RESUMO
Patients with coronavirus disease 2019 (COVID-19) with cardiovascular diseases who are at higher risk of progressing to critical illness should be treated with nirmatrelvir/ritonavir (Paxlovid). Ritonavir, the booster in nirmatrelvir/ritonavir, modulates multiple drug metabolizing enzymes and transporters, complicating its use in real-world clinics. We aimed to apply physiologically-based pharmacokinetic (PBPK) modeling to simulate the complex drug-drug interactions (DDIs) of ritonavir with two anticoagulants, rivaroxaban and racemic warfarin, to address this important clinical conundrum. Simulations were implemented within Simcyp Simulator. Compound and population models were adopted from Simcyp and our previous studies. Upon verification and validation of the PBPK model of ritonavir, prospective DDI simulations with the anticoagulants were performed in both the general population (20-65 years) and geriatric subjects (65-85 years) with or without moderate renal impairment. Elevated rivaroxaban concentrations were simulated with nirmatrelvir/ritonavir treatment, where the impact was more profound among geriatric subjects with renal impairment. The overexposure of rivaroxaban was restored to normal range on day 4 post-discontinuation of nirmatrelvir/ritonavir, corroborating with the recovery of enzyme activity. A lower 10 mg daily dose of rivaroxaban could effectively maintain acceptable systemic exposure of rivaroxaban during nirmatrelvir/ritonavir treatment. Treatment of ritonavir marginally declined simulated S-warfarin concentrations, but substantially elevated that of R-warfarin, resulting in a decrease in the international normalized ratio (INR). As INR only recovered 2 weeks post-nirmatrelvir/ritonavir treatment, a longer surveillance INR for warfarin becomes important. Our PBPK-guided simulations evaluated clinically important yet untested DDIs and supports clinical studies to ensure proper anticoagulation management of patients with COVID-19 with chronic coagulative abnormalities when initiating nirmatrelvir/ritonavir therapy.
Assuntos
Tratamento Farmacológico da COVID-19 , Ritonavir , Idoso , Anticoagulantes/efeitos adversos , Combinação de Medicamentos , Interações Medicamentosas , Humanos , Lactamas , Leucina , Nitrilas , Prolina , Estudos Prospectivos , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Rivaroxabana/farmacocinética , VarfarinaRESUMO
The drug delivery platform for folic acid (FA)-coated nanoformulated ritonavir (RTV)-boosted atazanavir (FA-nanoATV/r) using poloxamer 407 was developed to enhance cell and tissue targeting for a range of antiretroviral drugs. Such formulations would serve to extend the drug half-life while improving the pharmacokinetic profile and biodistribution to reservoirs of human immunodeficiency virus (HIV) infection. To this end, we now report enhanced pharmacokinetics and drug biodistribution with limited local and systemic toxicities of this novel nanoformulation. The use of FA as a targeting ligand for nanoATV/r resulted in plasma and tissue drug concentrations up to 200-fold higher compared to equimolar doses of native drug. In addition, ATV and RTV concentrations in plasma from mice on a folate-deficient diet were up to 23-fold higher for mice administered FA-nanoATV/r than for mice on a normal diet. Compared to earlier nanoATV/r formulations, FA-nanoATV/r resulted in enhanced and sustained plasma and tissue ATV concentrations. In a drug interaction study, ATV plasma and tissue concentrations were up to 5-fold higher in mice treated with FA-nanoATV/r than in mice treated with FA-nanoATV alone. As observed in mice, enhanced and sustained plasma concentrations of ATV were observed in monkeys. NanoATV/r was associated with transient local inflammation at the site of injection. There were no systemic adverse reactions associated with up to 10 weeks of chronic exposure of mice or monkeys to FA-nanoATV/r.
Assuntos
Fármacos Anti-HIV/farmacocinética , Portadores de Fármacos/farmacocinética , Ácido Fólico/química , Nanoestruturas , Oligopeptídeos/farmacocinética , Piridinas/farmacocinética , Ritonavir/farmacocinética , Animais , Fármacos Anti-HIV/sangue , Sulfato de Atazanavir , Esquema de Medicação , Portadores de Fármacos/química , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Ácido Fólico/metabolismo , Alimentos Formulados , Meia-Vida , Humanos , Injeções Intramusculares , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nanoestruturas/química , Oligopeptídeos/sangue , Poloxâmero/química , Piridinas/sangue , Ritonavir/sangue , Distribuição TecidualRESUMO
STUDY OBJECTIVE: Panax ginseng has been shown in preclinical studies to modulate cytochrome P450 enzymes involved in the metabolism of HIV protease inhibitors. Therefore, the purpose of this study was to determine the influence of P. ginseng on the pharmacokinetics of the HIV protease inhibitor combination lopinavir-ritonavir (LPV-r) in healthy volunteers. DESIGN: Single-sequence, open-label, single-center pharmacokinetic investigation. SETTING: Government health care facility. SUBJECTS: Twelve healthy human volunteers. MEASUREMENTS AND MAIN RESULTS: Twelve healthy volunteers received LPV-r (400-100 mg) twice/day for 29.5 days. On day 15 of LPV-r administration, serial blood samples were collected over 12 hours for determination of lopinavir and ritonavir concentrations. On study day 16, subjects began taking P. ginseng 500 mg twice/day, which they continued for 2 weeks in combination with LPV-r. On day 30 of LPV-r administration, serial blood samples were again collected over 12 hours for determination of lopinavir and ritonavir concentrations. Lopinavir and ritonavir pharmacokinetic parameter values were determined using noncompartmental methods, and preadministration and postadministration ginseng values were compared using a Student t test, where p<0.05 was accepted as statistically significant. CONCLUSION: Neither lopinavir nor ritonavir steady-state pharmacokinetics were altered by 2 weeks of P. ginseng administration to healthy human volunteers. Thus, a clinically significant interaction between P. ginseng and LPV-r is unlikely to occur in HIV-infected patients who choose to take these agents concurrently. It is also unlikely that P. ginseng will interact with other ritonavir-boosted protease inhibitor combinations, although confirmatory data are necessary.
