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1.
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 de Medicamentos , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , Humanos , Ritonavir/farmacocinética
3.
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 de Medicamentos , 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
4.
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
6.
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 Ambiente , Distribuição Tecidual
7.
Expert Opin Drug Metab Toxicol ; 15(5): 417-427, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30951643

RESUMO

INTRODUCTION: Drugs used in HIV treatment; all protease inhibitors, some non-nucleoside reverse transcriptase inhibitors, and pharmacoenhancers ritonavir and cobicistat can inhibit cytochrome P450 (CYP) enzymes. CYP inhibition can cause clinically significant drug-drug interactions (DDI), leading to increased drug exposure and potential toxicity. Areas covered: A complete understanding of pharmacodynamics and CYP-mediated DDI is crucial to prevent adverse side effects and to achieve optimal efficacy. We summarized the pharmacodynamics of all the CYP inhibitors used for HIV treatment, followed by a discussion of drug interactions between these CYP inhibitors and other drugs, and a discussion on the effect of CYP polymorphisms. We also discussed the potential advancements in improving the pharmacodynamics of these CYP inhibitors by using nanotechnology strategy. Expert opinion: The drug-interactions in HIV patients receiving ARV drugs are complicated, especially when patients are on CYP inhibitors-based ART regimens. Therefore, evaluation of CYP-mediated drug interactions is necessary prior to prescribing ARV drugs to HIV subjects. To improve the treatment efficacy and minimize DDI, novel approaches such as nanotechnology may be the potential alternative approach. However, further studies with large cohort need to be conducted to provide strong evidence for the use of nano-formulated ARVs to effectively treat HIV patients.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Inibidores das Enzimas do Citocromo P-450/administração & dosagem , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Inibidores das Enzimas do Citocromo P-450/farmacocinética , Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/efeitos dos fármacos , Sistema Enzimático do Citocromo P-450/genética , Interações de Medicamentos , Humanos
8.
Int J Pharm ; 564: 207-213, 2019 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-30999049

RESUMO

The past fifteen years have witnessed a resurgence of interest in vaginal ring technologies for drug delivery applications, mostly driven by the impetus for development of vaginally-administered antiretroviral microbicides to help reduce the high acquisition rates for human immunodeficiency virus (HIV) among Sub-Saharan African women. Currently, the lead candidate microbicide is a 28-day silicone elastomer vaginal ring releasing dapivirine (Ring-004), an experimental non-nucleoside reverse transcriptase inhibitor. The ring was tested in two pivotal Phase III clinical studies in 2016 and is currently undergoing review by the European Medicines Agency. Recently, we described a new type of silicone elastomer vaginal ring offering sustained release of the protein molecule 5P12-RANTES, a potent experimental chemokine analogue that potently blocks the HIV CCR5 coreceptor. Building on our previous work, here we report the preclinical development of a new combination vaginal ring that offers sustained release of both 5P12-RANTES and dapivirine, in which the 5P12-RANTES is incorporated into an exposed core within the ring body and the dapivirine in the sheath. In this way, in vitro release of dapivirine matches closely that for Ring-004. Also, we report the pharmacokinetic testing of this combination ring formulation in sheep, where vaginal concentrations of both drugs are maintained over 28 days at levels potentially useful for preventing HIV infection in women.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Quimiocinas CC/administração & dosagem , Dispositivos Anticoncepcionais Femininos , Infecções por HIV/prevenção & controle , Pirimidinas/administração & dosagem , Animais , Fármacos Anti-HIV/farmacocinética , Quimiocinas CC/farmacocinética , Preparações de Ação Retardada/administração & dosagem , Combinação de Medicamentos , Feminino , Pirimidinas/farmacocinética , Ovinos , Vagina/metabolismo
9.
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 de Medicamentos , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Lamivudina/farmacocinética , Lamivudina/farmacologia
10.
J Pept Sci ; 25(4): e3155, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30809901

