New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model.

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3-5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.

Semi-Mechanistic Pharmacokinetic Model to Guide the Dose Selection of Nimotuzumab in Patients with Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disease characterized by an overexpression of epidermal growth factor receptor (EGFR). Nimotuzumab is a recombinant humanized monoclonal antibody against human EGFR. The aim of this study was to develop a population pharmacokinetic model for nimotuzumab and to identify demographic and clinical predictive factors of the pharmacokinetic variability. The population pharmacokinetics (PopPK) of nimotuzumab was characterized using a nonlinear mixed-effect modeling approach with NONMEM®. A total of 422 log-transformed concentration-versus-time datapoints from 20 patients enrolled in a single-center phase I clinical trial were used. Quasi steady state approximation of the full TMDD (target-mediated drug disposition) model with constant target concentration best described the concentration-time profiles. A turnover mediator was included which stimulates the non-specific clearance of mAb in the central compartment in order to explain the reduced levels at higher doses. Covariates had no influence on the PK (pharmacokinetics) parameters. The model was able to detect that the maximum effective dose in ADPKD subjects is 100 mg. The developed PopPK model may be used to guide the dose selection for nimotuzumab during routine clinical practice in patients with polycystic kidney disease. The model will further support the ongoing investigations of the PK/PD relationships of nimotuzumab to improve its therapeutic use in other disease areas.

Assessment of the clinical utility of pharmacogenetic guidance in a comprehensive medication management service.

INTRODUCTION: Pharmacists are poised to be the health care professionals best suited to provide medication-related consults and services based on a patient's genetics. Despite its potential benefits, the implementation of pharmacogenetic (PGx) testing into primary clinical settings has been slow among medically underserved populations. To our knowledge, this is the first time that PGx-driven recommendations have been incorporated into a Comprehensive Medication Management (CMM) service in a Hispanic population. OBJECTIVES: The aim of this study is to evaluate the clinical utility of adding PGx guidance into pharmacist-driven CMM. METHODS: This is a pre- and post-interventional design study. Patients were recruited from a psychologist's clinic. A total of 24 patients had a face-to-face interview with a pharmacist to complete a CMM, Personal Medication Record, and Medication-Related Action Plan (MAP) blind to PGx findings. Collected buccal DNA samples were genotyped using drug-metabolizing enzymes and transporters (DMET) Plus Array. RESULTS: The pharmacist generated new MAPs for each patient based on PGx results. Genetic variants that could potentially affect the safety and effectiveness of at least one drug in the pharmacotherapy were identified in 96% of patients, for whom the pharmacist changed the initial recommendations. Polymorphisms in genes encoding for isoenzymes CYP2D6, CYP2C19, and CYP2C9 were identified in 83%, 52%, and 41% of patients, respectively. Pharmacists performing CMM identified 22 additional medication problems after PGx determinations. Moreover, they agreed with the clinical utility of PGx in the studied sample based on perceived value of adding PGx to traditional CMM and its utility in the decision-making process of pharmacists. CONCLUSIONS: The study confirmed the critical role to be played by pharmacists in facilitating the clinical usage of relevant genetic information to optimize drug therapy decisions as well as their involvement on many levels of these multidisciplinary implementation efforts, including championing and leading PGx-guided CMM services.

Teorías acerca de los mecanismos celulares y moleculares en la enfermedad de Alzheimer / Theories about the cellular and molecular mechanisms in Alzheimer's disease

La enfermedad de Alzheimer es neurodegenerativa, progresiva, reconocida como un problema creciente en el orden médico, epidemiológico, sociológico y económico. Afecta aproximadamente al 10 por ciento de la población mayor de 65 años y al 40 por ciento en grupos de 80 años o más. En la presente revisión se abordan aspectos relacionados con su epidemiología, factores de riesgo, mecanismos celulares y moleculares. Estos últimos revelan que la formación de betaamilode y otros derivados de la proteína precursora de amiloide son los principales responsables de los cambios en el cerebro de pacientes con Alzheimer. Se incluyeron además la disfunción mitocondrial y de neurotransmisores, el estrés oxidativo, la inflamación, los trastornos neuroinmunes y tróficos. El conocimiento de estas alteraciones permite dilucidar nuevos blancos terapéuticos(AU)

Alzheimer disease is a neurodegenerative and progressive disease recognized as an increasing problem from the medical, epidemiological, sociological and economic point of view. It approximately affects 10 percent of the population over 65 years old and 40 percent in groups aged 80 and over. Aspects connected with its epidemiology, risk factors, cellular and molecular mechanisms are dealt with in this review. The latter reveal that the formation of amyloid beta and other derivatives of the amyloid precursor protein are the main responsible for the changes in the brain of the patients with Alzheimer. The mitochondrial and neurotransmitter dysfunction, the oxidative stress, inflammation, and the neuroimmune and trophic disorders were also included. The knowledge of these alterations allow to elucidate new therapeutic targets(AU)

Teorías acerca de los mecanismos celulares y moleculares en la enfermedad de Alzheimer / Theories about the cellular and molecular mechanisms in Alzheimer's disease

La enfermedad de Alzheimer es neurodegenerativa, progresiva, reconocida como un problema creciente en el orden médico, epidemiológico, sociológico y económico. Afecta aproximadamente al 10 por ciento de la población mayor de 65 años y al 40 por ciento en grupos de 80 años o más. En la presente revisión se abordan aspectos relacionados con su epidemiología, factores de riesgo, mecanismos celulares y moleculares. Estos últimos revelan que la formación de betaamilode y otros derivados de la proteína precursora de amiloide son los principales responsables de los cambios en el cerebro de pacientes con Alzheimer. Se incluyeron además la disfunción mitocondrial y de neurotransmisores, el estrés oxidativo, la inflamación, los trastornos neuroinmunes y tróficos. El conocimiento de estas alteraciones permite dilucidar nuevos blancos terapéuticos.

Alzheimer disease is a neurodegenerative and progressive disease recognized as an increasing problem from the medical, epidemiological, sociological and economic point of view. It approximately affects 10 percent of the population over 65 years old and 40 percent in groups aged 80 and over. Aspects connected with its epidemiology, risk factors, cellular and molecular mechanisms are dealt with in this review. The latter reveal that the formation of amyloid beta and other derivatives of the amyloid precursor protein are the main responsible for the changes in the brain of the patients with Alzheimer. The mitochondrial and neurotransmitter dysfunction, the oxidative stress, inflammation, and the neuroimmune and trophic disorders were also included. The knowledge of these alterations allow to elucidate new therapeutic targets.