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1.
Lancet HIV ; 7(7): e472-e481, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32497491

RESUMO

BACKGROUND: Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. METHODS: HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18-65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52-76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov, NCT02178800. FINDINGS: Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p<0·0001). At 52-60 weeks after final injection, nine (23%) of 40 male participants had detectable cabotegravir concentrations and at week 76, four (13%) of 30 male participants had detectable cabotegravir concentrations compared with 52 (63%) of 82 female participants and 27 (42%) of 64 female participants at the same timepoints. The median time from the last injection to the time when cabotegravir concentration decreased below the LLOQ was 43·7 weeks (IQR 31·1-66·6; range 20·4-152·5) for male participants and 67·3 weeks (29·1-89·6; 17·7-225·5) for female participants (p=0·0003). t1/2app was longer for female participants than male participants (geometric mean fold-change 1·33, 95% CI 1·06-1·68; p=0·014), and longer for participants with a high body-mass index (BMI) than those with a low BMI (1·31, 1·06-1·63; p=0·015). INTERPRETATION: The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. FUNDING: National Institute of Allergy and Infectious Diseases.


Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/prevenção & controle , Inibidores de Integrase de HIV/farmacologia , Piridonas/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Brasil , Estudos de Coortes , Método Duplo-Cego , Feminino , Inibidores de Integrase de HIV/administração & dosagem , Humanos , Injeções , Malaui , Masculino , Pessoa de Meia-Idade , Placebos , Piridonas/administração & dosagem , África do Sul , Estados Unidos , Adulto Jovem
2.
Int J Infect Dis ; 97: 365-370, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32553717

RESUMO

OBJECTIVES: The aim was to fully characterize the plasma and urine washout pharmacokinetics of tenofovir (TFV) in adults following 6 weeks of controlled levels of tenofovir disoproxil fumarate (TDF) adherence, in order to inform the utility of clinic-based adherence testing. DESIGN: This was a three-arm, randomized, open-label study in adult volunteers. Participants were randomized to receive TDF 300 mg/emtricitabine (FTC) 200 mg as (1) 7 doses/week (perfect adherence), (2) 4 doses/week (moderate adherence), or (3) 2 doses/week (low adherence). Plasma and urine samples were collected regularly during the 6-week dosing phase and for 4 weeks following drug cessation. RESULTS: Twenty-eight adults were included in this analysis. Median (range) age was 33 (20-49) years. No differences in TFV pharmacokinetic parameters during the washout were observed across the study arms. Small differences in TFV plasma concentrations occurred across arms between 4 and 10 h post-dose. The cumulative amount of TFV excreted in urine was not different at 24 h post-dose, but at 148 h it was 24.8 mg, 21.0 mg, and 17.2 mg for the perfect, moderate, and low adherence arms, respectively (p = 0.043). CONCLUSIONS: Among adults with different TDF adherence patterns, relative differences in plasma concentrations and cumulative urine extraction of TFV were minor following cessation. TFV measurement in plasma or urine is more indicative of last drug ingestion, rather than prior dose patterns.


Assuntos
Infecções por HIV/tratamento farmacológico , Infecções por HIV/psicologia , Tenofovir/farmacocinética , Adulto , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Fármacos Anti-HIV/urina , Emtricitabina/administração & dosagem , Emtricitabina/sangue , Emtricitabina/farmacocinética , Feminino , Infecções por HIV/sangue , Infecções por HIV/urina , Comportamentos Relacionados com a Saúde , Humanos , Masculino , Adesão à Medicação , Pessoa de Meia-Idade , Plasma/química , Tenofovir/sangue , Tenofovir/uso terapêutico , Tenofovir/urina , Adulto Jovem
3.
AIDS Behav ; 24(9): 2520-2531, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32052214

