RESUMO
BACKGROUND: Efavirenz is among the most widely used antiretroviral drugs. Increased efavirenz exposure has been associated with CNS side effects and also with the chance of emergence of resistance upon treatment interruptions. The objective of this study was to evaluate factors associated with efavirenz plasma concentrations in a cohort of HIV-infected individuals. METHODS: From July 2009 to March 2010, HIV-infected patients with efavirenz as part of antiretroviral therapy (600 mg at night), undetectable viral load for at least 1 year and CD4 cell count >200 cells/mm(3) were consecutively enrolled at the HIV/AIDS ambulatory care unit in southern Brazil. Plasma samples were taken 18-23 h after efavirenz last dose and analysed by validated ultra-performance liquid chromatography. RESULTS: Forty-one subjects were included (21 females). Mean age and weight were 45.4 years and 70.9 kg, respectively. Mean efavirenz plasma concentration was 2.20â±â2.17 mg/L. Most plasma concentrations (73%) were within the therapeutic window (1-4 mg/L); 17% were below and 10% above the limits. There were no significant associations between efavirenz concentration and age, CD4 cell count, time on antiretroviral treatment and gender. There was significant and inverse correlation between efavirenz concentrations and body weight (Pâ=â0.013) and body mass index (Pâ=â0.001). CONCLUSIONS: In this cohort of well-controlled HIV-positive individuals, patients with lower weight or body mass index had a higher chance of presenting elevated plasma concentrations of efavirenz. Therapeutic drug monitoring to adjust dose might be a helpful tool to decrease efavirenz dose in order to minimize costs and adverse effects.
Assuntos
Fármacos Anti-HIV/sangue , Benzoxazinas/sangue , Peso Corporal , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/sangue , Adulto , Idoso , Envelhecimento , Alcinos , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/administração & dosagem , Benzoxazinas/efeitos adversos , Contagem de Linfócito CD4 , Ciclopropanos , Monitoramento de Medicamentos , Feminino , Infecções por HIV/sangue , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/efeitos adversos , Carga ViralRESUMO
This study describes the preparation and evaluation of biodegradable poly(l-lactide) (PLA) and poly(l-lactide)-poly(ethylene glycol) (PLA-PEG) blend nanoparticles containing zidovudine as model drug. The prepared nanoparticles were characterized in terms of size, zeta potential, morphology and drug entrapment efficiency. The pharmacokinetics of zidovudine following intranasal administration in mice was assessed. The results showed that although PLA and blend nanoparticles had the same morphology, the particle size and zeta potential were changed by the PEG. The drug entrapment efficiency was increased by PEG presence. The pharmacokinetic study showed that all the nanoparticles were able to sustain zidovudine delivery over time, but greater efficiency was obtained with PLA-PEG blend nanoparticles, whose T(max) was twice that of PLA nanoparticles. The PLA and PLA-PEG nanoparticles formulations increased the zidovudine mean half-life by approximately 5.5 and 7h, respectively, compared to zidovudine aqueous solution. The relative bioavailability of zidovudine-loaded PLA-PEG blend nanoparticles was 2.7, relative to zidovudine-loaded PLA nanoparticles and 1.3 relative to aqueous solution formulation. Thus, the PLA nanoparticles were unable to increase the zidovudine bioavailability compared to aqueous solution formulation. The results obtained in this study indicate the potential of the PLA-PEG blend nanoparticles as carriers for zidovudine delivery by the intranasal route.
Assuntos
Portadores de Fármacos , Ácido Láctico/química , Polietilenoglicóis/química , Polímeros/química , Inibidores da Transcriptase Reversa/administração & dosagem , Zidovudina/administração & dosagem , Administração Intranasal , Animais , Disponibilidade Biológica , Química Farmacêutica , Composição de Medicamentos , Meia-Vida , Masculino , Camundongos , Tamanho da Partícula , Poliésteres , Ratos , Ratos Wistar , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacocinética , Propriedades de Superfície , Tecnologia Farmacêutica/métodos , Zidovudina/sangue , Zidovudina/química , Zidovudina/farmacocinéticaRESUMO
OBJECTIVE: The present study describes the determination of the bioequivalence of two different nevirapine tablet formulations (nevirapine tablets 200 mg, Novatec, as the test formulation vs. viramune tablets 200 mg, Boehringer Ingelheim, as the reference formulation). METHOD: A single 200 mg oral dose of each preparation was administered to 11 human immunodeficiency virus (HIV)-infected patients volunteers and their bioequivalence was assessed by comparing the both plasma nevirapine concentrations-time curves and others pharmacokinetic parameters. RESULTS: The pharmacokinetic parameters obtained for each formulation were the area under the time-concentration curve from 0 to 12 h (AUC(0-12)) and from 0 to infinity (AUC(0-infinite)), maximum concentration (C(max)), and the time at which it occurred (T(max)). These parameters were determined by high-performance liquid chromatography (HPLC). No significant differences were observed in these parameters. The 90% confident interval for the ratio of means for the lnAUC(0-12 T/R) (0.92-1.10), lnAUC(0-infinite T/R) (0.86-1.17) and lnC(max T/R) (0.71-1.38) are within the guideline range of bioequivalence (0.80 to 1.25 and 0.70 to 1.43). For T(max) the mean of test formulation is in the range 2.64 +/- 0.53 h. CONCLUSIONS: The results show that the formulations were bioequivalent in the extent and in the rate of absorption.
