the treatment of HIV-1 infection in adults and pediatric patients weighing ≥40 kg. Alternative formulations with acceptable palatability and convenient dosing are needed for children who require smaller doses and have difficulty swallowing tablets. SETTING: A phase 1, open-label, randomized study was conducted in healthy adults to evaluate the relative bioavailability of a novel dispersible FDC tablet of abacavir 150 mg/dolutegravir 10 mg/lamivudine 75 mg administered under 4 different dosing conditions compared with dolutegravir plus abacavir/lamivudine nondispersible, film-coated tablets. METHODS: The test treatments were 4 dispersible FDC tablets reconstituted in water with high- or zero-mineral content and administered either immediately or after a 30-minute delay. The reference treatment was 4 nondispersible dolutegravir 10-mg tablets plus 1 nondispersible abacavir 600-mg/lamivudine 300-mg tablet administered with zero-mineral content water. The primary endpoints were area under the concentration-time curve from time 0 extrapolated to infinity and the maximum observed plasma concentration. RESULTS: Following administration of dispersible abacavir/dolutegravir/lamivudine, the relative bioavailability of dolutegravir was approximately 50% higher. Abacavir and lamivudine demonstrated bioequivalence when administered as the dispersible FDC tablet compared with coadministration of dolutegravir plus abacavir/lamivudine nondispersible, film-coated tablets. Neither the mineral content of the water nor dosing times affected the pharmacokinetics of individual components. The dispersible tablet was safe and well tolerated, and the palatability was acceptable. CONCLUSIONS: These pharmacokinetic results support further development of a dispersible FDC tablet of abacavir/dolutegravir/lamivudine for future use in pediatric patients.


Assuntos
Fármacos Anti-HIV/farmacocinética , Disponibilidade Biológica , Didesoxinucleosídeos/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Lamivudina/farmacocinética , Minerais/análise , Água/química , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Didesoxinucleosídeos/administração & dosagem , Combinação de Medicamentos , Feminino , Voluntários Saudáveis , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Comprimidos/administração & dosagem , Adulto Jovem
17.
Artigo em Inglês | MEDLINE | ID: mdl-30249694

RESUMO

We evaluated microbiological correlates for the successful treatment of Neisseria gonorrhoeae isolates from a phase 2 study of gepotidacin, a novel triazaacenaphthylene antibacterial, for therapy of uncomplicated urogenital gonorrhea. Culture, susceptibility testing, genotypic characterization, and frequency of resistance (FoR) were performed for selected isolates. Microbiological success was defined as culture-confirmed eradication of N. gonorrhoeae Against 69 baseline urogenital isolates, gepotidacin MICs ranged from ≤0.06 to 1 µg/ml (MIC90 = 0.5 µg/ml). For gepotidacin, the ratio of the area under the free-drug concentration-time curve to the MIC (fAUC/MIC) was associated with therapeutic success. Success was 100% (61/61) at fAUC/MICs of ≥48 and decreased to 63% (5/8) for fAUC/MICs of ≤25. All 3 isolates from microbiological failures were ciprofloxacin resistant, had a baseline gepotidacin MIC of 1 µg/ml, and carried a preexisting ParC D86N mutation, a critical residue for gepotidacin binding. In a test-of-cure analysis, the resistance to gepotidacin emerged in 2 isolates (MICs increased ≥32-fold) with additional GyrA A92T mutations, also implicated in gepotidacin binding. Test-of-cure isolates had the same sequence type as the corresponding baseline isolates. For 5 selected baseline isolates, all carrying a ParC D86N mutation, the in vitro FoR to gepotidacin was low (10-9 to 10-10); the resistant mutants had the same A92T mutation as the 2 isolates in which resistance emerged. Five participants with isolates harboring the ParC D86N mutation were treatment successes. In summary, fAUC/MICs of ≥48 predicted 100% microbiological success, including 3 isolates with the ParC D86N mutation (fAUC/MICs ≥ 97). Pharmacokinetic/pharmacodynamic determinations may help to evaluate new therapies for gonorrhea; further study of gepotidacin is warranted. (This study has been registered at ClinicalTrials.gov under identifier NCT02294682.).