RESUMO

Previously, we reported the discovery of macrocyclic peptide triazoles (cPTs) that bind to HIV-1 Env gp120, inhibit virus cell infection with nanomolar potencies, and cause irreversible virion inactivation. Given the appealing virus-killing activity of cPTs and resistance to protease cleavage observed in vitro, we here investigated in vivo pharmacokinetics of the cPT AAR029b. AAR029b was investigated both alone and encapsulated in a PEGylated liposome formulation that was designed to slowly release inhibitor. Pharmacokinetic analysis in rats showed that the half-life of FITC-AAR029b was substantial both alone and liposome-encapsulated, 2.92 and 8.87 hours, respectively. Importantly, liposome-encapsulated FITC-AAR029b exhibited a 15-fold reduced clearance rate from serum compared with the free FITC-cPT. This work thus demonstrated both the in vivo stability of cPT alone and the extent of pharmacokinetic enhancement via liposome encapsulation. The results obtained open the way to further develop cPTs as long-acting HIV-1 inactivators against HIV-1 infection.


Assuntos
Fármacos Anti-HIV/farmacocinética , HIV-1/efeitos dos fármacos , Compostos Macrocíclicos/farmacocinética , Peptídeos/farmacocinética , Triazóis/farmacocinética , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Lipossomos , Compostos Macrocíclicos/química , Compostos Macrocíclicos/farmacologia , Testes de Sensibilidade Microbiana , Peptídeos/química , Peptídeos/farmacologia , Triazóis/química , Triazóis/farmacologia
11.
Enferm Infecc Microbiol Clin ; 36 Suppl 2: 10-16, 2018 12.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30545466

RESUMO

Symtuza® is the first and only treatment for HIV-1 that combines 2 nucleos(t)ide analogues (emtricitabine and tenofovir alafenamide) together with a boosted protease inhibitor (darunavir/cobicistat) in a once-daily single tablet regimen (STR). This combination is active against a wide variety of HIV strains and, in turn, avoids bone and renal toxicity associated with the use of tenofovir disoproxil fumarate, combining efficacy, convenience, tolerability and high genetic barrier. Pharmacokinetic studies of its components show a favourable profile, allowing its use in a wide variety of patients and clinical situations. Although, as in any boosted combination, possible interactions with concomitant medication should be borne in mind, cobici-stat inhibits cytochrome P-450 more selectively and has no inducing effect, so it has a more predictable interaction profile than ritonavir. Supplement information: This article is part of a supplement entitled "Co-formulated cobicistat-boosted darunavir, emtricitabine, and tenofovir alafenamide for the treatment of HIV infection", which is sponsored by Janssen.


Assuntos
Fármacos Anti-HIV/farmacologia , Darunavir/farmacologia , Tenofovir/farmacologia , Fármacos Anti-HIV/farmacocinética , Darunavir/farmacocinética , Combinação de Medicamentos , Interações de Medicamentos , Humanos , Tenofovir/farmacocinética
12.
APMIS ; 126(11): 842-851, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30357957