RESUMO

Long-acting injectable PrEP could offer an alternative to daily oral PrEP, improve adherence and protection, if found acceptable, safe and effective. HPTN 077 evaluated injectable cabotegravir safety, tolerability and pharmacokinetics among HIV-uninfected males and females in sequentially-enrolled cohorts of two dosing strategies. We compared acceptability of product attributes, prevention preferences and future interest in injectable PrEP (FIIP) by region, sex-at-birth, arm and cohort and used multivariable analysis to identify FIIP determinants. Baseline injectable PrEP preferences were higher in non-U.S. sites and increased in both regions over time. In multivariable models, FIIP was most strongly associated with acceptability of product attributes, was higher in non-U.S. sites and more altruistic participants. Treatment arm and report of pain were not associated with FIIP. Injectable acceptability was highest in non-U.S. sites. Preferences for injectable versus other PrEP methods were higher among U.S. males than females, but higher among males and females in non-U.S. settings.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Infecções por HIV/prevenção & controle , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Participação do Paciente/psicologia , Profilaxia Pré-Exposição/métodos , Piridonas/administração & dosagem , Piridonas/farmacocinética , Adulto , Fármacos Anti-HIV/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Injeções , Masculino , Pessoa de Meia-Idade , Piridonas/efeitos adversos , Resultado do Tratamento
4.
AAPS PharmSciTech ; 21(3): 91, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32060665

RESUMO

Doravirine is a non-nucleoside reverse transcriptase inhibitor indicated for the treatment of human immunodeficiency virus-1 infection, available as a single tablet in combination with other antiretroviral agents or as a fixed-dose regimen with lamivudine and tenofovir disoproxil fumarate (TDF). Alternative formulations of these drugs are being developed for individuals who have difficulty swallowing tablets. Two phase 1 trials were conducted, both in 24 healthy adults, to assess the pharmacokinetics of uncoated and coated oral granule formulations of doravirine, lamivudine, and TDF administered alone and with vanilla pudding or apple sauce. The pharmacokinetics for all uncoated granules, and of coated lamivudine and TDF granules, were similar to those of currently marketed tablets (geometric mean ratios [GMRs] 0.92-1.04). Coated doravirine granules had decreased AUC0-∞ (11%) and Cmax (23%) values versus the tablet. The pharmacokinetics were similar for uncoated and coated doravirine granules administered with or without pudding (GMRs 0.96-1.10); administration with apple sauce increased doravirine AUC0-∞ (26-29%), Cmax (56-59%), and C24 (20-21%) versus administration of granules alone. Lamivudine granules administered with pudding or apple sauce decreased AUC0-∞ and Cmax (14-25%) versus granules alone. Tenofovir AUC0-∞, Cmax, and C24 increased for TDF granules administered with pudding or apple sauce versus alone (11-23%). Pharmacokinetic differences when administering doravirine, lamivudine, or TDF as uncoated or coated granules versus tablets, or when granules were administered with (versus without) pudding or apple sauce, are not considered clinically meaningful, supporting further development of these granule formulations.


Assuntos
Fármacos Anti-HIV/farmacocinética , Antirretrovirais/farmacocinética , Lamivudina/farmacocinética , Piridonas/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Tenofovir/farmacocinética , Triazóis/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Antirretrovirais/administração & dosagem , Disponibilidade Biológica , Estudos Cross-Over , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Lamivudina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Piridonas/administração & dosagem , Inibidores da Transcriptase Reversa/administração & dosagem , Comprimidos , Tenofovir/administração & dosagem , Triazóis/administração & dosagem , Adulto Jovem
5.
J Med Chem ; 63(4): 1724-1749, 2020 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-32031803

RESUMO

We previously reported a milestone in the optimization of NBD-11021, an HIV-1 gp120 antagonist, by developing a new and novel analogue, NBD-14189 (Ref1), which showed antiviral activity against HIV-1HXB2, with a half maximal inhibitory concentration of 89 nM. However, cytotoxicity remained high, and the absorption, distribution, metabolism, and excretion (ADME) data showed relatively poor aqueous solubility. To optimize these properties, we replaced the phenyl ring in the compound with a pyridine ring and synthesized a set of 48 novel compounds. One of the new analogues, NBD-14270 (8), showed a marked improvement in cytotoxicity, with 3-fold and 58-fold improvements in selectivity index value compared with that of Ref1 and NBD-11021, respectively. Furthermore, the in vitro ADME data clearly showed improvements in aqueous solubility and other properties compared with those for Ref1. The data for 8 indicated that the pyridine scaffold is a good bioisostere for phenyl, allowing the further optimization of this molecule.