Assuntos
Fármacos Anti-HIV/farmacocinética , Infecções por HIV/tratamento farmacológico , Nevirapina/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Administração Oral , Adulto , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Fármacos Anti-HIV/uso terapêutico , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Absorção Intestinal , Masculino , Nevirapina/administração & dosagem , Nevirapina/sangue , Nevirapina/uso terapêutico , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Sensibilidade e Especificidade , Comprimidos , Equivalência TerapêuticaRESUMO
BACKGROUND: We estimate the variance between between- and within-subjects, using mixed effect models, as a way to assess the genetic component in explaining the observed heterogeneity of ddl kinetics among healthy individuals. Our work expands on a previous reported method known as RGC. METHODS: Repeated measurements of ddl concentration in the serum were obtained from 48 healthy adult volunteers enrolled in two bioequivalence study. We use the NONMEM program (Non-linear Mixed Effect Model) to estimate the between- and within-subject variability and the corresponding pharmacokinetic parameters. We assess the genetic contribution to the variability of each pharmacokinetic parameter through the RGC method. RESULTS: Pharmacokinetic parameters, expressed as functions of covariates gender and creatinine clearance (CLCR), were: Oral clearance (CL = 55.1 + 240 * CLCR + 16.6 l/h for male and CL = 55.1 + 240 * CLCR for female), central volume (V2 = 9.82), inter-compartmental clearance (Q = 40.90/h), peripheral volume (V3 = 62.7 + 22.90 for male and V3 = 62.70 for female), absorption rate constant (Ka = 1.51 h(-1)) and duration of the dose administration (D = 0.44 h). The RGC of CL, Q, V3, Ka and D were 0.58, 0.97, 0.60, 0.53 and 0.88, respectively. CONCLUSION: We estimated parameter-specific RGC indices and rank them according to the potential genetic contribution as an explanation for the observed variance. Our study design improved precision by decreasing background noise and, thus, improved the chances that indices such as the RGC are in fact describing genetic variability.
Assuntos
Fármacos Anti-HIV/sangue , Didanosina/sangue , Inibidores da Transcriptase Reversa/sangue , Adulto , Feminino , Transcriptase Reversa do HIV/antagonistas & inibidores , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Farmacogenética , Fatores SexuaisRESUMO
The intracellular triphosphorylation and plasma pharmacokinetics of lamivudine (3TC), stavudine (d4T), and zidovudine (ZDV) were assessed in a pharmacokinetic substudy, in 56 human immunodeficiency virus-hepatitis C virus (HIV-HCV) coinfected patients receiving peginterferon alfa-2a (40KD) 180 microg/week plus either placebo or ribavirin (RBV) 800 mg/day in the AIDS PEGASYS Ribavirin International Coinfection Trial. There were no significant differences between patients treated with RBV and placebo in plasma pharmacokinetics parameters for the nucleoside reverse transcriptase inhibitors (NRTIs) at steady state (weeks 8 to 12): ratios of least squares mean of area under the plasma concentration-time curve (AUC(0-12 h)) were 1.17 (95% confidence interval, 0.91 to 1.51) for 3TC, 1.44 (95% confidence interval, 0.58 to 3.60) for d4T and 0.85 (95% confidence interval, 0.50 to 1.45) for ZDV, and ratios of least squares mean plasma C(max) were 1.33 (95% confidence interval, 0.99 to 1.78), 1.06 (95% confidence interval, 0.68 to 1.65), and 0.84 (95% confidence interval, 0.46 to 1.53), respectively. Concentrations of NRTI triphosphate (TP) metabolites in relation to those of the triphosphates of endogenous deoxythymidine-triphosphate (dTTP) and deoxcytidine-triphosphate (dCTP) were similar in the RBV and placebo groups. Differences (RBV to placebo) in least squares mean ratios of AUC(0-12 h) at steady state were 0.274 (95% confidence interval, -0.37 to 0.91) for 3TC-TP:dCTP, 0.009 (95% confidence interval, -0.06 to 0.08) for d4T-TP:dTTP, and -0.081 (95% confidence interval, -0.40 to 0.24) for ZDV-TP:dTTP. RBV did not adversely affect HIV-1 replication. In summary, RBV 800 mg/day administered in combination with peginterferon alfa-2a (40KD) does not significantly affect the intracellular phosphorylation or plasma pharmacokinetics of 3TC, d4T, and ZDV in HIV-HCV-coinfected patients.