RESUMO

Hepatic CYP2D6 enzyme metabolizes antiretroviral drugs (ARVs) including nevirapine. Polymorphism in CYP2D6 gene affects drug metabolism and displays distinctive phenotypes in the population. Hence, we investigated the prevalence of CYP2D6*4 1934G/A polymorphism in a total of 165 HIV patients that include 34 with and 131 without hepatotoxicity and 160 unrelated healthy controls by the PCR-RFLP method. The prevalence of CYP2D6*4 1934AA genotype was higher in total HIV patients as compared to healthy controls (1.81% vs 0.6%, OR = 2.86). Similarly, CYP2D6*4 1934AA genotype was much more prevalent in HIV patients without hepatotoxicity as compared to healthy controls (2.3% vs 0.6%, OR = 2.87). Likewise, CYP2D6*4 1934AA genotype was predominant in advanced HIV disease stage as compared to healthy controls (3.8% vs 0.6%, OR = 6.15). CYP2D6*4 1934GA genotype was distributed higher in HIV patients taking tobacco and nevirapine as compared to non-users (23.3% vs 19.3%, OR = 1.21, 21.0% vs 16.7%, OR = 1.2). Likewise, CYP2D6*4 1934GA genotype was overrepresented in patients with hepatotoxicity taking alcohol + nevirapine as compared to alcohol non-users + nevirapine users (20.00% vs 16.67%, OR = 1.25). Thus, there was no significant difference in genotype or allele frequencies of CYP2D6*4 1934G/A polymorphism between the patients with hepatotoxicity and those without or healthy controls.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Fármacos Anti-HIV/uso terapêutico , Citocromo P-450 CYP2D6/genética , Infecções por HIV/genética , Fígado/efeitos dos fármacos , Nevirapina/uso terapêutico , Polimorfismo de Nucleotídeo Único , Adulto , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Consumo de Bebidas Alcoólicas/patologia , Alelos , Fármacos Anti-HIV/metabolismo , Fármacos Anti-HIV/farmacocinética , Biotransformação , Estudos de Casos e Controles , Citocromo P-450 CYP2D6/metabolismo , Feminino , Expressão Gênica , Frequência do Gene , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Infecções por HIV/virologia , Humanos , Índia , Fígado/enzimologia , Fígado/patologia , Masculino , Nevirapina/metabolismo , Nevirapina/farmacocinética , Polimorfismo de Fragmento de Restrição
13.
Expert Opin Drug Metab Toxicol ; 14(8): 773-779, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29985071

RESUMO

INTRODUCTION: Co-formulated fixed dose combination (FDC) of antiretroviral drugs tenofovir disoproxil fumarate, lamivudine, and reduced dose efavirenz [TDF 300 mg/3TC 300mg/EFV400 mg (TLE-400)] is a single daily tablet recently approved for the treatment of HIV-1 infection. Areas covered: An overview of the pharmacokinetics, pharmacodynamics and role of TLE-400 in the treatment of HIV-1 infection based on the publications from Medline and Pubmed as of February, 2018. Expert opinion: Although TLE-400 has not been formally evaluated in a clinical trial as a new formulation, previous studies have evaluated its components individually and in different doses as other FDCs have shown favorable efficacy and safety results to support continuing its approval and indication in the management of HIV-1 infection. Due to the lower dose of EFV, TLE-400 has a lower rate of toxicity and higher tolerability compared to its predecessor, the TLE-600, which contained a higher 600 mg dose of EFV. Given its low cost and ease of administration, TLE-400 is a promising alternative first line FDC in the management of HIV-1.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Infecções por HIV/tratamento farmacológico , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Benzoxazinas/administração & dosagem , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Lamivudina/administração & dosagem , Tenofovir/administração & dosagem
14.
Expert Opin Drug Metab Toxicol ; 14(8): 781-802, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30010446

RESUMO

INTRODUCTION: Peripheral blood mononuclear cells (PBMCs) are a critical component of the immune system and the target cells for human immunodeficiency virus, type 1 (HIV-1) infection. Nucleoside/nucleotide analogs for the treatment of HIV infection are prodrugs that require cellular activation to triphosphate (TP) metabolites for antiviral activity. A reliable method of PBMC isolation and subsequent cell counting, as well as an accurate bioanalytical determination of the TPs in PBMCs are important for understanding the intracellular pharmacokinetic (PK) of the TPs and its correlation with plasma PK, the drug effect, and dose determination. Areas covered: The authors review the challenges and solutions in PBMC sample collection, sample processing, cell lysis, cell counting methods, analyte extraction, and liquid chromatography/tandem mass spectrometry (LC-MS/MS) quantitative analysis of the nucleoside reverse transcriptase inhibitor-triphosphate (NRTI-TP) metabolites, and analogs. Expert opinion: Analyzing large numbers of clinical PBMC samples for determination of NRTI-TPs and analogs in PBMCs requires not only a validated LC-MS/MS bioanalytical method but also reliable methods for PBMC isolation, counting, cell lysis, and analyte recovery, and an approach for assessing analyte stability. Furthermore, a simple, consistent, and validated cell counting method often involves DNA quantitation of the PBMCs samples collected from clinical studies.


