Diferencias entre agalsidasa alpha y agalsidasa Beta en el tratamiento de la enfermedad de Fabry / Differences between agalsidase alpha and agalsidase Beta in the treatment of Fabry disease

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Gene-gene interactions between DRD3, MRP4 and CYP2B6 polymorphisms and its influence on the pharmacokinetic parameters of efavirenz in HIV infected patients.

Genetic factors have a significant impact on the PK variability of EFV, much higher than other non-genetic factors, such as demography. In this work we have performed a comprehensive PG analysis of genes encoding the major metabolizing enzymes and transporters of EFV, establishing a clear relationship between the PK parameters and genetic factors, which explain 50% of the variability in EFV PK parameters. The most relevant associations for metabolizing enzymes were found in CYP2B6 (rs3745274), in agreement with previous studies. The influence of transporters on the kinetics of EFV was also proved with significant correlations between the PK parameters of EFV and MRP4 (rs1751034, rs2274407). Analysis of gene-gene interactions with CYP2B6 was particularly useful to reinforce the role of MRP4 and to reveal unknown associations, such as that of DRD3. However, the role of DRD3 cannot be a direct effect but an indirect one due to physical proximity of NAT and the DRD3 locus in the genome.

CYP3A4 polymorphism and lopinavir toxicity in an HIV-infected pregnant woman.

Cytochrome P450 (CYP) 3A4 has been considered to be the most important enzyme system for metabolism of lopinavir/ritonavir (LPV/r), a widely used HIV protease inhibitor (PI) recommended during pregnancy. Herein we present a clinical case of a pregnant HIV-infected woman who was taking standard doses of LPV/r, 400/100 mg twice daily. The trough plasma concentrations for LPV were fourfold above that recommended for PI-pretreated patients and toxicity associated with LPV/r and PI regimens was observed. These high concentrations continued after delivery in spite of a dosage reduction. The pharmacogenetic analysis revealed a genetic polymorphism in the CYP3A4 gene that encodes a non-functional protein. The pharmacokinetic study could indicate the occurrence of a phenomenon of non-linear pharmacokinetics which would justify why dosage reduction after pregnancy did not proportionally affect the patient's degree of exposure to the drug. In addition, an increment in CYP3A activity during pregnancy could explain lower LPV/r exposure during this period compared to postpartum, despite the impaired activity of CYP3A4 caused by the polymorphism.

Population pharmacokinetic/pharmacogenetic model of lopinavir/ritonavir in HIV-infected patients.

AIM: This study aims to develop a population pharmacokinetic/pharmacogenetic model for lopinavir/ritonavir (LPV/r) in European HIV-infected patients. MATERIALS & METHODS: A total of 693 LPV/r plasma concentrations were assessed and 15 single-nucleotide polymorphisms were genotyped. The population pharmacokinetic/pharmacogenetic model was created using a nonlinear mixed-effect approach (NONMEM® v.7.2.0., ICON Development Solutions, Dublin, Ireland). RESULTS: Covariates significantly related to LPV/r apparent clearance (CL/F) were ritonavir trough concentration (RTC), BMI, high-density lipoprotein cholesterol (HDL-C) and certain single-nucleotide polymorphisms in genes encoding for metabolizing enzymes, which are representable as follows: CL/F = (0.216BMI + 0.0125HDL-C) × 0.713RTC × 1.26rs28371764[C/T] × 0.528rs6945984[C/C] × 0.302 CYP3A4[1461insA/del] Conclusion: The LPV/r standard dose appears to be appropriate for the rs28371764[C/T] genotype. However, lower doses should be recommended for the rs6945984[C/C] and CYP3A4[1461insA/del] genotypes and even for those patients without any of these variants, as the standard dose seems to be higher than that which is required in order to achieve therapeutic levels.

Impact of a pharmaceutical care program on clinical evolution and antiretroviral treatment adherence: a 5-year study.