Assuntos
Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Piridinas/farmacologia , Pirróis/farmacologia , Tiazóis/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacocinética , Células CACO-2 , Células HEK293 , Proteína gp120 do Envelope de HIV/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridinas/síntese química , Piridinas/farmacocinética , Pirróis/síntese química , Pirróis/farmacocinética , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinética
6.
Lancet HIV ; 7(3): e164-e172, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31911147

RESUMO

BACKGROUND: Islatravir (also known as ISL and MK-8591) is a unique nucleoside reverse transcriptase translocation inhibitor in clinical development for treatment of people with HIV-1 infection. In preclinical studies, intracellular islatravir-triphosphate exhibits a long half-life and prolonged virological effects. In this study, we aimed to assess islatravir safety, pharmacokinetics, and antiretroviral activity in treatment-naive adults with HIV-1 infection. METHODS: This open-label, consecutive-panel, phase 1b trial was done at Charité Research Organisation (Berlin, Germany) and included men and women (aged 18-60 years, inclusive) with HIV-1 infection who were ART naive. Participants were required to have plasma HIV-1 RNA counts of at least 10 000 copies per mL within 30 days before the trial treatment phase, without evidence of resistance to nucleoside reverse transcriptase inhibitors. Participants were enrolled in one of five consecutive dosing panels, receiving a single oral dose of islatravir (0·5-30 mg). The primary outcomes were safety and tolerability of islatravir and change from baseline in HIV-1 plasma RNA; secondary outcomes were islatravir plasma and islatravir-triphosphate intracellular pharmacokinetics. We obtained descriptive safety and pharmacokinetics statistics, and estimated efficacy results from a longitudinal data analysis model. This study is registered with ClinicalTrials.gov, NCT02217904, and EudraCT, 2014-002192-28. FINDINGS: Between Sept 17, 2015, and May 11, 2017, we enrolled 30 participants (six per panel). Islatravir was generally well tolerated. 27 (90%) participants had 60 adverse events after receipt of drug, of which 21 (35%) were deemed to be drug related. The most common (n>1) drug-related adverse events were headache (in nine [30%] participants) and diarrhoea (in two [7%]). No serious adverse events were reported, and no participants discontinued due to an adverse event. Plasma islatravir pharmacokinetics and intracellular islatravir-triphosphate pharmacokinetics were approximately dose proportional. The islatravir-triphosphate intracellular half-life was 78·5-128·0 h. Least-squares mean HIV-1 RNA at 7 days after dose decreased from 1·67 log10 copies per mL (95% CI 1·42-1·92) at 10 mg dose to 1·20 log10 copies per mL (0·95-1·46) at 0·5 mg dose. No genetic changes consistent with development of viral resistance were detected. INTERPRETATION: Single doses of islatravir as low as 0·5 mg significantly suppressed HIV-1 RNA by more than 1·0 log at day 7 in treatment-naive adults with HIV-1 infection and were generally well tolerated, supporting the further development of islatravir as a flexible-dose treatment for individuals with HIV-1 infection. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, NJ, USA.


Assuntos
Fármacos Anti-HIV/farmacocinética , Desoxiadenosinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/farmacocinética , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Desoxiadenosinas/administração & dosagem , Desoxiadenosinas/efeitos adversos , Feminino , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , HIV-1/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Adulto Jovem
7.
Artigo em Inglês | MEDLINE | ID: mdl-31929402