Assuntos
Acenaftenos/farmacocinética , Antibacterianos/farmacocinética , DNA Topoisomerase IV/genética , Farmacorresistência Bacteriana/genética , Gonorreia/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Neisseria gonorrhoeae/efeitos dos fármacos , Acenaftenos/sangue , Acenaftenos/farmacologia , Administração Oral , Adulto , Antibacterianos/sangue , Antibacterianos/farmacologia , Área Sob a Curva , Técnicas de Tipagem Bacteriana , Hemocultura , Ciprofloxacino/uso terapêutico , DNA Topoisomerase IV/metabolismo , Esquema de Medicação , Feminino , Expressão Gênica , Gonorreia/sangue , Gonorreia/microbiologia , Gonorreia/patologia , Compostos Heterocíclicos com 3 Anéis/sangue , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Masculino , Testes de Sensibilidade Microbiana , Mutação , Neisseria gonorrhoeae/enzimologia , Neisseria gonorrhoeae/genética , Neisseria gonorrhoeae/isolamento & purificação , Resultado do Tratamento
18.
Artigo em Inglês | MEDLINE | ID: mdl-29987139

RESUMO

A complete 2-drug regimen of dolutegravir at 50 mg and rilpivirine at 25 mg was approved to treat HIV-1 infection in virologically suppressed patients after demonstrating acceptable efficacy and tolerability. This study investigated the bioequivalence and pharmacokinetics of the fixed-dose combination tablet compared with those of separate tablets. Secondary endpoints were the tolerability and safety of the fixed-dose combination tablet. In this open-label, randomized-sequence, 2-way crossover trial, single doses of the fixed-dose combination tablet (the test treatment) and the combination of separate tablets (the reference treatment) were administered to healthy adults after a moderate-fat meal, with a 21-day washout between treatments. Pharmacokinetic samples were collected through 12 days after dosing. The primary endpoints were the area under the plasma concentration-time curve (AUC) and the maximum concentration of drug in plasma (Cmax). The study employed a prespecified sample size reestimation based on a blind midpoint review of Cmax variability to update the enrollment size to achieve statistical power. Of 118 participants enrolled, 113 received both treatments and underwent pharmacokinetic assessment. The 90% confidence intervals for the geometric least-squares mean ratios for the AUC from 0 h to infinity, the AUC from 0 h to the last quantifiable measurement, and Cmax (test treatment versus reference treatment) were within the bioequivalence range of 0.80 to 1.25 for both drugs, indicating bioequivalence. In this study, a single dose of either treatment was well tolerated overall, with 4% (n = 5) and 3% (n = 3) of participants reporting adverse events considered related to the test and reference treatments, respectively. The dolutegravir-rilpivirine fixed-dose combination tablet is bioequivalent to a combination of separate tablets, and no new safety signals emerged. (This study has been registered at ClinicalTrials.gov under identifier NCT02741557.).


Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Rilpivirina/farmacocinética , Adulto , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacologia , Quimioterapia Combinada/efeitos adversos , Quimioterapia Combinada/métodos , Feminino , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Rilpivirina/efeitos adversos , Rilpivirina/farmacologia , Equivalência Terapêutica
19.
J Clin Oncol ; 36(30): 3007-3014, 2018 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-29733771

