Cost-Utility Study of Warfarin Genotyping in the VACHS Affiliated Anticoagulation Clinic of Puerto Rico.

OBJECTIVE: To evaluate the cost-utility of the pharmacogenetic-guided dosing of warfarin (PGx), when compared to the current dosing strategy. METHODS: A Markov model was developed to assess the impact of the genotypingguided warfarin dosing in a hypothetical cohort of patients. The model was based on the percentage of time patients spent within the therapeutic international normalized ratio (INR) range (PTTR). PTTR estimates and genotype distribution were derived from a cohort of patients (n = 206) treated in the Veteran Affairs Caribbean Healthcare System (VACHS) and from results of other research study. Costs, utilities and event probability data were obtained from the literature. Probabilistic and one-way sensitivity analyses were performed to explore the range of plausible results. Willingness to pay was established at $50,000 per Quality Adjusted Life Year (QALY) gained. RESULTS: According to our model, the PGx strategy showed a QALY increase of 0.0021, with an increase in total cost of $272. This corresponds to an incremental cost-utility ratio (ICUR) of $127,501, ranging from $95,690 to $148,611. One-way sensitivity analysis revealed that the ICURs were more sensitive to the cost of genotyping and the effect of genotyping on the PTTR. CONCLUSION: Our model suggests that the warfarin PGx was not superior to the standard of care dosing strategy in terms of cost-utility.

Warfarin Anticoagulation Therapy in Caribbean Hispanics of Puerto Rico: A Candidate Gene Association Study.

Existing algorithms account for ~50% of observed variance in warfarin dose requirements after including common polymorphisms. However, they do not perform as well in populations other than Caucasians, in part because some ethno-specific genetic variants are overlooked. The objective of the present study was to identify genetic polymorphisms that can explain variability in warfarin dose requirements among Caribbean Hispanics of Puerto Rico. Next-Generation Sequencing of candidate genes CYP2C9 and VKORC1 and genotyping by DMET® Plus Assay of cardiovascular patients were performed. We also aimed at characterizing the genomic structure and admixture pattern of this study cohort. Our study used the Extreme Discordant Phenotype approach to perform a case-control association analysis. The CYP2C9 variant rs2860905, which was found in all the major haplotypes occurring in the Puerto Rican population, showed stronger association with warfarin sensitivity (<4 mg/day) than common variants CYP2C9*2 and CYP2C9*3. Although, CYP2C9*2 and CYP2C9*3 are separately contained within two of the haplotypes, 10 subjects with the sensitive phenotype were carriers of only the CYP2C9 rs2860905 variant. Other polymorphisms in CES2 and ABCB1 were found to be associated with warfarin resistance. Incorporation of rs2860905 in a regression model (R2 = 0.63, MSE = 0.37) that also includes additional genetics (i.e., VKORC1-1639 G>A; CYP2C9 rs1856908; ABCB1 c.IVS9-44A>G/ rs10276036; CES2 c.269-965A>G/ rs4783745) and non-genetic factors (i.e., hypertension, diabetes and age) showed better prediction of warfarin dose requirements than CYP2C9*2 and CYP2C9*3 combined (partial R2 = 0.132 vs. 0.023 and 0.007, respectively, p < 0.001). The genetic background of Puerto Ricans in the study cohort showed a tri-hybrid admixture pattern, with a slightly higher than expected contribution of Native American ancestry (25%). The genomic diversity of Puerto Ricans is highlighted by the presence of four different major haplotype blocks in the CYP2C9 locus. Although, our findings need further replication, this study contributes to the field by identifying novel genetic variants that increase predictability of stable warfarin dosing among Caribbean Hispanics.

Análisis inferencial de las potencialidades de promoción de absorción de una familia de 1-O-alquil gliceroles / Inferable analysis related to promotion of the absorption potentialities from 1-O-alkyl glycerol family