RESUMO

BACKGROUND: The choice of malaria treatment for HIV-infected pregnant women receiving efavirenz-based antiretroviral therapy must consider the potential impact of drug interactions on antimalarial exposure and clinical response. The aim of this study was to investigate the effects of efavirenz on artemether-lumefantrine (AL) because no studies have isolated the impact of efavirenz for HIV-infected pregnant women. METHODS: A prospective clinical pharmacokinetic (PK) study compared HIV-infected, efavirenz-treated pregnant women with HIV-uninfected pregnant women in Tororo, Uganda. All women received the standard 6-dose AL treatment regimen for Plasmodium falciparum malaria with intensive PK samples collected over 21 days and 42-days of clinical follow-up. PK exposure parameters were calculated for artemether, its active metabolite dihydroartemisinin (DHA), and lumefantrine to determine the impact of efavirenz. RESULTS: Nine HIV-infected and 30 HIV-uninfected pregnant women completed intensive PK evaluations. Relative to controls, concomitant efavirenz therapy lowered the 8-hour artemether concentration by 76% (P = 0.013), DHA peak concentration by 46% (P = 0.033), and day 7 and 14 lumefantrine concentration by 61% and 81% (P = 0.046 and 0.023), respectively. In addition, there were nonsignificant reductions in DHA area under the concentration-time curve0-8hr (35%, P = 0.057) and lumefantrine area under the concentration-time curve0-∞ (34%, P = 0.063) with efavirenz therapy. CONCLUSIONS: Pregnant HIV-infected women receiving efavirenz-based antiretroviral therapy during malaria treatment with AL showed reduced exposure to both the artemisinin and lumefantrine. These data suggest that malaria and HIV coinfected pregnant women may require adjustments in AL dosage or treatment duration to achieve exposure comparable with HIV-uninfected pregnant women.


Assuntos
Antirretrovirais/farmacocinética , Antimaláricos/farmacocinética , Combinação Arteméter e Lumefantrina/farmacocinética , Benzoxazinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Malária/tratamento farmacológico , Adolescente , Adulto , Fármacos Anti-HIV/farmacocinética , Antirretrovirais/administração & dosagem , Artemeter , Combinação Arteméter e Lumefantrina/administração & dosagem , Artemisininas , Benzoxazinas/administração & dosagem , Combinação de Medicamentos , Interações Medicamentosas , Feminino , Infecções por HIV/complicações , Humanos , Lumefantrina , Malária/complicações , Malária Falciparum/tratamento farmacológico , Gravidez , Estudos Prospectivos , Uganda , Adulto Jovem
8.
J Med Chem ; 63(3): 1298-1312, 2020 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-31935327

RESUMO

Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60-21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50= 155 µM), and reduced hERG inhibition (IC50 > 30 µM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate.


Assuntos
Fármacos Anti-HIV/farmacologia , Canal de Potássio ERG1/metabolismo , HIV-1/efeitos dos fármacos , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Tiofenos/farmacologia , Animais , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/toxicidade , Linhagem Celular , Cristalografia por Raios X , Descoberta de Drogas , Feminino , Flúor/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ligação Proteica , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/toxicidade , Ratos Wistar , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Inibidores da Transcriptase Reversa/toxicidade , Relação Estrutura-Atividade , Tiofenos/metabolismo , Tiofenos/farmacocinética , Tiofenos/toxicidade
9.
J Acquir Immune Defic Syndr ; 83(2): 135-139, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31929401

RESUMO

BACKGROUND: Young women aged 15-24 years are disproportionately affected by the HIV epidemic. Two phase III trials of a vaginal ring containing 25-mg dapivirine demonstrated HIV-1 risk reduction in adult women older than 21 years but not in those aged 18-21 years. Lack of protection was correlated with low adherence. METHODS: In this phase-IIa, randomized, double-blind, placebo-controlled, US, multicenter trial of the dapivirine ring in sexually active females, aged 15-17 years, participants were randomized 3:1 to a dapivirine or placebo ring to be inserted monthly for 6 months (NCT02028338). Primary safety end points included grade 2 product related adverse events and any grade 3 and higher adverse events. Adherence to ring use was assessed by plasma dapivirine concentrations, residual levels in used rings, and self-report. A plasma dapivirine concentration of >95 pg/mL was used to define short-term adherence; a residual ring level of <23.5 mg was used to define long-term adherence. Acceptability was assessed through computer-assisted self-interviews. RESULTS: Ninety-six participants were enrolled across 6 US sites. The median age was 16.0 years. There were no differences in safety outcomes between treatment arms. Adherence to the dapivirine ring was demonstrated by both plasma measurements (87%) and residual drug levels in rings (95%). Forty-two percent (95% confidence interval: 32 to 52) of participants reported that they never removed the ring. Participants noted no discomfort due to the ring at 87% of visits and "liking" the ring at 93% of visits. CONCLUSION: The dapivirine vaginal ring, a promising topical microbicide, was well tolerated and acceptable in young US adolescents.