Assuntos
Fármacos Anti-HIV/farmacocinética , Leucócitos Mononucleares/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Fármacos Anti-HIV/administração & dosagem , Contagem de Células , Cromatografia Líquida/métodos , Infecções por HIV/tratamento farmacológico , Humanos , Polifosfatos/metabolismo , Reprodutibilidade dos Testes , Inibidores da Transcriptase Reversa/administração & dosagem , Espectrometria de Massas em Tandem/métodos
15.
Drugs ; 78(10): 1013-1024, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29915897

RESUMO

Darunavir/cobicistat/emtricitabine/tenofovir AF (Symtuza®) is the first protease inhibitor (PI)-based single-tablet regimen (STR) available for the treatment of adults and adolescents (aged ≥ 12 years) with HIV-1 infection. It combines the PI darunavir (which has a high genetic barrier to resistance) with the pharmacokinetic booster cobicistat and the nucleos(t)ide reverse transcriptase inhibitors emtricitabine and tenofovir alafenamide (tenofovir AF), the latter being associated with less off-target tenofovir exposure than its predecessor tenofovir disoproxil fumarate (tenofovir DF). Over 48 weeks in phase 3 trials, darunavir/cobicistat/emtricitabine/tenofovir AF was noninferior to darunavir/cobicistat plus emtricitabine/tenofovir DF in establishing virological suppression in antiretroviral therapy (ART)-naïve adults and, likewise, was noninferior to an ongoing boosted PI, emtricitabine plus tenofovir DF regimen in preventing virological rebound in virologically-suppressed, ART-experienced adults. Resistance did not emerge to the STR components, with the exception being an emtricitabine resistance-associated mutation (RAM) [M184I/V] in one of seven recipients who experienced virological failure (although M184V was a minority variant at screening in this patient). Darunavir/cobicistat/emtricitabine/tenofovir AF was generally well tolerated, with renal and bone profile improvements but less favourable effects on some lipids versus tenofovir DF-based regimens. Thus, although longer-term and cost-effectiveness data would be beneficial, darunavir/cobicistat/emtricitabine/tenofovir AF is a welcome addition to the STRs available for the treatment of adults and adolescents with HIV-1 infection, being the first to combine the high genetic resistance barrier of darunavir with the renal/bone profile of tenofovir AF, thus expanding the patient population for whom an STR may be suitable.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacocinética , Adenina/farmacologia , Adenina/uso terapêutico , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Densidade Óssea/efeitos dos fármacos , Cobicistat/farmacocinética , Cobicistat/uso terapêutico , Darunavir/farmacocinética , Darunavir/uso terapêutico , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Emtricitabina/farmacocinética , Emtricitabina/farmacologia , Emtricitabina/uso terapêutico , Genes MDR/efeitos dos fármacos , Humanos , Reabsorção Renal/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/uso terapêutico , Tenofovir/farmacologia , Tenofovir/uso terapêutico , Resultado do Tratamento
16.
Expert Opin Drug Metab Toxicol ; 14(6): 601-611, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29775551