BACKGROUND: Antiretroviral treatments (ART) form the basis of adequate clinical control in human immunodeficiency virus-infected patients, and adherence plays a primary role in the grade and duration of the antiviral response. The objectives of this study are: (1) to determine the impact of the implementation of a pharmaceutical care program on improvement of ART adherence and on the immunovirological response of the patients; and (2) to detect possible correlations between different adherence evaluation measurements. METHODS: A 60-month long retrospective study was conducted. Adherence measures used were: therapeutic drug monitoring, a simplified medication adherence questionnaire, and antiretroviral dispensation records (DR). The number of interviews and interventions related to adherence made for each patient in yearly periods was related to the changes in the adherence variable (measured with DR) in these same yearly periods. The dates when the laboratory tests were drawn were grouped according to proximity with the study assessment periods (February-May, 2005-2010). RESULTS: A total of 528 patients were included in the study. A significant relationship was observed between the simplified medication adherence questionnaire and DR over the 60-month study period (P < 0.01). Improvement was observed in the mean adherence level (P < 0.001), and there was a considerable decrease in the percentage of patients with CD4+ lymphocytes less than 200 cells/mm(3) (P < 0.001). A relationship was found between the number of patients with optimum adherence levels and the time that plasma viral load remained undetected. The number of interviews and interventions performed in each patient in the first 12 months from the onset of the pharmaceutical care program (month 6), was related to a significant increase in adherence during this same time period. CONCLUSION: The results suggest that the establishment and permanence of a pharmaceutical care program may increase ART adherence, increase permanence time of the patient with undetectable plasma viral loads, and improve patients' lymphocyte count.

Nuevas estrategias en la optimización posológica de lopinavir/ritonavir en pacientes infectados por el virus de la inmunodeficiencia humana / No disponible

El lopinavir/ritonavir (LPV/r) ha demostrado eflcacia virológica e inmunológica en el tratamiento antirretroviral (TAR) combinado, tanto en pacientes naïve como pretratados. Además presenta una alta barreragenética al desarrollo de resistencias y su perfll de tolerancia es aceptable, aunque son frecuentes alteraciones gastrointestinales y del perfll lipídico. Se revisan diferentes estrategias utilizadas en la optimización del TAR con este fármaco en la práctica clínica diaria, haciendo especial incidencia en la monitorización de concentraciones plasmáticas de LPV/r y la caracterización farmacogenética de las principales isoenzimas responsables de su metabolismoy transporte. En este sentido, la correlación del genotipo con el fenotipo establecida en la monitorización de niveles de LPV/r facilitaría la individualización posológica de los tratamientos con este fármaco. Así mismo, se revisa la estrategia de simpliflcación del tratamiento a monoterapia, lo que permitiría incrementar la seguridad y disminuir los costes (AU)

Lopinavir/ritonavir (LPV/r) has demonstrated virological and immunological efflcacy in the combined antiretroviral treatment (cART), in both naïve and experienced patients. Furthermore, LPV/r showed a high barrier to the development of resistance. Although generally well tolerated, adverse gastrointestinal side effects and metabolic disorders are frequent. The different tools used to optimise the cART with this drug combination in the daily clinical practice, emphasising the therapeutic drug monitoring (TDM) of LPV/r and the genetic analysis of the main enzymes responsible for the metabolism and transport, are reviewed. The relationship between phenotype and genotype, established through TDM, could be useful for the physician to improve the clinical management of the HIV infection, due to the possibility of individualising the dose with this drug. Monotherapyis also reviewed as a new strategy used in the simpliflcation of the treatment with this drug, which could increase safety and reduce costs (AU)

[New strategies in the optimisation of lopinavir/ritonavir doses in human immunodeficiency virus-infected patients]. / Nuevas estrategias en la optimización posológica de lopinavir/ritonavir en pacientes infectados por el virus de la inmunodeficiencia humana.

Lopinavir/ritonavir (LPV/r) has demonstrated virological and immunological efficacy in the combined antiretroviral treatment (cART), in both naïve and experienced patients. Furthermore, LPV/r showed a high barrier to the development of resistance. Although generally well tolerated, adverse gastrointestinal side effects and metabolic disorders are frequent. The different tools used to optimise the cART with this drug combination in the daily clinical practice, emphasising the therapeutic drug monitoring (TDM) of LPV/r and the genetic analysis of the main enzymes responsible for the metabolism and transport, are reviewed. The relationship between phenotype and genotype, established through TDM, could be useful for the physician to improve the clinical management of the HIV infection, due to the possibility of individualising the dose with this drug. Monotherapy is also reviewed as a new strategy used in the simplification of the treatment with this drug, which could increase safety and reduce costs.