Assuntos
Indutores do Citocromo P-450 CYP3A/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Suplementos Nutricionais/efeitos adversos , Interações Alimento-Droga , Inibidores da Protease de HIV/farmacocinética , Lopinavir/farmacocinética , Panax/efeitos adversos , Ritonavir/farmacocinética , Adulto , Inibidores do Citocromo P-450 CYP3A/sangue , Combinação de Medicamentos , Feminino , Inibidores da Protease de HIV/sangue , Meia-Vida , Humanos , Fatores Imunológicos/efeitos adversos , Lopinavir/sangue , Masculino , Maryland , Taxa de Depuração Metabólica , National Institute of Allergy and Infectious Diseases (U.S.) , Nootrópicos/efeitos adversos , Raízes de Plantas/efeitos adversos , Ritonavir/sangue , Estados Unidos , Adulto JovemRESUMO
Atazanavir (ATV) causes an elevation of unconjugated hyperbilirubinemia (HBR) as a result of UDP glucuronyltransferase (UGT) 1A1 inhibition. Zinc sulfate (ZnSO4) reduces unconjugated hyperbilirubinemia in individuals with Gilbert's syndrome. We assessed the changes in total, conjugated, and unconjugated bilirubin and the effect on ATV pharmacokinetics (PK) after single and 14-day dosing of ZnSO(4). HIV patients, stable on ATV/ritonavir (ATV/r)-containing regimens with a total bilirubin level of >25 mmol/liter received 125 mg daily of ZnSO(4) as Solvazinc tablets for 14 days. ATV/r and bilirubin concentrations were measured pre-ATV/r dose and 2, 4, 6, 8, and 24 h post-ATV/r dose; before ZnSO4 initiation (phase 1), after a single dose (phase 2) and after 14 days (phase 3). Changes in bilirubin and ATV/r concentrations in the absence or presence of ZnSO4 were evaluated by geometric mean ratios (GMRs) and 90% confidence intervals (CIs; we used phase 1 as a reference). Sixteen male patients completed the study maintaining virologic suppression; ZnSO(4) was well tolerated. Statistically significant declines in total bilirubin C(max) and AUC(0-24) of 16 and 17% were seen in phase2 and 20% in phase 3. Although there were no significant changes in conjugated bilirubin, unconjugated bilirubin Cmax and AUC(0-24) of were lower (17 and 19%, phase 2; 20 and 23% during phase 3). The ATV GMRs (90% CI) for C(trough), C(max), and AUC(0-24) were 0.74 (0.62 to 0.89), 0.82 (0.70 to 0.97), and 0.78 (0.70 to 0.88). Intake of ZnSO(4) decreases total and unconjugated bilirubin and causes modest declines in ATV exposure. ZnSO(4) supplementation may be useful in management of ATV-related HBR in selected patients.
Assuntos
Infecções por HIV/tratamento farmacológico , Hiperbilirrubinemia/prevenção & controle , Oligopeptídeos/administração & dosagem , Piridinas/administração & dosagem , Ritonavir/farmacocinética , Sulfato de Zinco/uso terapêutico , Adolescente , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Área Sob a Curva , Sulfato de Atazanavir , Bilirrubina/análise , Intervalos de Confiança , Estudos Cross-Over , Esquema de Medicação , Quimioterapia Combinada , Tolerância a Medicamentos , Feminino , HIV-1 , Humanos , Hiperbilirrubinemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Oligopeptídeos/farmacocinética , Piridinas/farmacocinética , Ritonavir/administração & dosagem , Adulto Jovem , Sulfato de Zinco/administração & dosagemRESUMO
OBJECTIVE: African potato (Hypoxis obtusa) is commonly used in Sub-Saharan Africa as a complementary herbal remedy for HIV-infected patients. It is unknown whether or not co-administration of African potato alters the pharmacokinetics of protease inhibitor antiretrovirals. The objective of this study was to investigate the impact of the African potato on the steady-state pharmacokinetics of ritonavir-boosted lopinavir (LPV/r). METHODS: Sixteen adult volunteers were administered LPV/r 400/100 mg twice a day for 14 days, followed by concomitant administration with African potato given once daily for 7 days. Lopinavir plasma exposure as estimated by the area under the concentration-time curve over the 12-h dosing interval (AUC(0-12h), AUCτ) was determined on day 14 and again on day 21. Lopinavir in plasma was analyzed using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method. Steady-state AUCτ and the maximum concentration following dose administration (C(max)) were determined using non-compartmental methods using WinNonlin Professional version 5.2.1. Statistical analyses were performed using Stata version 12.1. RESULTS: Co-administration of African potato was not associated with any change in lopinavir AUCτ, C(max), or C(trough). CONCLUSIONS: African potato when taken concomitantly with LPV/r is well-tolerated and not associated with clinically significant changes in lopinavir pharmacokinetics.