Assuntos
Fármacos Anti-HIV/efeitos adversos , Dispositivos Anticoncepcionais Femininos/efeitos adversos , Infecções por HIV/prevenção & controle , Pirimidinas/efeitos adversos , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Placebos , Plasma , Pirimidinas/administração & dosagem , Pirimidinas/sangue , Pirimidinas/farmacocinética , Autorrelato , Estados Unidos , Vagina/efeitos dos fármacos , Adulto Jovem
10.
Expert Opin Drug Saf ; 19(1): 23-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31809218

RESUMO

Introduction: Antiretroviral and anti-tuberculosis (TB) drugs are often co-administered in people living with HIV (PLWH). Early initiation of antiretroviral therapy (ART) during TB treatment improves survival in patients with advanced HIV disease. However, safety concerns related to clinically significant changes in drug exposure resulting from drug-drug interactions, development of overlapping toxicities and specific challenges related to co-administration during pregnancy represent barriers to successful combined treatment for HIV and TB.Areas covered: Pharmacokinetic interactions of different classes of ART when combined with anti-TB drugs used for sensitive-, drug-resistant (DR) and latent TB are discussed. Overlapping drug toxicities, implications of immune reconstitution inflammatory syndrome (IRIS), safety in pregnancy and research gaps are also explored.Expert opinion: New antiretroviral and anti-tuberculosis drugs have been recently introduced and international guidelines updated. A number of effective molecules and clinical data are now available to build treatment regimens for PLWH with latent or active TB. Adopting a systematic approach that also takes into account the need for individualized variations based on the available evidence is the key to successfully integrate ART and TB treatment and improve treatment outcomes.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Antituberculosos/administração & dosagem , Animais , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Antituberculosos/efeitos adversos , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Humanos , Tuberculose Latente/tratamento farmacológico , Tuberculose/tratamento farmacológico
11.
J Assoc Nurses AIDS Care ; 31(2): 241-248, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31855873

RESUMO

Approximately one third of patients coinfected with HIV and hepatitis C virus (HCV) who initiate direct-acting antivirals (DAAs) for HCV treatment may have to switch antiretroviral therapy (ART) because of drug interactions. ART switches can negatively affect quality of life, increase HIV symptom burden, and delay HCV therapy. Approaches to identify ART/DAA drug interactions that minimize the impact of switching ART are urgently needed. Nurses can lead the way in addressing this new and major need. We provide a guide for registered nurses and nurse practitioners who care for patients coinfected with HIV and HCV to identify HIV/HCV drug interactions and manage ART/DAA coadministration when needed.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Antivirais/uso terapêutico , Coinfecção/tratamento farmacológico , Interações Medicamentosas/fisiologia , Quimioterapia Combinada/efeitos adversos , Hepatite C Crônica/tratamento farmacológico , Hepatite C/tratamento farmacológico , Profissionais de Enfermagem , Enfermeiras e Enfermeiros , Fármacos Anti-HIV/farmacocinética , Antivirais/farmacocinética , Coinfecção/virologia , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hepacivirus/efeitos dos fármacos , Humanos , Guias de Prática Clínica como Assunto , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/uso terapêutico , Qualidade de Vida
12.
Biopharm Drug Dispos ; 40(9): 341-349, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31693190