Population pharmacokinetics of lopinavir/ritonavir (Kaletra) in HIV-infected patients.

BACKGROUND: A relationship between plasma concentrations and viral suppression in patients receiving lopinavir (LPV)/ritonavir (RTV) has been observed. Therefore, it is important to increase our knowledge about factors that determine interpatient variability in LPV pharmacokinetics (PK). METHODS: The study, designed to develop and validate population PK models for LPV and RTV, involved 263 ambulatory patients treated with 400/100 mg of LPV/RTV twice daily. A database of 1110 concentrations of LPV and RTV (647 from a single time-point and 463 from 73 full PK profiles) was available. Concentrations were determined at steady state using high-performance liquid chromatography with ultraviolet detection. PK analysis was performed with NONMEM software. Age, gender, height, total body weight, body mass index, RTV trough concentration (RTC), hepatitis C virus coinfection, total bilirubin, hospital of origin, formulation and concomitant administration of efavirenz (EFV), saquinavir (SQV), atazanavir (ATV), and tenofovir were analyzed as possible covariates influencing LPV/RTV kinetic behavior. RESULTS: Population models were developed with 954 drug plasma concentrations from 201 patients, and the validation was conducted in the remaining 62 patients (156 concentrations). A 1-compartment model with first-order absorption (including lag-time) and elimination best described the PK. Proportional error models for interindividual and residual variability were used. The final models for the drugs oral clearance (CL/F) were as follows: CL/F(LPV)(L/h)=0.216·BMI·0.81(RTC)·1.25(EFV)·0.84(ATV); CL/F(RTV)(L/h) = 8.00·1.34(SQV)·1.77(EFV)·1.35(ATV). The predictive performance of the final population PK models was tested using standardized mean prediction errors, showing values of 0.03 ± 0.74 and 0.05 ± 0.91 for LPV and RTV, and normalized prediction distribution error, confirming the suitability of both models. CONCLUSIONS: These validated models could be implemented in clinical PK software and applied to dose individualization using a Bayesian approach for both drugs.

The convergence of therapeutic drug monitoring and pharmacogenetic testing to optimize efavirenz therapy.

The aim of this study was to show the benefits of combining therapeutic drug monitoring (TDM) and pharmacogenetic analyses to optimize efavirenz (EFV) therapy. Patients were selected to minimize nongenetic differences between patients: 32 HIV adherent patients without drug interactions treated with an EFV nonindividualized dose over at least 1 year and included in a TDM program were genotyped according to minimum steady-state concentrations (C ss min). The EFV plasma concentrations (n = 158) were quantified by high-performance liquid chromatography-ultraviolet, and genetic polymorphisms were analyzed using the PHARMAchip. Central nervous system side effects were assessed systematically. Genetic polymorphisms were detected in 79.2% of patients with EFV Css min outside the therapeutic range (1-4 mg/L), showing the high diagnostic efficacy of combining TDM with pharmacogenetic testing. CYP2B6 (516 G>T) polymorphisms were associated with a significant decrease in EFV plasma clearance in 80% of the poor metabolizer patients (G/T, T/T). All homozygous patients had C ss min greater than 4 mg/L, 75% of them showing central nervous system side effects. For such patients, pharmacogenetic testing with TDM could be advantageous because the polymorphism is a determinant of these circumstances and TDM would allow reductions in dose to be specified without assuming an equal dose for any given genotype. In fact, poor metabolizer patients required less than a 600 mg standard starting dose, implying that if CYP2B6 screening were available, EFV therapy could be started at 400 mg and later TDM-individualized. The results of this study clarify the genotype versus phenotype debate for optimizing drug therapy. Pharmacogenetic testing together with TDM links genotype to phenotypic differences in drug concentrations and adverse events, providing additional support for dosage adjustment and a more efficient use of both approaches. As genotype screens become cheaper, and in combination with TDM, adjusting dosages in the light of genetic polymorphisms will become a reality.

Long-term efficacy and safety of efavirenz dose reduction to 200 mg once daily in a Caucasian patient with HIV.