Assuntos
Alcinos/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Glucosídeos/administração & dosagem , Infecções por HIV/tratamento farmacológico , Lopinavir/farmacocinética , Ritonavir/farmacocinética , Adulto , Alcinos/farmacologia , Fármacos Anti-HIV/administração & dosagem , Área Sob a Curva , Estudos Cross-Over , Quimioterapia Combinada , Feminino , Glucosídeos/farmacologia , Humanos , Lopinavir/administração & dosagem , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Ritonavir/administração & dosagem , Solanum tuberosum/química , Adulto JovemRESUMO
Interspecies differences in drug metabolism have made it difficult to use preclinical animal testing data to predict the drug metabolites or potential drug-drug interactions (DDIs) that will occur in humans. Although chimeric mice with humanized livers can produce known human metabolites for test substrates, we do not know whether chimeric mice can be used to prospectively predict human drug metabolism or a possible DDI. Therefore, we investigated whether they could provide a more predictive assessment for clemizole, a drug in clinical development for the treatment of hepatitis C virus (HCV) infection. Our results demonstrate, for the first time, that analyses performed in chimeric mice can correctly identify the predominant human drug metabolite before human testing. The differences in the rodent and human pathways for clemizole metabolism were of importance, because the predominant human metabolite was found to have synergistic anti-HCV activity. Moreover, studies in chimeric mice also correctly predicted that a DDI would occur in humans when clemizole was coadministered with a CYP3A4 inhibitor. These results demonstrate that using chimeric mice can improve the quality of preclinical drug assessment.
Assuntos
Antivirais/metabolismo , Benzimidazóis/metabolismo , Fígado , Quimeras de Transplante/metabolismo , Animais , Antivirais/sangue , Antivirais/farmacocinética , Antivirais/uso terapêutico , Benzimidazóis/sangue , Benzimidazóis/farmacocinética , Benzimidazóis/uso terapêutico , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Meia-Vida , Hepacivirus/efeitos dos fármacos , Hepatite C/tratamento farmacológico , Hepatite C/enzimologia , Hepatite C/virologia , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Valor Preditivo dos Testes , Ratos , Ritonavir/metabolismo , Ritonavir/farmacocinética , Ritonavir/farmacologia , Especificidade da Espécie , Replicação Viral/efeitos dos fármacosRESUMO
The aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement milk thistle (silymarin) to interact with the boosted protease inhibitor combination darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy with darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. Silymarin (150 mg every 8 h) was added to the antiretroviral treatment from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on day 0 and darunavir-ritonavir plus silymarin on day 14. Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 48 years (interquartile range, 44 to 50 years), and the median body weight was 70 kg (interquartile range, 65 to 84 kg). Silymarin was well tolerated, and all participants completed the study. The GMRs for darunavir coadministered with silymarin relative to darunavir alone were 0.86 (90% CI, 0.70 to 1.05) for the area under the concentration-time curve from 0 to 12 h, 0.83 (90% CI, 0.80 to 0.98) for the maximum concentration, and 0.94 (90% CI, 0.73 to 1.19) for the concentration at the end of the dosing interval. In summary, coadministration of silymarin with darunavir-ritonavir seems to be safe in HIV-infected patients; no dose adjustment for darunavir-ritonavir seems to be necessary.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Silybum marianum/química , Silimarina/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Fármacos Anti-HIV/administração & dosagem , Darunavir , Esquema de Medicação , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Sulfonamidas/administração & dosagemRESUMO
INTRODUCTION: Knowledge of drug interactions is vital to maximize antiretroviral efficacy and avoid drug-related toxicities. Treatment of co-morbidities has become a difficult task in HIV-infected individuals because pharmacokinetic and/or pharmacodynamic interactions are common when other medications are prescribed along with antiretroviral agents. AREAS COVERED: This article provides an update of the most relevant drug interactions that occur between antiretroviral agents and other drugs. The article additionally revisits how these drug interactions can be prevented from occurring as well as how they can be managed. EXPERT OPINION: Interactions between antiretrovirals and other drugs are frequent in clinical practice. The most common are those affecting drug metabolism due to induction or inhibition of the CYP450, leading to abnormal drug exposure. It is by this mechanism that most HIV protease inhibitors, non-nucleoside reverse transcriptase inhibitors and maraviroc often interact with other medications. In contrast, nucleoside reverse transcriptase inhibitors and some integrase inhibitors, which do not or only marginally affect CYP450, are relatively free of significant pharmacokinetic interactions, although nucleoside analogs might be involved in some pharmacodynamic interactions.