RESUMO

Antiretroviral therapy has been the mainstay of treatment for neonates born to HIV infected mothers. Neonates born prematurely to HIV positive mothers are underdeveloped not only in anatomical terms but also in their physiological systems. Zidovudine, the first antiretroviral drug in clinical therapy for the treatment of HIV has been approved for use in preterm neonates both prophylactically and therapeutically. The present work describes the whole body physiologically based pharmacokinetic (WB-PBPK) model development for zidovudine in preterm neonates of varying gestational ages, to observe the pharmacokinetic behavior of the drug in this vulnerable group of the population. Along with the height, weight, post-natal, and gestational ages of the preterm neonates, metabolic enzymes CYP2A6, CYP2C8, etc. were incorporated for each neonate. The composition of the different organs in terms of water and lipid components, blood flow rates, etc. were specified during simulations according to the gestational ages of these neonates. The following PK parameters were estimated for preterm neonates using simulated plasma profiles: AUC 2686.41 ± 123.49 µmol min/L, Cmax 6.46 ± 0.74 µmol/L, half-life 8.98 ± 2.36 hr, mean residence time 12.23 ± 3.43 hr, and total plasma clearance 1.48 ± 0.19 ml/min/kg in comparison with the observed PK parameters of a clinical study by Mirochknic et al. in preterm neonates with AUC 2020.04 µmol/min/L, Cmax 6.10 µmol/L, and total plasma clearance 1.62 ml/min/kg. PBPK simulations provide an opportunity to visualize the possible impact of physiological maturity levels at varying gestational ages on the pharmacokinetic behavior of zidovudine in preterm neonates.


Assuntos
Recém-Nascido Prematuro/metabolismo , Modelos Biológicos , Zidovudina/farmacocinética , Fármacos Anti-HIV/farmacocinética , Idade Gestacional , Humanos , Recém-Nascido
13.
Expert Opin Drug Metab Toxicol ; 15(11): 927-935, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31668105

RESUMO

Introduction: Ritonavir and cobicistat are pharmacoenhancers used to improve the disposition of other HIV antiretrovirals. These drugs are, however, characterized by important pharmacokinetic differences.Areas covered: Here, the authors firstly update the available information on the pharmacokinetics of ritonavir and cobicistat. Subsequently, the review focuses on the description of drug-drug interactions (DDIs) involving cobicistat and comedications that might beneficiate from a shift-back to ritonavir. A MEDLINE Pubmed search for articles published from January 1995 to April 2019 was completed matching the term ritonavir or cobicistat with pharmacokinetics, DDIs, and pharmacology. Moreover, additional studies were identified from the reference list of retrieved articles.Expert opinion: Despite more than 20 years after its introduction on the market, ritonavir still represents a valid option for the treatment of selected HIV-infected patients. The large-scale switch to cobicistat may result in some unexpected DDIs not previously reported for ritonavir. Besides the issue of DDIs, additional advantage of ritonavir over cobicistat is its use in pregnancy, and its availability as single component of pharmaceutical formulations allowing the fine-tuning of antiretroviral regimens in patients with heavy polypharmacy when other unboosted-based therapeutic options cannot be used.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Cobicistat/administração & dosagem , Ritonavir/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Cobicistat/farmacocinética , Interações Medicamentosas , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , Humanos , Ritonavir/farmacocinética
14.
J Mol Histol ; 50(6): 593-599, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31686324

RESUMO

Central nervous system (CNS) HIV infection causes brain tissue inflammation and tissue deficit that contributes to neuroAIDS. This complication is escalated by the blood-brain barrier (BBB), which prevents easy access to antiretroviral drugs entering the CNS. In this study the aims were to investigate the BBB membrane penetration and brain localization patterns of Nevirapine (NVP) using Imaging Mass Spectrometry (MSI). Sprague-Dawley rats received an intraperitoneal dose of NVP (50 mg kg-1). Plasma and brain samples were harvested, and mass spectrometric methods were then applied to determine the pharmacokinetic properties and localization patterns of NVP in the brain. The pharmacokinetic parameters demonstrated a rapid bio-distribution of NVP in plasma and brain. The plasma Cmax was 6320 ng mL-1 and the brain Cmax was 1923 ng mL-1, both at a Tmax of 0.25 h. MSI of coronal brain sections showed that NVP penetrated and localized in the brain regions implicated with the development of HIV associated neurodegeneration. NVP has great potential to combat neuroAIDS.


Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Espectrometria de Massas/métodos , Nevirapina/farmacocinética , Adulto , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/farmacocinética , Feminino , Humanos , Injeções Intraperitoneais , Masculino , Taxa de Depuração Metabólica , Nevirapina/administração & dosagem , Nevirapina/sangue , Ratos Sprague-Dawley , Fatores de Tempo
16.
Expert Opin Drug Metab Toxicol ; 15(10): 787-802, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31512529

RESUMO

Introduction: Drug-drug interactions (DDI) between antiretroviral drugs and drugs for the treatment of metabolic disturbances in people living with human immunodeficiency virus (HIV) (PLWH) have represented a problem of paramount importance in the recent times. The problem has been mainly driven by sharing common metabolizing pathways. This problem has classically been worsened by the frequent use of pharmacokinetic boosters to enhance protease inhibitors and some integrase inhibitors plasma levels. Areas covered: This article focuses on the interactions between antiretroviral drugs and those drugs used to treat metabolic disturbances which frequently appear in PLWH. These include dyslipidemia, diabetes mellitus, hyperuricemia, and finally, drugs for the treatment of overweight and clinical obesity. References from PubMed, Embase, or Web of Science, among others, were reviewed. Expert opinion: The advent of safer drugs, in terms of DDI, in the antiretroviral and the metabolic field,such as non-boosted antiretrovirals and drugs with divergent metabolizing paths. Besides, learning by the caregivers on how to decrease and manage DDI, together with the extensive use of online updated DDI databases, has undoubtedly minimized the problem. The foreseeable increase in the burden of HIV-associated comorbidities and their associated treatments anticipates further complexities in the management of DDI in PLWH.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Doenças Metabólicas/tratamento farmacológico , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Interações Medicamentosas , Infecções por HIV/complicações , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Humanos , Doenças Metabólicas/etiologia , Doenças Metabólicas/fisiopatologia
17.
Expert Opin Drug Metab Toxicol ; 15(10): 813-829, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31556749

RESUMO

Introduction: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are essential components of highly active antiretroviral therapy against HIV-1 infections. Here, we provide a comprehensive overview of approved and emerging NNRTIs. Areas covered: This review covers the latest trend of NNRTIs regarding their pharmacodynamics, pharmacokinetics, mechanisms of drug action, drug resistance as well as new applications such as two-drug regimens and long-acting formulations. Expert opinion: Since the first NNRTI, nevirapine, was approved in 1996, antiviral drug discovery led to the approval of seven NNRTIs, including nevirapine, delavirdine (discontinued), etravirine, elsulfavirine, efavirenz, rilpivirine, and doravirine. The latter three compounds with favorable pharmacodynamic profiles and minimal adverse effects are often combined with one integrase inhibitor or two NRTIs in once-daily fixed-dose tablets. NNRTI-anchored regimens have been approved as initial therapies in treatment-naïve patients (efficacy: 72% to 86%) or maintaining therapies in virologically-suppressed patients (efficacy: 91% to 95%). Future development of NNRTIs includes: (i) better resistance and cross-resistance profiles; (ii) reduction of drug burden by optimizing two-drug or three-drug combinations; and (iii) improvement of patient adherence by novel long-acting formulations with weekly or monthly administration. Overall, NNRTIs play an important role in the management of HIV-1 infections, especially in resource-limited countries.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Terapia Antirretroviral de Alta Atividade/métodos , Preparações de Ação Retardada , Farmacorresistência Viral , HIV-1/efeitos dos fármacos , Humanos , Adesão à Medicação , Inibidores da Transcriptase Reversa/efeitos adversos , Inibidores da Transcriptase Reversa/farmacocinética
18.
Artigo em Inglês | MEDLINE | ID: mdl-31374423