Assuntos
Infecções por HIV/sangue , Infecções por HIV/complicações , HIV-1/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Hepatite C/sangue , Inibidores da Transcriptase Reversa/farmacocinética , Ribavirina/farmacocinética , Adulto , Área Sob a Curva , Quimioterapia Combinada , Feminino , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Hepacivirus/fisiologia , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Humanos , Interferon alfa-2 , Interferon-alfa/efeitos adversos , Interferon-alfa/sangue , Interferon-alfa/farmacocinética , Lamivudina/sangue , Lamivudina/farmacocinética , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/efeitos adversos , Polietilenoglicóis/farmacocinética , Proteínas Recombinantes , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/sangue , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Ribavirina/sangue , Estavudina/sangue , Estavudina/farmacocinética , Fatores de Tempo , Zidovudina/sangue , Zidovudina/farmacocinéticaRESUMO
A method based on solid-phase extraction (SPE) coupled to high-performance liquid chromatography (HPLC) with positive ion electrospray ionization tandem mass spectrometry (ESI-MS/MS) detection was developed for the simultaneous determination of lamivudine (3TC) and zidovudine (AZT) in human serum, using didanosine (ddI) as internal standard. The acquisition was performed in multiple reaction monitoring (MRM) mode, monitoring the transitions m/z 230.0 --> 111.8 for 3TC, m/z 268.1 --> 126.8 for AZT, and m/z 237.2 --> 136.8 for ddI. The limits of detection and quantitation were 3 and 10 ng/mL for 3TC, and 5 and 15 ng/mL for AZT. The method was linear in the studied ranges (10-1500 ng/mL for 3TC and 15-3000 ng/mL for AZT), with r(2) > 0.99 for each drug, and the run time was 4 min. The intra-assay precisions (%) were in the ranges 1.9-8.7 (3TC) and 2.2-8.9 (AZT), the inter-assay precisions were in the ranges 2.6-9.0 (3TC) and 4.2-8.1 (AZT), and the intra- and inter-assay accuracies were >97% for both drugs. The absolute recoveries were 95-99% for 3TC (45, 600 and 1200 ng/mL) and 104-112% for AZT (45, 1000 and 2400 ng/mL). The analytical method was applied to a bioequivalence study in which 24 healthy adult volunteers received single oral doses of the reference formulation and two test combined AZT/3TC tablets, in an open, three-period, balanced, randomized, crossover protocol. Based on the 90% confidence interval of the individual ratios (test formulation/reference formulation) for C(max) (peak serum concentration) and AUC(0-inf) (extrapolated area under the serum concentration vs. time curve from time zero to infinity), it was concluded that the two test formulations are bioequivalent to the reference formulation with respect to the rate and extent of absorption of both 3TC and AZT.
