Population pharmacokinetic/pharmacogenetic model for optimization of efavirenz therapy in Caucasian HIV-infected patients.

Despite extensive clinical experience with efavirenz (EFV), unpredictable interindividual variabilities in efficacy and toxicity remain important limitations associated with the use of this antiretroviral. The purpose of this study was to determine the factors affecting EFV pharmacokinetics and to develop a pharmacokinetic/pharmacogenetic (PK/PG) model in a Caucasian population of HIV-infected patients. In total, 869 EFV plasma concentrations from 128 HIV-infected patients treated with EFV were quantitatively assessed using a validated high-performance liquid chromatography technique. All patients were genotyped for 90 single nucleotide polymorphisms (SNPs) in genes coding for proteins involved in the metabolism and transport of EFV, using a MassArray platform provided by Sequenom. The influence of these polymorphisms on EFV pharmacokinetics and the effects of demographic, clinical, biochemical, lifestyle, and concurrent drug covariates were evaluated. Plasma concentrations were fitted by a one-compartment model, with first-order absorption and elimination using nonlinear mixed-effect modeling (NONMEM program). The CYP2B6*6 allele, multidrug resistance-associated protein 4 (MRP4) 1497C → T, and gamma-glutamyltranspeptidase (GGT) were identified as major factors influencing the apparent EFV oral clearance (CL/F), reducing the initial interindividual variability by 54.8%, according to the model CL/F = (12.2 - 0.00279 · GGT) · 0.602(CYP2B6*6 [G/T]) · 0.354(CYP2B6*6 [T/T]) · 0.793(MRP4 1497C → T), where CYP2B6*6 [G/T], CYP2B6*6 [T/T], and MRP4 1497C → T take values of 0 or 1 to indicate the absence or presence of polymorphisms. The detailed genetic analysis conducted in this study identified two of 90 SNPs that significantly impacted CL/F, which might indicate that the remaining SNPs analyzed do not influence this PK parameter, at least in Caucasian populations with characteristics similar to those of our study population.

Influence of the cytochrome P450 2B6 genotype on population pharmacokinetics of efavirenz in human immunodeficiency virus patients.

A population pharmacokinetic model for efavirenz has been developed from therapeutic drug monitoring data in human immunodeficiency virus (HIV)-positive patients by using a nonlinear mixed-effect model. The efavirenz plasma concentrations (n = 375) of 131 patients were analyzed using high-performance liquid chromatography with UV detection. Pharmacokinetic parameters were estimated according to a one-compartment model. The effects of sex, age, total body weight, height, body mass index, and HIV treatment were analyzed. In a subgroup of 32 patients, genetic polymorphisms of the cytochrome P450 2B6 gene (CYP2B6), CYP3A4, and MDR1 were also investigated. Efavirenz oral clearance and the apparent volume of distribution were 9.50 liters/h and 311 liters, respectively. The model included only the effect of CYP2B6 polymorphisms on efavirenz clearance; this covariate reduced the intersubject variability of clearance by about 27%. Patients showing G/T and T/T CYP2B6 polymorphisms exhibited efavirenz clearances that were about 50% and 75% lower than those observed in the patients without these polymorphisms (G/G). Accordingly, to obtain EFV steady-state concentrations within the therapeutic range (1 to 4 mg/liter), it would be advisable to implement a gradual reduction in dose to 400 or 200 mg/day for patients that are intermediate or poor metabolizers, respectively. However, the remaining interindividual variability observed in the pharmacokinetic parameters of the model highlights the need for dose individualization to avoid inadequate exposure to efavirenz and suggests that these recommended doses be used with caution and confirmed by therapeutic drug monitoring and clinical efficacy. The population model can be implemented in pharmacokinetic clinical software for dosage optimization by using the Bayesian approach.

[Evaluation of a health care programme with nursing tutor in a hospital traumatological facility in a hospital, Granada, Spain, 2004]. / Evaluación de un programa de atención sanitaria con enfermera tutora en cirugía de traumatologia en un hospital de Granada, 2004.