RESUMO

Thanks to highly active antiretroviral treatments, HIV infection is now considered as a chronic condition. Consequently, people living with HIV (PLWH) live longer and encounter more age-related chronic co-morbidities, notably cardiovascular diseases, leading to polypharmacy. As the management of drug-drug interactions (DDIs) constitutes a key aspect of the care of PLWH, the magnitude of pharmacokinetic DDIs between cardiovascular and anti-HIV drugs needs to be more thoroughly characterized. To that endeavour, an UHPLC-MS/MS bioanalytical method has been developed for the simultaneous determination in human plasma of amlodipine, metoprolol, pravastatin, rosuvastatin, atorvastatin and its active metabolites. Plasma samples were subjected to protein precipitation with methanol, followed by evaporation at room temperature under nitrogen of the supernatant, allowing to attain measurable plasma concentrations down to sub-nanogram per milliliter levels. Stable isotope-labelled analytes were used as internal standards. The five drugs and two metabolites were analyzed using a 6-min liquid chromatographic run coupled to electrospray triple quadrupole mass spectrometry detection. The method was validated over the clinically relevant concentrations ranging from 0.3 to 480 ng/mL for amlodipine, atorvastatin and p-OH-atorvastatin, and 0.4 to 480 ng/mL for pravastatin, 0.5 to 480 ng/mL for rosuvastatin and o-OH-atorvastatin, and 3 to 4800 ng/mL for metoprolol. Validation performances such as trueness (95.4-110.8%), repeatability (1.5-13.4%) and intermediate precision (3.6-14.5%) were in agreement with current international recommendations. Accuracy profiles (total error approach) were lying within the limits of ±30% accepted in bioanalysis. This rapid and robust UHPLC-MS/MS assay allows the simultaneous quantification in plasma of the major currently used cardiovascular drugs and offers an efficient analytical tool for clinical pharmacokinetics as well as DDIs studies.


Assuntos
Anlodipino/sangue , Atorvastatina/sangue , Infecções por HIV , Metoprolol/sangue , Pravastatina/sangue , Rosuvastatina Cálcica/sangue , Anlodipino/química , Anlodipino/metabolismo , Anlodipino/farmacocinética , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Atorvastatina/química , Atorvastatina/metabolismo , Atorvastatina/farmacocinética , Cromatografia Líquida de Alta Pressão/métodos , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Humanos , Modelos Lineares , Metoprolol/química , Metoprolol/metabolismo , Metoprolol/farmacocinética , Pravastatina/química , Pravastatina/metabolismo , Pravastatina/farmacocinética , Reprodutibilidade dos Testes , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/metabolismo , Rosuvastatina Cálcica/farmacocinética , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos
19.
Biomater Sci ; 7(9): 3801-3811, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31237275

RESUMO

Nanotechnology-based systems have been proposed for rectal drug delivery, often rendering promising outcomes concerning disease prophylaxis or therapeutics. However, nanocarriers often feature reduced colorectal retention when administered in liquid vehicles (enemas). Semi-solid platforms may be considered as alternative but usually result in limited local distribution. Thermosensitive enemas undergoing sol-gel transition just below body temperature have been used for abbreviating these issues, but the actual impact on the colorectal distribution and retention of incorporated nanosystems is not clear. We prepared and characterized a potential drug delivery platform by incorporating poly(lactic-co-glycolic acid)-based nanoparticles (170-180 nm mean hydrodynamic diameter) into a poloxamer 407-based thermosensitive enema (NPs-in-thermo). The system featured suitable functional properties for rectal administration such as sol-gel transition temperature of approximately 27-28 °C, sol-gel transition time of 1.6 min, and viscosity around 31 and 2100 mPa s at 20 °C and 37 °C, respectively. NPs-in-thermo presented osmolality and pH values deemed compatible with the colorectal compartment, as well as reduced toxicity to the Caco-2 colorectal cell line. The composite system was also used to incorporate the anti-HIV microbicide model drug dapivirine. In vitro studies showed that dapivirine-loaded NPs-in-thermo was able to provide overall faster drug release as compared to dapivirine directly dispersed into phosphate buffered saline or the thermosensitive enema base. Finally, NPs-in-thermo was tested for distribution and retention in a mouse model by in vivo and ex vivo near infrared imaging. Qualitative and semi-quantitative data indicated that NPs exhibited slower but overall wider distribution and enhanced retention in the distal colon of mice treated intrarectally with NPs-in-thermo, namely when compared to NPs dispersed in liquid phosphate buffered saline. Overall, our data support that thermosensitive enemas may provide suitable platforms for the rectal administration of polymeric NPs, namely in the context of drug delivery.


Assuntos
Colo/metabolismo , Enema/métodos , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Reto/metabolismo , Administração Retal , Animais , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos , Humanos , Camundongos Endogâmicos ICR , Concentração Osmolar , Tamanho da Partícula , Transição de Fase , Poloxâmero/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Temperatura , Distribuição Tecidual
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