RESUMO

INTRODUCTION: Several antiretroviral drugs used to treat infection with the human immunodeficiency virus (HIV) are substrates of enzymes belonging to the cytochrome P450 (CYP) superfamily, which are polymorphically expressed. It may therefore be useful to take into account the genetic variation in these enzymes to predict the likelihood of anti-HIV treatment success, toxicity and the potential for drug-drug interactions. Areas covered: In this manuscript, the authors discuss the current state of knowledge regarding pharmacogenetic associations between CYP and all major antiretrovirals, as well as the importance of these associations. Expert opinion: While many pharmacogenetic associations for CYP have been described in the literature, replication studies are sometimes lacking. The implementation of this knowledge in clinical practice also remains difficult. Further efforts are required both to expand this field of knowledge and to enable its use in everyday clinical practice.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Sistema Enzimático do Citocromo P-450/genética , Farmacogenética , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Sistema Enzimático do Citocromo P-450/metabolismo , Interações de Medicamentos , Variação Genética , Infecções por HIV/tratamento farmacológico , Humanos
17.
Eur J Pharm Sci ; 119: 90-101, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29635009

RESUMO

Lumefantrine is a widely used antimalarial in children in sub-Saharan Africa and is predominantly metabolised by CYP3A4. The concomitant use of lumefantrine with the antiretroviral efavirenz, which is metabolised by CYP2B6 and is an inducer of CYP3A4, increases the risk of lumefantrine failure and can result in an increased recrudescence rate in HIV-infected children. This is further confounded by CYP2B6 being highly polymorphic resulting in a 2-3 fold higher efavirenz plasma concentration in polymorphic subjects, which enhances the potential for an efavirenz-lumefantrine drug-drug interaction (DDI). This study developed a population-based PBPK model capable of predicting the impact of efavirenz-mediated DDIs on lumefantrine pharmacokinetics in African paediatric population groups, which also considered the polymorphic nature of CYP2B6. The validated model demonstrated a significant difference in lumefantrine target day 7 concentrations (Cd7) in the presence and absence of efavirenz and confirmed the capability of efavirenz to initiate this DDI. This was more apparent in the *6/*6 compared to *1/*1 population group and resulted in a significantly lower (P < 0.001) lumefantrine Cd7. A prospective change in dosing schedule from 3-days to 7-days resulted in a greater number of *6/*6 subjects (28-57%) attaining the target Cd7 across age bands (0.25-13 years), with the greatest increase evident in the 1-4 year old group (3-day: 1%; 7-day: 28%).


Assuntos
Fármacos Anti-HIV , Antimaláricos , Benzoxazinas , Citocromo P-450 CYP2B6/genética , Etanolaminas , Fluorenos , Infecções por HIV , Malária , Adolescente , Adulto , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Antimaláricos/farmacocinética , Antimaláricos/farmacologia , Benzoxazinas/farmacocinética , Benzoxazinas/farmacologia , Criança , Pré-Escolar , Simulação por Computador , Interações de Medicamentos , Etanolaminas/farmacocinética , Etanolaminas/farmacologia , Fluorenos/farmacocinética , Fluorenos/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/metabolismo , Humanos , Lactente , Lumefantrina , Malária/tratamento farmacológico , Malária/genética , Malária/metabolismo , Pessoa de Meia-Idade , Modelos Biológicos , Polimorfismo Genético , Adulto Jovem
18.
Artigo em Inglês | MEDLINE | ID: mdl-29635209

RESUMO

Tenofovir disoproxil fumarate is a pro-drug of the active metabolite tenofovir widely used against the HIV1, HIV2, and Hepatitis B virus. Several studies have been conducted and found kidney injury associated with tenofovir exposure. High tenofovir plasma concentration correlated with kidney injury in tenofovir-exposed patients. The present study developed and validated a simple and cost-effective LC/MS/MS method to determine tenofovir level in human plasma. A small plasma volume of 80 µl is utilized for the sample preparation. The samples were separated by Luna C18 (100 mm × 2.0 mm, 3 µm) using gradient elution with a mobile phase consisting of water (containing 0.1% formic acid) and acetonitrile (90:10, v/v). The detection was achieved through multiple reaction monitoring using positive ionization mode on the triple quadrupole mass spectrometer with a run time of 10 min. The monitoring transitions were set at m/z 288.0 → 176.1 and 136.1 for tenofovir and m/z 226.1 → 152.0 for acyclovir (as the internal standard). This standard curve was linear from 10 to 640 ng/ml, with the lower limit of quantification of 10 ng/ml. The inter- and intra-day precision results were less than 12.3% and their accuracies were within the acceptable range of 84.9-113.1%. The validated method was successfully applied to the study of tenofovir induced kidney injury in HIV-1 infected patients taking 300 mg once daily for more than 4 weeks.