BACKGROUND: The current trend in patient care is towards a more humanized and higher-quality healthcare. The objective of the present study was to evaluate the results of implementing a programme of healthcare with a reference nurse who welcomes the patient at hospital admission, visits regularly during hospital stay, and resolves doubts and problems. METHODS: Quasi-experimental study (149 cases and 454 non-tutored controls) in patients admitted for scheduled trauma surgery at the Virgen de las Nieves University Hospital, Granada. Sociodemographic and clinical data were gathered at admission. At 15 days after discharge, patients were administered with an interviewer-administered Zung score and an ad hoc questionnaire on satisfaction with different healthcare aspects during hospital stay and understanding of information received. Bivariate analyses and linear and multivariate logistic regression analyses were performed with a study of confounding variables. RESULTS: For the outcome variable anxiety level non-tutored patients had a B coefficient of 2.64 (p<0,01) in the multivariate linear regression analysis controlling for the other variables in the final model: sex, presence of informal career, professional activity, days of hospital stay and understanding of health information. For the outcome variable inadequate understanding information non-tutored patients showed an odds ratio of 3.48 in the multivariate analysis controlling for educational level and presence of informal career. Satisfaction with he friendliness of health care personnel and with the hospital setting did not significantly difference, although the percentage of dissatisfied patients was higher in the non-tutored group: 15% vs 11% (p= 0.34) and 18% vs 12 % (p= 0.11) respectively. CONCLUSIONS: The implemented continued care programme proved effective for these patients, increasing their understanding of information received and reducing anxiety levels.

Evaluación de un programa de atención sanitaria con enfermera tutora en cirugía de traumatología en un hospital de Granada, 2004 / Evaluation of a health care programme with nursing tutor in a hospital traumatological facility in a hospital. Granada, Spain, 2004

Fundamento: La tendencia actual en la atención al paciente es hacia un aumento de la calidad en los servicios sanitarios. El objetivo de este trabajo fue evaluar los resultados de la aplicación de un programa de atención sanitaria a través de una enfermera de referencia que acogía al paciente al ingreso hospitalario, le visitaba regularmente durante su estancia y le resolvía dudas y problemas. Métodos: Estudio cuasi-experimental realizado en pacientes (149 casos y 454 controles) ingresados para cirugía traumatológica en el Hospital Virgen de las Nieves de Granada. Al ingreso se recogieron variables sociodemográficas y clínicas. A los 15 días tras el alta se les administró la "Escala heteroevaluada de ansiedad de Zung" y un cuestionario ad hoc sobre la satisfacción con diferentes aspectos de la atención sanitaria durante la estancia en el hospital y la comprensión de la información recibida. Se realizó análisis bivariante y análisis de regresión lineal y regresión logística multivariante con estudio de variables confundentes. Resultados: Para la variable nivel de ansiedad los pacientes no tutorizados en el análisis de regresión lineal multivariante tenían un coeficiente B=2,64 (p<0,01), controlando por la otras variables en el modelo final: sexo, presencia de cuidador informal actividad profesional, días de estancia, y comprensión de la información sanitaria. Para la variable de resultado insuficiente comprensión de la información los pacientes no tutorizados tenían una Odds Ratio de 3,48 en el análisis de regresión logística multivariante controlando por educación y presencia de cuidador informal. La satisfacción con la amabilidad del personal y con el medio hospitalario no se modificó significativamente aunque el porcentaje de insatisfacción fue mayor en el grupo no tutorizado, 15% frente a 11% (p= 0,34), y 18% frente a 12% (p=0,11) respectivamente. Conclusiones: El programa de atención continuada aplicado se ha manifestado eficaz para los pacientes, aumentando la comprensión de la información y disminuyendo los niveles de ansiedad (AU)

Background: The current trend in patient care is towards a more humanized and higher-quality healthcare. The objective of the present study was to evaluate the results of implementing a programme of healthcare with a reference nurse who welcomes the patient at hospital admission, visits regularly during hospital stay, and resolves doubts and problems. Methods: Quasi-experimental study (149 cases and 454 non-tutored controls) in patients admitted for scheduled trauma surgery at the Virgen de las Nieves University Hospital, Granada. Sociodemographic and clinical data were gathered at admission. At 15 days after discharge, patients were administered with an interviewer-administered Zung score and anad hoc questionnaire on satisfaction with different healthcare aspects during hospital stay and understanding of information received. Bivariate analyses and linear and multivariate logistic regression analyses were performed with a study of confunding variables. Results: For the outcome variable anxiety level non-tutored patiens had a B coeficient of 2.64 (p<0,01) in the multivariate linear regression analisys controlling for the other variables in the final model: sex, presence of informal carer, professional activitiy, days of hospital stay and understanding of health information. For the outcome variable inadequate understanding information non-tutored patients showed an odds ratio of 3.48 in the multivariate analysis controlling for educational level and presence of informal carer. Satisfaction with he friendliness of health care personnel and with the hospital setting did not significantly diference, although the percentage of dissatisfied patiens was higher in the non-tutored group: 15% vs 11% (p= 0.34) and 18% vs 12 % (p= 0.11) respectively. Conclusions: The implemented continued care programme proved effective for these patients, increasing their understanding of information received and reducing anxiety levels (AU)