Assuntos
Antirretrovirais/farmacocinética , Antirretrovirais/uso terapêutico , Interações Medicamentosas , Infecções por HIV/tratamento farmacológico , HIV/patogenicidade , Anticonvulsivantes/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Sistema Enzimático do Citocromo P-450/metabolismo , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/uso terapêutico , Medicina Herbária , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imunossupressores/uso terapêutico , Psicotrópicos/uso terapêutico , Ritonavir/farmacocinética , Ritonavir/uso terapêuticoRESUMO
The aim of this open-label, fixed-sequence study was to investigate the potential of Echinacea purpurea, a commonly used botanical supplement, to interact with the boosted protease inhibitor darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy including darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. E. purpurea root extract capsules were added to the antiretroviral treatment (500 mg every 6 h) from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on days 0 (darunavir-ritonavir) and 14 (darunavir-ritonavir plus echinacea). Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 with the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 49 (range, 43 to 67) years, and the body mass index was 24.2 (range, 18.7 to 27.5) kg/m(2). Echinacea was well tolerated, and all participants completed the study. The GMR for darunavir coadministered with echinacea relative to that for darunavir alone was 0.84 (90% CI, 0.63-1.12) for the concentration at the end of the dosing interval, 0.90 (90% CI, 0.74-1.10) for the area under the concentration-time curve from 0 to 12 h, and 0.98 (90% CI, 0.82-1.16) for the maximum concentration. In summary, coadministration of E. purpurea with darunavir-ritonavir was safe and well tolerated. Individual patients did show a decrease in darunavir concentrations, although this did not affect the overall darunavir or ritonavir pharmacokinetics. Although no dose adjustment is required, monitoring darunavir concentrations on an individual basis may give reassurance in this setting.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Echinacea/química , Infecções por HIV/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas/uso terapêutico , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/farmacocinética , Darunavir , Interações Medicamentosas , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Extratos Vegetais/efeitos adversos , Extratos Vegetais/farmacocinética , Ritonavir/administração & dosagem , Ritonavir/efeitos adversos , Ritonavir/farmacocinética , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Sulfonamidas/farmacocinéticaRESUMO
BACKGROUND/AIMS: The aim of this study was to elucidate the impact of first-pass intestinal metabolism to therapeutic efficacy of antiretrovirals and to ascertain interaction mechanisms between garlic supplements (aged garlic extract) and HIV-protease inhibitors. METHODS: In vitro permeability through rat jejunum, Caco-2 cell monolayers was determined and CYP3A4 metabolism studies were performed. RESULTS: Saquinavir and darunavir efflux from enterocytes into gastrointestinal lumen significantly increased in the presence of aged garlic extract, whereas their CYP3A4 metabolism was inhibited. In the case of saquinavir a significant increase of its efflux was observed also in the presence of lower ritonavir doses. Because both drugs bound to different binding sites on P-glycoprotein and/or multidrug resistance associated protein 2 than garlic phytochemicals or ritonavir, lower amounts of antiretrovirals were absorbed. CONCLUSIONS: The fractions of tested anti-HIV drugs absorbed could decrease significantly during self-medication with garlic supplements or ritonavir dose adjustments. Due to distinct saquinavir and darunavir preferences for binding sites on efflux transporters, the presence of other compounds (garlic phytochemicals, ritonavir), capable of influencing intestinal transporter-enzyme interplay, might lead to pharmacokinetic interactions observed in clinical studies and case reports with anti-HIV drugs.
Assuntos
Fármacos Anti-HIV/metabolismo , Alho , Inibidores da Protease de HIV/metabolismo , Mucosa Intestinal/metabolismo , Extratos Vegetais/metabolismo , Ritonavir/metabolismo , Saquinavir/metabolismo , Sulfonamidas/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Fármacos Anti-HIV/farmacocinética , Fármacos Anti-HIV/farmacologia , Transporte Biológico , Células CACO-2 , Citocromo P-450 CYP3A/metabolismo , Darunavir , Suplementos Nutricionais , Interações Medicamentosas , Enterócitos/metabolismo , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/farmacologia , Humanos , Absorção Intestinal , Jejuno/metabolismo , Masculino , Proteína 2 Associada à Farmacorresistência Múltipla , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Extratos Vegetais/farmacocinética , Extratos Vegetais/farmacologia , Ratos , Ratos Wistar , Ritonavir/farmacocinética , Ritonavir/farmacologia , Saquinavir/farmacocinética , Saquinavir/farmacologia , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologiaRESUMO
OBJECTIVES: Studies have shown the importance of having a high protein-binding-adjusted inhibitory quotient (IQ) for protease inhibitors (PIs) boosted with ritonavir. The objective of this study was to explore the virological response when combination atazanavir/ritonavir was administered to treatment-nai¨ve patients. METHODS: Protein-binding-adjusted IQs were calculated in 100 treatment-nai¨ve patients initiating therapy with atazanavir 300 mg/ritonavir 100 mg plus two nucleoside reverse transcriptase inhibitors. RESULTS: The median atazanavir trough level was 635 ng/mL [interquartile range (IQR) 342-1000] and the median atazanavir protein-binding-adjusted IQ was 45 (IQR 24-71). Eighty-four per cent of patients had a successful virological response, and those who failed did not develop resistance. The IQ for boosted atazanavir is high, resulting in rare treatment failure without resistance mutations. CONCLUSIONS: This study showed that the protein-binding-adjusted IQ of atazanavir is close to those measured for lopinavir and darunavir used once daily in first-line treatment. Finally the selection of resistance in the case of virological failure (plasma viral load 4400 HIV-1 RNA copies/mL) to atazanavir/ritonavir used in first-line therapy seems uncommon, as it is for all boosted PIs.