La interrelación entre las propiedades físico-químicas y la biodisponibilidad de una familia de 1-O-alquil gliceroles son discutidas, se han utilizado como compuestos de referencia, moléculas que presentan una analogía estructural-funcional con estos compuestos, los cuales han sido reconocidos como agentes promotores clase I, de alta capacidad. El enfoque TOPS-MODE (ModesLab) fue utilizado para estimar los momentos espectrales, con diferentes ponderaciones, como descriptores de las propiedades físico-químicas más relevantes utilizadas en los modelos predictivos de permeabilidad intestinal obtenidos, e interpretar estos en términos de contribución de grupos funcionales de los 1-O-alquil gliceroles. A partir de este análisis se establecieron interpretaciones de tipo inferencial sobre las reales potencialidades teóricas de esta familia para su evaluación perspectiva como agentes promotores de absorción clase I. Este enfoque de tamizaje in sílico asistido por computadora permitió postular que los 1-O-alquil gliceroles, en particular el 1-O-hexadecil glicerol y 1-O-octadecil glicerol, son excelentes candidatos para demostrar su elevada capacidad promotora en estudios in vivo, los que han alcanzado altos niveles porcentuales de biodisponibilidad (> 90 por ciento). Se concluye, según análisis por discriminante, que todos los miembros de la familia presentaron potencialidades para la absorción gastrointestinal(AU)

The interrelation among the physical-chemical properties and the bioavailability of a 1-O-alkyl glycerol family is discussed. As reference compounds we used molecules presenting a structural-functional similarity with these compounds, which have been recognized as class I high quality promoting agents. TOPS-MODE approach (ModesLab) was used to estimate spectral moments with different weighing as descriptors of the more relevant physical-chemical properties used in the achieved predictive models of intestinal permeability, and its interpretation in terms of contribution of 1-O-alkyl glycerols functional groups of. From this analysis we established inferred interpretations on the theoretical potentials of this family for its prospective evaluation as promoting agents of class I absorption. This computer-assisted in silico screening approach allowed us to call for that 1-O-alkin glycerols, particularly in the 1-O-hexadecyl glycerol, and 1-O-octadecil glycerol, are excellent candidates to demonstrate its high promotion capacity according to in vivo studies, which have gained percentage high levels of bioavailability (> 90 ). We conclude that according a discriminating analysis, all family members had potentials for gastrointestinal absorption(AU)

Análisis inferencial de las potencialidades de promoción de absorción de una familia de 1-O-alquil gliceroles / Inferable analysis related to promotion of the absorption potentialities from 1-O-alkyl glycerol family

La interrelación entre las propiedades físico-químicas y la biodisponibilidad de una familia de 1-O-alquil gliceroles son discutidas, se han utilizado como compuestos de referencia, moléculas que presentan una analogía estructural-funcional con estos compuestos, los cuales han sido reconocidos como agentes promotores clase I, de alta capacidad. El enfoque TOPS-MODE (ModesLab) fue utilizado para estimar los momentos espectrales, con diferentes ponderaciones, como descriptores de las propiedades físico-químicas más relevantes utilizadas en los modelos predictivos de permeabilidad intestinal obtenidos, e interpretar estos en términos de contribución de grupos funcionales de los 1-O-alquil gliceroles. A partir de este análisis se establecieron interpretaciones de tipo inferencial sobre las reales potencialidades teóricas de esta familia para su evaluación perspectiva como agentes promotores de absorción clase I. Este enfoque de tamizaje in sílico asistido por computadora permitió postular que los 1-O-alquil gliceroles, en particular el 1-O-hexadecil glicerol y 1-O-octadecil glicerol, son excelentes candidatos para demostrar su elevada capacidad promotora en estudios in vivo, los que han alcanzado altos niveles porcentuales de biodisponibilidad (> 90 por ciento). Se concluye, según análisis por discriminante, que todos los miembros de la familia presentaron potencialidades para la absorción gastrointestinal.

The interrelation among the physical-chemical properties and the bioavailability of a 1-O-alkyl glycerol family is discussed. As reference compounds we used molecules presenting a structural-functional similarity with these compounds, which have been recognized as class I high quality promoting agents. TOPS-MODE approach (ModesLab) was used to estimate spectral moments with different weighing as descriptors of the more relevant physical-chemical properties used in the achieved predictive models of intestinal permeability, and its interpretation in terms of contribution of 1-O-alkyl glycerols functional groups of. From this analysis we established inferred interpretations on the theoretical potentials of this family for its prospective evaluation as promoting agents of class I absorption. This computer-assisted in silico screening approach allowed us to call for that 1-O-alkin glycerols, particularly in the 1-O-hexadecyl glycerol, and 1-O-octadecil glycerol, are excellent candidates to demonstrate its high promotion capacity according to in vivo studies, which have gained percentage high levels of bioavailability (> 90 ). We conclude that according a discriminating analysis, all family members had potentials for gastrointestinal absorption.