Assuntos
Lamivudina/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Zidovudina/sangue , Adulto , Análise Química do Sangue/métodos , Análise Química do Sangue/estatística & dados numéricos , Cromatografia Líquida de Alta Pressão/métodos , Estudos Cross-Over , Humanos , Lamivudina/administração & dosagem , Lamivudina/farmacocinética , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/sangue , Inibidores da Transcriptase Reversa/farmacocinética , Sensibilidade e Especificidade , Espectrometria de Massas por Ionização por Electrospray/estatística & dados numéricos , Equivalência Terapêutica , Zidovudina/administração & dosagem , Zidovudina/farmacocinéticaRESUMO
A rapid, sensitive and specific method to quantify nevirapine in human plasma using dibenzepine as the internal standard (IS) was developed and validated. The method employed a liquid-liquid extraction. The analyte and the IS were chromatographed on a C(18) analytical column, (150 x 4.6 mm i.d. 4 microm) and analyzed by tandem mass spectrometry in the multiple reaction monitoring mode. The method had a chromatographic run time of 5.0 min and a linear calibration curve over the range 10-5000 ng ml(-1) (r(2) > 0.9970). The between-run precision, based on the relative standard deviation for replicate quality controls was 1.3% (30 ng ml(-1)), 2.8% (300 ng ml(-1)) and 3.6% (3000 ng ml(-1)). The between-run accuracy was 4.0, 7.0 and 6.2% for the above-mentioned concentrations, respectively. This method was employed in a bioequivalence study of two nevirapine tablet formulations (Nevirapina from Far-Manguinhos, Brazil, as a test formulation, and Viramune from Boehringer Ingelheim do Brasil Química e Farmacêutica, as a reference formulation) in 25 healthy volunteers of both sexes who received a single 200 mg dose of each formulation. The study was conducted using an open, randomized, two-period crossover design with a 3 week washout interval. The 90% confidence interval (CI) of the individual ratio geometric mean for Nevirapina/Viramune was 96.4-104.5% for AUC((0-last)), 91.4-105.1% for AUC((0-infinity)) and 95.3-111.6% for C(max) (AUC = area under the curve; C(max) = peak plasma concentration). Since both 90% CI for AUC((0-last)) and AUC((0-infinity)) and C(max) were included in the 80-125% interval proposed by the US Food and Drug Administration, Nevirapina was considered bioequivalent to Viramune according to both the rate and extent of absorption.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Nevirapina/farmacocinética , Inibidores da Transcriptase Reversa/farmacocinética , Espectrometria de Massas por Ionização por Electrospray/métodos , Adulto , Área Sob a Curva , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nevirapina/sangue , Distribuição Aleatória , Reprodutibilidade dos Testes , Inibidores da Transcriptase Reversa/sangue , Sensibilidade e Especificidade , Equivalência TerapêuticaRESUMO
Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not correlate with clinical efficacy or toxicity. These agents need to be phosphorylated to become active against HIV-infection. Thus, the characterization of the NRTIs intracellular metabolite pharmacological parameters will provide a better understanding that could lead to the development of more rational dose regimens in the HIV-infected population. Furthermore, intracellular measurements of NRTIs may provide a better marker with respect to clinical efficacy and toxicity than plasma concentrations. Thus, in this article we review the latest information regarding the intracellular pharmacological parameters of zidovudine (ZDV) and lamivudine (3TC) active metabolites in HIV-infected patients including the results from our recent clinical studies. We will start the discussion with ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We will then discuss the in vitro and in vivo intracellular studies with particular emphasis in the method development to measure these metabolites and we will conclude with the most current data from our clinical trials.
Assuntos
Fármacos Anti-HIV/farmacocinética , Antimetabólitos/farmacocinética , Lamivudina/farmacocinética , Leucócitos Mononucleares/metabolismo , Inibidores da Transcriptase Reversa/farmacocinética , Zidovudina/farmacocinética , Adulto , Idoso , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/sangue , Antimetabólitos/administração & dosagem , Antimetabólitos/sangue , Células Cultivadas , Criança , Cromatografia Líquida de Alta Pressão , Ensaios Clínicos como Assunto , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Lamivudina/administração & dosagem , Lamivudina/sangue , Masculino , Pessoa de Meia-Idade , Fosfatos/metabolismo , Fosforilação , Polifosfatos/metabolismo , Radioimunoensaio , Inibidores da Transcriptase Reversa/administração & dosagem , Inibidores da Transcriptase Reversa/sangue , Fatores de Tempo , Zidovudina/administração & dosagem , Zidovudina/sangueRESUMO
Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not correlate with clinical efficacy or toxicity. These agents need to be phosphorylated to become active against HIV-infection. Thus, the characterization of the NRTIs intracellular metabolite pharmacological parameters will provide a better understanding that could lead to the development of more rational dose regimens in the HIV-infected population. Furthermore, intracellular measurements of NRTIs may provide a better marker with respect to clinical efficacy and toxicity than plasma concentrations. Thus, in this article we review the latest information regarding the intracellular pharmacological parameters of zidovudine (ZDV) and lamivudine (3TC) active metabolites in HIV infected patients including the results from our recent clinical studies. We will start the discussion with ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We will then discuss the in vitro and in vivo intracellular studies with particular emphasis in the method development to measure these metabolites and we will conclude with the most current data from our clinical trials.