RESUMO

PURPOSE: Birabresib (MK-8628/OTX015) is a first-in-class bromodomain inhibitor with activity in select hematologic tumors. Safety, efficacy, and pharmacokinetics of birabresib were evaluated in patients with castrate-resistant prostate cancer, nuclear protein in testis midline carcinoma (NMC), and non-small-cell lung cancer in this phase Ib study. PATIENTS AND METHODS: Forty-seven patients were enrolled to receive birabresib once daily at starting doses of 80 mg continuously (cohort A) or 100 mg for 7 consecutive days (cohort B) in 21-day cycles using a parallel dose escalation 3 + 3 design. The primary objective was occurrence of dose-limiting toxicities (DLTs) and determination of the recommended phase II dose. RESULTS: Of 46 treated patients, 26 had castrate-resistant prostate cancer, 10 NMC, and 10 non-small-cell lung cancer. For cohort A, four of 19 (21%) evaluable patients had DLTs at 80 mg once daily (grade 3 thrombocytopenia [n = 3], ALT/hyperbilirubinemia [n = 1]) and two of three had DLTs at 100 mg once daily (grade 2 anorexia and nausea with treatment delay > 7 days [n = 1], grade 4 thrombocytopenia [n = 1]). No DLTs occurred in cohort B. Of 46 patients, 38 (83%) had treatment-related adverse events (diarrhea, 17 [37%]; nausea, 17 [37%]; anorexia, 14 [30%]; vomiting, 12 [26%]; thrombocytopenia 10 [22%]). Three patients with NMC (80 mg once daily) had a partial response (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) with duration of 1.4 to 8.4 months. Pharmacokinetic analysis indicated a dose-proportional increase in birabresib exposure and rapid absorption. CONCLUSION: The recommended phase II dose of birabresib in patients with select solid tumors is 80 mg once daily with continuous dosing. Birabresib has dose-proportional exposure and a favorable safety profile, with clinical activity observed in NMC. Future studies of birabresib must consider intermittent scheduling to possibly mitigate the toxicities of chronic dosing.


Assuntos
Acetanilidas/administração & dosagem , Acetanilidas/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Neoplasias/tratamento farmacológico , Acetanilidas/farmacocinética , Adulto , Idoso , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Adulto Jovem
20.
J Antimicrob Chemother ; 73(9): 2430-2434, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29796595

RESUMO

Background: If HIV patients are unconscious or cannot swallow tablets for other reasons, antiretroviral medication is crushed and dissolved prior to administration. Crushing can alter drug exposure, possibly leading to treatment failure, development of resistance or toxicity. Currently, there is no information about crushing of the branded fixed-dose combination of dolutegravir/abacavir/lamivudine (Triumeq®, referred to as TRI); therefore, crushing of TRI is not recommended. Objectives: To investigate whether the TRI fixed-dose combination tablet can be crushed and combined with enteral nutrition without influencing pharmacokinetics (PK). Methods: We carried out an open-label, three-period, randomized, single-dose, crossover trial in 22 healthy adult volunteers. Subjects randomly received whole-tablet TRI with fasting (reference), crushed and suspended TRI with fasting or crushed and suspended TRI with oral intake of enteral nutrition. Bioequivalence criteria (80%-125% acceptance range) of AUC0-∞ and Cmax were used. ClinicalTrials.gov: NCT02569346. Results: Crushing TRI leads to higher dolutegravir exposure (AUC0-∞: +26% and Cmax: +30%) and, if crushed TRI is combined with enteral nutrition, to a decrease in abacavir Cmax (-17%). Lamivudine concentrations were not affected as geometric mean ratios with 90% CIs fell within the 80%-125% range. Conclusions: Bioequivalence could not be demonstrated for a crushed and suspended tablet or a crushed and suspended tablet with oral intake of enteral nutrition compared with whole-tablet TRI with fasting. Both scenarios led to higher dolutegravir exposure, but this did not exceed exposure after intake with food or in twice-daily dosing. In our opinion, TRI can be crushed for patients with swallowing difficulties and can be simultaneously administered with enteral nutrition.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Didesoxinucleosídeos/administração & dosagem , Didesoxinucleosídeos/farmacocinética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Comprimidos/administração & dosagem , Comprimidos/farmacocinética , Administração Oral , Adolescente , Adulto , Combinação de Medicamentos , Voluntários Saudáveis , Humanos , Pessoa de Meia-Idade , Adulto Jovem
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