Assuntos
Infecções por HIV/metabolismo , Inibidores da Protease de HIV/farmacocinética , Oligopeptídeos/farmacocinética , Piridinas/farmacocinética , Ritonavir/farmacocinética , Adulto , Idoso , Sulfato de Atazanavir , Proteínas Sanguíneas/metabolismo , Farmacorresistência Viral Múltipla , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , HIV-1/efeitos dos fármacos , HIV-1/genética , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Ligação Proteica , Piridinas/administração & dosagem , Ritonavir/administração & dosagem , Resultado do Tratamento , Carga Viral , Adulto JovemAssuntos
Fármacos Anti-HIV/farmacocinética , Inibidores da Protease de HIV/farmacocinética , Pirimidinonas/farmacocinética , Ritonavir/farmacocinética , Animais , Fármacos Anti-HIV/administração & dosagem , Disponibilidade Biológica , Química Farmacêutica , Interpretação Estatística de Dados , Cães , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Interações Alimento-Droga , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Humanos , Lopinavir , Modelos Biológicos , Pirimidinonas/administração & dosagem , Ritonavir/administração & dosagem , Comprimidos , Equivalência TerapêuticaAssuntos
Unha-de-Gato , Inibidores da Protease de HIV , Interações Ervas-Drogas , Preparações de Plantas , Sulfato de Atazanavir , Unha-de-Gato/efeitos adversos , Feminino , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/sangue , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/uso terapêutico , Humanos , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Oligopeptídeos/administração & dosagem , Oligopeptídeos/sangue , Oligopeptídeos/farmacocinética , Oligopeptídeos/uso terapêutico , Preparações de Plantas/administração & dosagem , Preparações de Plantas/efeitos adversos , Piridinas/administração & dosagem , Piridinas/sangue , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/sangue , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Saquinavir/administração & dosagem , Saquinavir/sangue , Saquinavir/farmacocinética , Saquinavir/uso terapêuticoRESUMO
Minocycline and valproic acid are potential adjuvant therapies for the treatment of human immunodeficiency virus (HIV)-associated cognitive impairment. The purpose of this study was to determine whether minocycline alone or in combination with valproic acid affected atazanavir plasma concentrations. Twelve adult HIV-infected subjects whose regimen included atazanavir (300 mg)-ritonavir (100 mg) daily for at least 4 weeks were enrolled. Each subject received atazanavir-ritonavir on day 1, atazanavir-ritonavir plus 100 mg minocycline twice daily on days 2 to 15, and atazanavir-ritonavir plus 100 mg minocycline twice daily and 250 mg valproic acid twice daily on days 16 to 30 with meals. The subjects had 11 plasma samples drawn over a dosing interval on days 1, 15, and 30. The coadministration of minocycline and valproic acid with atazanavir-ritonavir was well tolerated in all 12 subjects (six male; mean [+/- standard deviation] age was 43.1 [8.2] years). The geometric mean ratios (GMRs; 95% confidence interval [CI]) for the atazanavir area under the concentration-time curve from 0 to 24 h at steady state (AUC(0-24)), the plasma concentration 24 h after the dose (C(min)), and the maximum concentration during the dosing interval (C(max)) with and without minocycline were 0.67 (0.50 to 0.90), 0.50 (0.28 to 0.89), and 0.75 (0.58 to 0.95), respectively. Similar decreases in atazanavir exposure were seen after the addition of valproic acid. The GMRs (95% CI) for atazanavir AUC(0-24), C(min), and C(max) with and without minocycline plus valproic acid were 0.68 (0.43 to 1.06), 0.50 (0.24 to 1.06), and 0.66 (0.41 to 1.06), respectively. Coadministration of neither minocycline nor minocycline plus valproic acid appeared to influence the plasma concentrations of ritonavir (P > 0.2). Minocycline coadministration resulted in decreased atazanavir exposure, and there was no evidence that the addition of valproic acid mediated this effect.
