Simultaneous population pharmacokinetic model for lopinavir and ritonavir in HIV-infected adults.

BACKGROUND: Lopinavir is a protease inhibitor indicated for the treatment of HIV infection. It is coformulated with low doses of ritonavir in order to enhance its pharmacokinetic profile. After oral administration, plasma concentrations of lopinavir can vary widely between different HIV-infected patients. OBJECTIVE: To develop and validate a population pharmacokinetic model for lopinavir and ritonavir administered simultaneously in a population of HIV-infected adults. The model sought was to incorporate patient characteristics influencing variability in the drug concentration and the interaction between the two compounds. METHODS: HIV-infected adults on stable therapy with oral lopinavir/ritonavir in routine clinical practice for at least 4 weeks were included. A concentration-time profile was obtained for each patient, and blood samples were collected immediately before and 1, 2, 4, 6, 8, 10 and 12 hours after a morning lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. First, a population pharmacokinetic model was developed for lopinavir and for ritonavir separately. The pharmacokinetic parameters, interindividual variability and residual error were estimated, and the influence of different patient characteristics on the pharmacokinetics of lopinavir and ritonavir was explored. Then, a simultaneous model estimating the pharmacokinetics of both drugs together and incorporating the influence of ritonavir exposure on oral clearance (CL/F) of lopinavir was developed. Population analysis was performed using nonlinear mixed-effects modelling (NONMEM version V software). The bias and precision of the final model were assessed through Monte Carlo simulations and data-splitting techniques. RESULTS: A total of 53 and 25 Caucasian patients were included in two datasets for model building and model validation, respectively. Lopinavir and ritonavir pharmacokinetics were described by one-compartment models with first-order absorption and elimination. The presence of advanced liver fibrosis decreased CL/F of ritonavir by nearly half. The volume of distribution after oral administration (Vd/F) and CL/F of lopinavir were reduced as alpha1-acid glycoprotein (AAG) concentrations increased. CL/F of lopinavir was inhibited by ritonavir concentrations following a maximum-effect model (maximum inhibition [Imax] = 1, concentration producing 50% of the I(max) [IC50] = 0.36 mg/L). The final model appropriately predicted plasma concentrations in the model-validation dataset with no systematic bias and adequate precision. CONCLUSION: A population model to simultaneously describe the pharmacokinetics of lopinavir and ritonavir was developed and validated in HIV-infected patients. Bayesian estimates of the individual parameters of ritonavir and lopinavir could be useful to predict lopinavir exposure based on the presence of advanced liver fibrosis and the AAG concentration in an individual manner, with the aim of maximizing the chances of treatment success.

Lopinavir/ritonavir pharmacokinetics in HIV and hepatitis C virus co-infected patients without liver function impairment: influence of liver fibrosis.

BACKGROUND AND OBJECTIVE: To assess the influence of hepatitis C virus (HCV) co-infection and the extent of liver fibrosis on lopinavir/ritonavir pharmacokinetics in HIV-infected patients without liver function impairment. METHODS: Cross-sectional, comparative study enrolling HIV-infected adults receiving lopinavir/ritonavir (400 mg/100 mg twice daily). HIV/HCV co-infected patients were grouped as having advanced fibrosis (HCV+/FIB+, n=7) or not (HCV+/FIB-, n=8) based on the FIB-4 index. A full concentration-time profile was obtained for each patient, and blood samples were collected before (0), and 1, 2, 4, 6, 8, 10 and 12 hours after a lopinavir/ritonavir dose. Lopinavir and ritonavir concentrations in plasma were determined by high-performance liquid chromatography. Maximum and minimum plasma concentrations (Cmax and Cmin), area under the plasma concentration-time curve from 0 to 12 hours (AUC12), apparent oral clearance at steady state (CLss/F), and apparent volume of distribution after oral administration (Vd/F) were calculated for each individual using a non-compartmental approach. RESULTS: Twenty-six HCV- and 22 HCV+patients were enrolled. Lopinavir and ritonavir pharmacokinetics were comparable between HCV- and HCV+patients. However, the Vd/F of lopinavir was 125% higher in HCV+/FIB+patients than in HCV-patients (p=0.015) and 107% higher than in HCV+/FIB-(p=0.040) patients. The CLss/F of ritonavir was 40% lower in HCV+/FIB+patients than in HCV-patients (p=0.005) and 44% lower than in HCV+/FIB-patients (p=0.040). Thus, for ritonavir AUC12, Cmax and Cmin in HCV+/FIB+patients were 63%, 86% and 100% higher, respectively, when compared with those parameters in HCV-patients (p=0.005, p=0.012 and p=0.015, respectively), and 80%, 86% and 100% higher, respectively, when compared with levels in HCV+/FIB- patients (p=0.040, p=0.040 and p=0.029, respectively). CONCLUSION: Lopinavir exposure is similar in HIV-infected patients with or without HCV co-infection and without liver function impairment. However, ritonavir exposure may be higher in this setting, particularly in individuals with advanced liver fibrosis.