A 48-year-old Caucasian male patient presented with severe adverse drug events (ADEs) while being treated with a standard dose (600 mg/day) of efavirenz. The patient's clinical course was favourable; however, he also described intense nightmares, cramps in his legs and anxiety disturbances that made him highly irritable. Measurement of the patient's efavirenz plasma concentrations revealed a mean minimum steady-state concentration during a dosage interval (C(min,ss)) of 12.7 mg/L, which was much higher than that recommended for this drug (therapeutic range 1-4 mg/L). Consequently, the dose of efavirenz was reduced to 400 mg/day, which resulted in a decrease in the frequency of ADEs. Subsequent genotype testing showed that the patient was homozygous for both the CYP2B6-G516T (T/T) and CYP2B6-A785G (G/G) alleles; these polymorphisms are associated with reduced enzymatic activity and elevated efavirenz plasma concentrations. Because of this and the fact that the patient's mean efavirenz C(min,ss) was still high (4.6 mg/L), a second dosage reduction was undertaken, to 200 mg/day. This also resulted in a reduction in ADEs. At present, the patient's CD4+ levels remain stable, his viral load continues to be undetectable and the mean efavirenz C(min,ss) is within the therapeutic range (2.7 mg/L).

[Pharmacogenetics in oncology]. / Farmacogenética en oncología.

Pharmacogenetics studies the relationship between genetic polymorphisms and individual responses to drugs. In recent years, there has been a great progress in our knowledge of the effects of drug-metabolizing enzymes and molecular target genetic polymorfisms on cancer chemotherapy. Pharmacogenetics focuses on the prediction of drug efficacy and toxicity based on a patient's genetic profile with routinely applicable genetic tests to select the most appropriate medication at optimal doses for each individual patient. Two years ago the FDA approved one genetic test to detect patients with increased risk of severe toxicity associated with irinotecan therapy. There have also been commercialized genetic chips to genotyping two cytochrome P450 enzymes at the same time. Prospectively, stratifying patients based on genotype may identify subpopulations likely to experience severe toxicity or to derive benefit from a particular treatment strategy, helping us move toward the ultimate goal of individualized therapy. In this review, we describe the clinical effects of polymorphisms that may influence cancer chemotherapy.

Farmacogenética en oncología / Pharmacogenetics in oncologybitm

La farmacogenética estudia la relación entre el polimorfismo genético y la respuesta individual a los fármacos. En los últimos años se ha producido un gran avance en el conocimiento de los polimorfismosgenéticos que afectan tanto a las enzimas involucradas en la activación y/o destoxificación de los agentes quimioterápicos como a determinadas dianas moleculares implicadas en el tratamiento del cáncer. El objetivo de la farmacogenética es predecir la eficacia y la toxicidadde los fármacos en función del perfil genético de cada paciente, lo que permitirá seleccionar el medicamento más apropiado y las dosis óptimas para cada tipo de cáncer y cada paciente concreto. Hace aproximadamente 2 años la Food and Drug Administration aprobó untest genético para la identificación de los pacientes susceptibles de presentar una elevada toxicidad por irinotecán, en quienes deberá reducirse la dosis inicial del fármaco. También se han comercializado chips genéticos para la genotipificación simultánea de 2 enzimas del citocromo P450. La farmacogenética permitirá identificar y definir poblaciones específicas de pacientes en quienes el beneficio terapéuticopuede ser máximo, lo que supondrá un tratamiento más efectivo e individualizado.En esta revisión se describen los principales polimorfismos genéticos conocidos que pueden influir en la quimioterapia del cáncer

Pharmacogenetics studies the relationship between genetic polymorphisms and individual responses to drugs. In recent years, there has been a great progress in our knowledge of the effects of drug-metabolizingenzymes and molecular target genetic polymorfisms on cancer chemotherapy. Pharmacogenetics focuses on the prediction of drug efficacy and toxicity based on a patient´s genetic profile with routinely applicable genetic tests to select the most appropriate medication at optimal doses for each individual patient. Two years ago the FDA approved one genetic test to detect patients with increased risk of severe toxicity associated with irinotecan therapy. There have also been commercialized genetic chips to genotyping two cytochrome P450enzymes at the same time. Prospectively, stratifying patients based on genotype may identify subpopulations likely to experience severe toxicity or to derive benefit from a particular treatment strategy, helpingus move toward the ultimate goal of individualized therapy.In this review, we describe the clinical effects of polymorphisms that may influence cancer chemotherapy