Assuntos
Anticonvulsivantes , Transtornos Cognitivos/tratamento farmacológico , Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/farmacocinética , Minociclina , Oligopeptídeos/farmacocinética , Piridinas/farmacocinética , Ácido Valproico , Adulto , Anticonvulsivantes/administração & dosagem , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Sulfato de Atazanavir , Interações Medicamentosas , Quimioterapia Combinada , Feminino , Infecções por HIV/psicologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/administração & dosagem , Inibidores da Protease de HIV/uso terapêutico , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Minociclina/administração & dosagem , Minociclina/farmacologia , Minociclina/uso terapêutico , Oligopeptídeos/administração & dosagem , Oligopeptídeos/uso terapêutico , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Ritonavir/administração & dosagem , Ritonavir/farmacocinética , Ritonavir/uso terapêutico , Ácido Valproico/administração & dosagem , Ácido Valproico/farmacologia , Ácido Valproico/uso terapêuticoRESUMO
OBJECTIVE: Animal and in vitro data suggest that Ginkgo biloba extract (GBE) may modulate CYP3A4 activity. As such, GBE may alter the exposure of HIV protease inhibitors metabolized by CYP3A4. It is also possible that GBE could alter protease inhibitor pharmacokinetics (PK) secondary to modulation of P-glycoprotein (P-gp). The primary objective of the study was to evaluate the effect of GBE on the exposure of lopinavir in healthy volunteers administered lopinavir/ritonavir. Secondary objectives were to compare ritonavir exposure pre- and post-GBE, and assess the effect of GBE on single doses of probe drugs midazolam and fexofenadine. METHODS: This open-label study evaluated the effect of 2 weeks of standardized GBE administration on the steady-state exposure of lopinavir and ritonavir in 14 healthy volunteers administered lopinavir/ritonavir to steady-state. In addition, single oral doses of probe drugs midazolam and fexofenadine were administered prior to and after 4 weeks of GBE (following washout of lopinavir/ritonavir) to assess the influence of GBE on CYP3A and P-gp activity, respectively. RESULTS: Lopinavir, ritonavir and fexofenadine exposures were not significantly affected by GBE administration. However, GBE decreased midazolam AUC(0-infinity) and C(max) by 34% (p = 0.03) and 31% (p = 0.03), respectively, relative to baseline. In general, lopinavir/ritonavir and GBE were well tolerated. Abnormal laboratory results included mild elevations in hepatic enzymes, cholesterol and triglycerides, and mild-to-moderate increases in total bilirubin. CONCLUSIONS: Our results suggest that GBE induces CYP3A metabolism, as assessed by a decrease in midazolam concentrations. However, there was no change in the exposure of lopinavir, likely due to ritonavir's potent inhibition of CYP3A4. Thus, GBE appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected. Limitations to our study include the single sequence design and the evaluation of a ritonavir-boosted protease inhibitor exclusively.
Assuntos
Ginkgo biloba/metabolismo , Inibidores da Protease de HIV/farmacologia , Midazolam/farmacocinética , Fitoterapia , Extratos Vegetais/metabolismo , Inibidores de Proteases/farmacocinética , Pirimidinonas/farmacocinética , Ritonavir/farmacocinética , Terfenadina/análogos & derivados , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Interações Medicamentosas , Feminino , Ginkgo biloba/efeitos adversos , Humanos , Lopinavir , Masculino , Extratos Vegetais/efeitos adversos , Terfenadina/farmacocinéticaRESUMO
To assess the QTc prolongation by ritonavir (RTV) 100 mg and explore its potential use as CYP3A inhibitor in thorough QTc (TQT) studies. Randomized, crossover study of single-dose RTV 100 mg, placebo, and moxifloxacin (MFLX) 400 mg in 65 healthy subjects with serial triplicate electrocardiograms obtained for 12 h post-dose. Largest mean placebo-adjusted QTcF increase from baseline (90% confidence interval (CI)) for RTV 100 mg was noninferior to placebo (0.16 ms (-1.38, 1.69)). Study sensitivity was validated by detecting the largest mean placebo-adjusted QTcF increase from baseline (90% CI) for MFLX of 8.31 ms (6.44, 10.18). A single dose of RTV 100 mg does not cause QTc prolongation in healthy subjects. Based on the potent CYP3A4 inhibition, lack of QTc effect and better safety profile, RTV 100 mg could replace ketoconazole as the CYP3A4 inhibitor in TQT studies.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Inibidores da Protease de HIV/efeitos adversos , Imidazóis/uso terapêutico , Fígado/efeitos dos fármacos , Síndrome do QT Longo/induzido quimicamente , Inibidores da Transcriptase Reversa/uso terapêutico , Ritonavir/efeitos adversos , Compostos de Enxofre/uso terapêutico , Adulto , Compostos Aza/farmacologia , Estudos Cross-Over , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Quimioterapia Combinada , Eletrocardiografia , Feminino , Fluoroquinolonas , Inibidores da Protease de HIV/farmacocinética , Frequência Cardíaca/efeitos dos fármacos , Humanos , Cetoconazol/farmacologia , Fígado/enzimologia , Síndrome do QT Longo/fisiopatologia , Masculino , Pessoa de Meia-Idade , Moxifloxacina , Quinolinas/farmacologia , Valores de Referência , Reprodutibilidade dos Testes , Projetos de Pesquisa , Ritonavir/farmacocinética , Resultado do TratamentoRESUMO