Ezetimibe, a promising lipid-lowering agent for the treatment of dyslipidaemia in HIV-infected patients with poor response to statins.

OBJECTIVE: To assess the efficacy, safety, and pharmacokinetic interactions of ezetimibe in HIV-infected patients with poorly controlled antiretroviral-associated dyslipidaemia while taking pravastatin alone. DESIGN: A prospective, open-label, one-arm study of 24 weeks duration. PATIENTS AND SETTING: Nineteen patients (18 on stable HAART), with low density lipoprotein (LDL)-cholesterol values of > or = 130 mg/dl despite the use of pravastatin. METHODS: Ezetimibe, 10 mg/day, was added to pravastatin 20 mg/day, while patients maintained the same antiretroviral regimen. Determinations of total, LDL-, and high density lipoprotein (HDL)-cholesterol, triglycerides, apoproteins, and inflammatory factors (homocystein and C-reactive protein) were performed at baseline, and at weeks 6, 12, and 24. Liver enzymes and creatinine phosphokinase were also assessed. Protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) Cmin was determined just before and 12 weeks after ezetimibe introduction. RESULTS: At week 24, 61.5% of patients achieved the endpoint of the study (LDL-cholesterol < 130 mg/dl). Significant declines in mean total and LDL-cholesterol levels were observed between baseline and weeks 6, 12, and 24, irrespective of antiretroviral type (PI or NNRTI). Mean HDL-cholesterol and apoprotein A increased significantly. No patients discontinued therapy due to intolerance or presented toxicity of grade 2 or more. No differences were observed in lopinavir or nevirapine Cmin measured just before and 12 weeks after ezetimibe introduction. CONCLUSION: The addition of ezetimibe to ongoing pravastatin seems to be an effective and safe option for HIV-infected patients not achieving the NCEP ATPIII LDL-cholesterol goals while receiving a statin alone. Its high tolerability and the lack of interactions with the cytochrome CYP3A4 indicate that ezetimibe will not increase the risk of toxicity or pharmacokinetic interactions with antiretrovirals.

Differential transcriptional expresión of the polymorphic myxovirus resistance protein A in response to interferon-alpha treatment.

Levels of myxovirus resistance protein A (MxA) mRNA were studied for a single nucleotide polymorphism in the promoter region at nucleotide position -88 of the gene to identify individual-specific responses to interferon (IFN)-alpha2 that might predict responsiveness to IFN-alpha therapy. We quantified MxA expression by reverse transcription and real-time polymerase chain reaction in peripheral blood mononuclear cells (PBMC) in vitro, induced by IFN-alpha2, from 22 healthy donors, in relation with G/T polymorphism located in the promoter of the MxA. MxA mRNA was significantly upregulated in all subjects (mean of 53-fold) in response to IFN-alpha2 in vitro (P < 0.01). Comparison of the inducibility of MxA mRNA expression in relation with G/T polymorphism showed a 4.26-fold higher induction of MxA mRNA levels in PBMC from carriers of the mutant allele (GT or TT) than homozygotes with the wild-type allele (GG) (P < 0.001). We propose that expression of the IFN-inducible MxA is affected by a single nucleotide polymorphism in the MxA promoter which can identify an individual response to IFN-alpha2.

Monitoring atazanavir concentrations with boosted or unboosted regimens in HIV-infected patients in routine clinical practice.

Although atazanavir pharmacokinetics and pharmacodynamics are related, the atazanavir plasma trough concentrations of patients on regimens that are not boosted by low doses of ritonavir may not be high enough to maintain viral suppression. In this cross-sectional study, the percentage of patients with atazanavir trough concentrations lower than the proposed minimum effective concentration was compared between HIV-infected patients receiving antiretroviral therapy with ritonavir-boosted (ATV/r, n = 31) or unboosted (ATV, n = 54) atazanavir in clinical practice. Blood samples were drawn 21 to 25 hours after the last atazanavir dose. Drug concentrations in plasma were determined by high-performance liquid chromatography and considered suboptimal if they were lower than 0.15 mg/L or potentially toxic if higher than 0.85 mg/L. The median (interquartile range) atazanavir concentration was 0.711 (0.394-0.914) mg/L in patients receiving ATV/r and 0.121 (0.052-0.209) mg/L in patients receiving ATV (P < 0.001). None of the patients receiving ATV/r and 62.9% of the subjects receiving ATV showed drug concentrations below 0.15 mg/L (odds ratio, 2.7; 95% confidence interval, 1.9-3.8; P < 0.001). In contrast, atazanavir concentrations were higher than 0.85 mg/L in 32.2% of the patients receiving ATV/r compared with 3.7% of the subjects receiving ATV (odds ratio, 8.7; 95% confidence interval, 2.0-37.2; P = 0.001). Atazanavir and total bilirubin concentrations in plasma were correlated. In conclusion, atazanavir trough concentrations may be lower than the proposed minimum effective concentration in a considerable percentage of HIV-infected patients receiving antiretroviral therapy with unboosted atazanavir. Therapeutic drug monitoring may be useful in this setting.