Assuntos
Fármacos Anti-HIV/sangue , Cromatografia Líquida/métodos , Espectrometria de Massas em Tandem/métodos , Tenofovir/sangue , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/uso terapêutico , Monitoramento de Medicamentos , Infecções por HIV/tratamento farmacológico , Humanos , Modelos Lineares , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Tenofovir/efeitos adversos , Tenofovir/farmacocinética , Tenofovir/uso terapêutico
19.
Int J Nanomedicine ; 13: 97-100, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29593405

RESUMO

Mannosylated polymeric nanoparticles (NPs) enable improvement of brain bioavailability and reduction of dosing due to efficient drug delivery at the target site. Mannose receptors are present on the surface of macrophages, and therefore, in this study, it is expected that mannosylated NPs of anti-human immunodeficiency virus drug may target the macrophages, which may improve the therapeutic outcome and reduce the toxicity of antiretroviral bioactives. Poly(lactic-co-glycolic acid) (PLGA) and mannosylated-PLGA NPs (Mn-PLGA NPs) were prepared and administered by intravenous route in a dose of 10 mg/kg. After predetermined time period, the pharmacokinetics and biodistribution of NPs were analyzed using high-performance liquid chromatography and confocal microscopy, respectively. Results of this study indicated that Mn-PLGA NPs would be a promising therapeutic system for efficient delivery of the drug into brain macrophages.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Encéfalo/efeitos dos fármacos , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , Administração Intravenosa , Animais , Fármacos Anti-HIV/farmacocinética , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Ácido Láctico/química , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Macrófagos/efeitos dos fármacos , Manose/química , Microscopia Confocal , Nanopartículas/química , Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Distribuição Tecidual
20.
Therapie ; 73(3): 185-191, 2018 May - Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29395300

RESUMO

BACKGROUND: To compare the steady state plasma concentrations (Css) of three antiretroviral drugs in both normal and overweight patients, and to determine the relationship between Css and fat mass (FM) or lean body mass. METHODS: Patients treated for more than 6 months once daily with one of the antiretroviral drugs: efavirenz (EFV) 600mg, atazanavir boosted with ritonavir (ATV-r) 300mg/100mg, or darunavir boosted with ritonavir (DRV-r) 800mg/100mg, combined with two nucleoside analogues, were enrolled prospectively. One at steady state, plasma samples for the assessment of drug concentration were taken and body composition was assessed by bioelectrical impedance. RESULTS: One hundred and thirty-nine patients were enrolled (46, 45 and 48 in the groups EFV, ATV-r and DRV-r respectively). Their mean age was 46.2±10.4 years, 58% were male, 55.4% were from Sub Sahara African (SSA); body mass index (BMI) was 25.4±4.4kg/m2. Mean drug plasma Css of the three drugs did not differ according to BMI group. DRV-r Css tended to be higher in patients with BMI≥25kg/m2 (2896.7±1689 versus 2091.9±1038, P=0.09) and was significantly correlated with FM (r=0.3, P=0.02). In subgroup analysis, the effect of FM on DRV-r Css was significant in patients from SSA (r=0.4, P=0.04). CONCLUSIONS: Css result from many factors and body composition has been shown to only weakly influence interindividual variability but should be investigated in morbidly obese patients treated with DRV-r.


Assuntos
Fármacos Anti-HIV/farmacocinética , Sulfato de Atazanavir/farmacocinética , Benzoxazinas/farmacocinética , Composição Corporal/fisiologia , Peso Corporal/fisiologia , Darunavir/farmacocinética , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sobrepeso/metabolismo
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