Recommendations for a highly active antiretroviral therapy in either pretreated patients or symptomatic patients with an AIDS-defining event include at least one protease inhibitor. The majority of currently available protease inhibitors are coadministrated with low-dose ritonavir, a pharmacoenhancer that significantly increases protease inhibitor plasma concentrations. In the class of protease inhibitors lopinavir plus ritonavir is the only coformulation. This coformulation was designed to overcome the problems of earlier agents of this class of drugs concerning unfavorable pharmacokinetics with a higher frequency of dosing and therapy failure. The pharmacoenhancing effect of ritonavir on lopinavir resulted in a highly potent, clinically effective antiretroviral drug with a high genetic barrier to viral resistance. Safety concerns have taken a backseat, focusing instead on the favorable efficacy of lopinavir, which recently led to the evaluation of its use in boosted double-protease-inhibitor regimens, as a once-daily application and even in HIV monotherapy. Nevertheless, since HIV infection became a chronic but controllable disease, side effects like metabolic disorders and cardiovascular disease have begun to draw increased attention in the long-term treatment with protease inhibitors. Coformulated lopinavir/ritonavir is available as a soft gelatin capsule (133.33/33.33 mg), liquid formulation (80/20 mg/ml) and recently approved melt-extrusion tablet (200/50 mg). Lopinavir/ritonavir is recommended for first- and second-line therapy in HIV-1 infection, in children as well as adolescents and adults.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/uso terapêutico , Pirimidinonas/uso terapêutico , Ritonavir/uso terapêutico , Animais , Combinação de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Farmacorresistência Viral , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Inibidores da Protease de HIV/farmacologia , HIV-1/efeitos dos fármacos , Humanos , Lopinavir , Pirimidinonas/efeitos adversos , Pirimidinonas/farmacocinética , Pirimidinonas/farmacologia , Ritonavir/efeitos adversos , Ritonavir/farmacocinética , Ritonavir/farmacologiaRESUMO
Objetivo: Desarrollo, validación y caracterización de la funcióndel error de tres métodos analíticos mediante la técnica decromatografía líquida de alta eficacia (HPLC) para el análisis cuantitativode ritonavir, saquinavir y abacavir en plasma humano.Método: Se han indicado los reactivos y aparatos empleados,la preparación de los diferentes estándares de referencia, el procedimientode extracción desde la matriz biológica y las condicionesde análisis ensayadas para la puesta a punto de los tres métodosanalíticos. Además, también se han descrito las metodologías devalidación y de obtención de la función del error analítico.Resultados: Los métodos analíticos desarrollados para ritonavir,saquinavir y abacavir en plasma humano fueron selectivos,lineales (r2 > 0,99), precisos (coeficientes de variación < 15%) yexactos (errores relativos < 15%) en el rango de concentracionesseleccionado. La recuperación fue mayor del 95% en todos losmétodos. Los antirretrovirales estudiados fueron estables en lascondiciones ensayadas de acuerdo con la rutina del laboratorio.La función del error discriminada para cada uno de los métodosanalíticos validados resultó ser lineal en saquinavir (DE = 4,84 +7,14·10-2C) y abacavir (DE = -1,072 + 3,70·10-2C) y no lineal enel caso de ritonavir (DE = 39,98 + 2,40·10-5C2).Conclusiones: Se han desarrollado y posteriormente validadotres métodos analíticos, encontrándose los parámetros de validacióndentro de las especificaciones y atributos de calidad establecidos. Lafunción del error de cada uno de los métodos validados puedeemplearse como método de ponderación heteroscedástica en laestimación de parámetros mediante regresión no lineal en estudiosde farmacocinética clínica de los antirretrovirales ensayados
Objective: Development, validation and error characterizationof three analytical methods, by high performance liquid chromatography(HPLC), for the quantitative analysis of ritonavir,saquinavir and abacavir in human plasma.Method: Reagents and instrumentation used, preparation ofdifferent standards, sample extraction procedure from biologicmatrix, and analytical conditions assayed were detailed to set upthree analytical methods. In addition, the validation and the determinationof analytical error were also described.Results: The analytical methods developed for ritonavir,saquinavir and abacavir in human plasma were selective, linear(r2 > 0.99), precise (coefficients of variation < 15%) and accurate(relative errors < 15%) over the concentration range selected. Therecovery was more than 95% in all methods. Antiretroviral drugswere stable in the storage conditions assayed according to theroutine laboratory. The error function discriminated for each analyticalmethod validated was linear in saquinavir (SD = 4.84 +7.14·10-2C) and abacavir (SD = -1.072 + 3.70·10-2C), and nonlinearin ritonavir (SD = 39.98 + 2.40·10-5C2).Conclusions: Three analytical methods were developed andsubsequently validated, with validation parameters being withinthe specifications and attributes of quality established. The errorfunction characterized for each validated method can be used as aheteroscedastic weighting method in the parameter estimation bynon-linear regression analysis in clinical pharmacokinetic studiesof antiretroviral drugs assayed