Variability in non-nucleoside reverse transcriptase and protease inhibitors concentrations among HIV-infected adults in routine clinical practice.

AIMS: The objective of this study was to assess interindividual variability in plasma trough concentrations of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in an outpatient routine clinical practice setting. METHODS: The study included 117 patients who attended our clinic for routine outpatient blood tests and who were receiving antiretroviral therapy which included NNRTI or PI. Patients were not informed that drug concentrations were going to be assessed until blood sampling. The time of the last antiretroviral treatment intake and blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective concentration. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were higher than 4.0 mg l(-1), 6.0 mg l(-1), and 0.85 mg l(-1), respectively. RESULTS: Overall, interindividual variability in NNRTI and PI plasma concentrations was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Inappropriate adherence only explained 35% of subtherapeutic drug concentrations. CONCLUSION: Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. Therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice.

Variability in non-nucleoside reverse transcriptase and protease inhibitor concentrations among HIV-infected adults in routine clinical practice.

AIMS: The objective of this study was to assess interindividual variability in trough concentrations of plasma of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in a routine outpatient setting. METHODS: One hundred and seventeen patients who attended our clinic for routine blood tests, and who were receiving antiretroviral therapy which included NNRTI or PI were studied. Patients were not informed that drug concentrations were going to be measured until blood sampling. The times of the last antiretroviral dose and of blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective value. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were > 4.0 mg l(-1), > 6.0 mg l(-1) and > 0.85 mg l(-1), respectively. RESULTS: Overall, interindividual variability of NNRTI and PI concentrations in plasma was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Poor adherence explained only 35% of subtherapeutic drug concentrations. CONCLUSION: Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. These findings provide further evidence that therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice.

Maduración del ovocito y su relación con algunos componentes del líquido folicular / Oocyte maturation and its relation with some follicular fluid components

Se analizaron 35 muestras de líquido folicular (LF) no hemático, obtenido de pacientes que recibieron inductores de ovulación múltiple para los protocolos de fertilización in vitro (FIV) y transferencia intratubaria de gametos (GIFT). El objetivo de este estudio retrospectivo, fue el de localizar uno o varios marcadores bioquímicos del estado de madurez del ovocito presentes en el LF, y correlacionalos con el aspecto morfológico del mismo. El grado de expanción del complejo ovocitocorona radiata-cumulus oofurus (COCC), sirvió para la primera clasificación de este. El líquido folicular fue sometido a barrido espectrofotométrico en el área de luz visible entre 350 a 600 nm para medir la absorbancia de su pigmento amarillo. Los niveles foliculares de proteínas estradiol y progesterona se midieron y correlacionaron con la morfología del COCC. La máxima absorbancia obtenida con el análisis espectrofotométrico, mostró una gama de picos que al ser agrupados y promediados formaron cuatro grupos principales: El primero formado por 20 muestras, con un pico promedio de 413.8 nm, el 45 por ciento de los ovocitos que formaron este grupo fueron clasificados como inmaduros de acuerdo al aspecto del COCC. El grupo dos con 7 muestras, presentó un pico a 457.2 nm, todos estos ovocitos fueron catalogados como maduros o preovulatorios. El grupo tres presentó una combinación de dos picos del primero a 416.4 nm y el segundo a 457.9 nm, con solo tres muestras de LF, con dos ovocitos clasificados como inmaduros y uno atrésico. El cuarto grupo con 5 LF, también presentó dos picos: el primero a 413.6 nm y otro a 562 nm, dos de estos ovocitos fueron clasificados como atrésicos y los restantes como preovulatorio. En este estudio no se encontró correlación entre los niveles de proteínas, estradiol y progesterona con la morfología del COCC. Se concluye que la presencia de estos picos de máxima absorbancia pueden ser de gran utilidad clínica para corroborar el estado de madurez del ovocito, sobre todo en los casos de GIFT en donde la transferencia de los mismos es inmediata, y se puede elegir con mayor seguridad los ovocitos maduros