Assuntos
Humanos , Antirretrovirais/farmacocinética , Avaliação de Medicamentos/métodos , Qualidade dos Medicamentos Homeopáticos , Estabilidade de Medicamentos , 25105 , Ritonavir/farmacocinética , Saquinavir/farmacocinética , Cromatografia Líquida de Alta Pressão/métodosRESUMO
The purpose of this study was to evaluate in vitro interactions of commercially obtained pure herbal constituents with p-glycoprotein P-gp and cytochrome P-450 3A4 (CYP3A4) activities, which can further modulate the transcellular transport and metabolism kinetics of orally administered drugs. Caco-2 cells grown in the presence of 0.25 micromol/L 1alpha,25-dihydroxy vitamin D3 and multidrug-resistant 1 (MDR1) transfected MDCK cells were used as models to evaluate the effect of purified herbal constituents (quercetin, hypericin, hyperforin from St. John's wort, kaempferol from ginseng, silibinin from milk thistle, and allicin from garlic) on P-gp-mediated efflux of the human immunodeficiency virus (HIV) protease inhibitor ritonavir. In addition, the inhibitory effect of these constituents on CYP3A4-mediated metabolism was determined by using cortisol as a model compound. Silibinin and hyperforin did not significantly alter cellular uptake of H-ritonavir in Caco-2 cells. A similar result was also observed for silibinin when tested in MDR1-MDCK cells. Quercetin, hypericin, and kaempferol exhibited a remarkable inhibition of P-gp-mediated efflux of ritonavir by increasing its cellular uptake in these models. These values were also comparable with the inhibitory effect of quinidine in Caco-2 cells, a well-known inhibitor of P-gp, on ritonavir efflux from Caco-2 cells. Allicin exhibited a concentration-dependent inhibition of ritonavir efflux when tested on MDR1-MDCK cells. There was a significant decrease in the Apical to Basal/Basal to Apical (AP-BL/BL-AP) transport ratio of ritonavir in presence of hypericin, kaempferol, and quercetin. These herbal constituents inhibited the CYP3A4 activity when tested with the Vivid CYP3A4 assay kit, whereas silibinin did not alter cortisol metabolism. Hypericin showed a significant inhibition in reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent metabolism of cortisol with 64.6% of intact drug at the end of a 1-hour study. Similarly, kaempferol and quercetin also caused substantial inhibition of cortisol metabolism with 89.7% and 90.1% of intact cortisol, respectively, compared with 45.9% in the control. Prolonged exposure of quercetin resulted in significant increase of mRNA expression of both MDR1 and CYP3A4 levels in Caco-2 cells. However, hyperforin caused upregulation of CYP3A4 and downregulation of MDR1, whereas the effect of silibinin and kaempferol remained inconclusive on these gene expressions. Hypericin, kaempferol, quercetin, and allicin inhibit the efflux and CYP3A4-mediated metabolism of xenobiotics in vitro. Hence, this study warns against the use of herbal constituents along with prescribed HIV protease inhibitors that are substrates for P-gp and/or CYP3A4.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/biossíntese , Sistema Enzimático do Citocromo P-450/biossíntese , Inibidores da Protease de HIV/farmacocinética , Interações Ervas-Drogas , Ritonavir/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Animais , Transporte Biológico , Permeabilidade da Membrana Celular , Células Cultivadas , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/genética , Relação Dose-Resposta a Droga , Humanos , Masculino , Microssomos Hepáticos/metabolismo , RNA Mensageiro/biossíntese , Ratos , Ratos Sprague-DawleyRESUMO
The pathophysiology of sepsis involves excessive lymphocyte apoptosis, which correlates with adverse outcomes, and disordered cytokine production, which may promote host injury. As the protease inhibitor (PI) class of antiretroviral agents is known to prevent apoptosis in vitro, we evaluated their effect on survival, lymphocyte apoptosis, and consequent cytokine production in mice with sepsis induced by cecal ligation and perforation. Mice pretreated with PIs have improved survival (67%; P<0.0005) compared with controls (17%) and a significant (P<0.05) reduction in lymphocyte apoptosis. Even mice receiving therapy beginning 4 h after perforation demonstrated improved survival (50%; P<0.05) compared with controls. PI therapy is also associated with an increase in the Th1 cytokine TNF-alpha (P<0.05) early in sepsis and a reduction in the Th2 cytokines IL-6 and IL-10 (P<0.05) late in sepsis; despite no intrinsic antibacterial effects, PI also reduced quantitative bacterial blood cultures. The beneficial effects of PI appear to be specific to lymphocyte apoptosis, as lymphocyte-deficient Rag1-/- mice did not experience benefit from treatment with PI. Thus, inhibition of lymphocyte apoptosis by PI is a candidate approach for the treatment of sepsis.