RESUMO
Warfarin-dosing algorithms combine clinical factors and dosing history with the current international normalized ratio (INR) to estimate the therapeutic warfarin dose. Unfortunately, these approaches can result in an overdose if the INR is spuriously low. Our goal was to develop an alert mechanism based on prior INRs in addition to the current INR. Using data from the Genetics InFormatics Trial (GIFT) of Warfarin to Prevent DVT, we analyzed warfarin dose estimates for days 3 through 11 that were ≥10 % higher than an average of the previous two dose estimates. We fit a stepwise mixed model to current and prior dose estimates, and subsequently compared the root-mean-square-error (RMSE) in predicting the final therapeutic dose using the GIFT algorithm versus the mixed model. From 861 dosing records (obtain from 556 patients), 646 dosing records (75 %) were randomly selected for the derivation cohort and 215 dosing records (25 %) for the validation cohort. Using one prior dose estimate improved the accuracy of the warfarin dose estimate. Compared to a dose estimate based on current INR (GIFT algorithm), the mixed model reduced the RMSE in the derivation cohort by 0.0015 mg/day (RMSE 0.2079 vs. 0.2094; p = 0.039). In the validation cohort, the RMSE reduction was not significant. A mixed model of dose estimates based on the current and most recent INRs shows potential to improve the safety of warfarin dosing. Clinicians should be cautious about aggressively escalating the warfarin dose after an INR that is lower than expected.
Assuntos
Algoritmos , Coeficiente Internacional Normatizado/métodos , Modelos Cardiovasculares , Trombose Venosa/prevenção & controle , Varfarina/administração & dosagem , Varfarina/farmacocinética , Idoso , Feminino , Humanos , Masculino , Trombose Venosa/sangue , Varfarina/efeitos adversosRESUMO
The risk of venous thromboembolism (VTE) is higher after the total hip or knee replacement surgery than after almost any other surgical procedure; warfarin sodium is commonly prescribed to reduce this peri-operative risk. Warfarin has a narrow therapeutic window with high inter-individual dose variability and can cause hemorrhage. The genetics-informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT) is a 2 × 2 factorial-design, randomized controlled trial designed to compare the safety and effectiveness of warfarin-dosing strategies. GIFT will answer two questions: (1) does pharmacogenetic (PGx) dosing reduce the rate of adverse events in orthopedic patients; and (2) is a lower target international normalized ratio (INR) non-inferior to a higher target INR in orthopedic participants? The composite primary endpoint of the trial is symptomatic and asymptomatic VTE (identified on screening ultrasonography), major hemorrhage, INR ≥ 4, and death.
Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Oxigenases de Função Mista/genética , Trombose Venosa/tratamento farmacológico , Varfarina , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Genótipo , Humanos , Período Pós-Operatório , Trombose Venosa/genética , Trombose Venosa/patologia , Trombose Venosa/cirurgia , Vitamina K Epóxido Redutases , Varfarina/administração & dosagem , Varfarina/efeitos adversos , Varfarina/farmacocinéticaRESUMO
This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
Assuntos
Alelos , Testes Genéticos/normas , Farmacogenética/normas , Terminologia como Assunto , Genes , Testes Genéticos/tendências , Variação Genética , Humanos , Farmacogenética/tendências , Medicina de PrecisãoRESUMO
Smoking marijuana during pregnancy can cause health problems in the neonate. The detection of exposure can guide treatment to meet the short- and long-term medical and social needs. Umbilical cord tissue was analyzed for 11-nor-delta-9-carboxy-tetrahydrocannabinol (THC-COOH) by gas chromatography-mass spectrometry (GC-MS), and compared with ultra-sensitive enzyme-linked immunosorbent assay (ELISA) and liquid chromatography time-of-flight mass spectrometry (LC-TOF-MS). Fortified extracts of drug-free cord tissue were used to determine the sensitivity and specificity of the LC-TOF-MS and ELISA assays, and 16 de-identified patient specimens previously analyzed by GC-MS were tested for THC-COOH by both methods. The cutoffs were 0.050 ng/g for the GC-MS assay, 0.1 ng/g for the ELISA assay and 1 ng/g for the LC-TOF-MS assay. Twelve specimens were negative by all three methods. Seven specimens were positive by GC-MS with concentrations from 0.066 to 6.095 ng/g. ELISA and LC-TOF-MS did not detect one specimen that was positive by GC-MS. LC-TOF-MS missed one specimen that was detected by GC-MS and ELISA. Five positive specimens were detected by all three methods. These results were consistent with the cutoff for each method. No false positives were detected by LC-TOF-MS or ELISA. Umbilical cord tissue is a viable specimen for the detection of in utero marijuana exposure. ELISA and GC-MS were more sensitive than LC-TOF-MS for the detection of THC-COOH in cord tissue, with the GC-MS method providing superior sensitivity.
Assuntos
Dronabinol/análise , Alucinógenos/análise , Fumar Maconha/sangue , Cordão Umbilical/química , Adulto , Ensaio de Imunoadsorção Enzimática , Reações Falso-Positivas , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Indicadores e Reagentes , Recém-Nascido , Espectrometria de Massas , Gravidez , Reprodutibilidade dos Testes , Detecção do Abuso de SubstânciasRESUMO
Well-characterized genes that affect warfarin metabolism (cytochrome P450 (CYP) 2C9) and sensitivity (vitamin K epoxide reductase complex 1 (VKORC1)) explain one-third of the variability in therapeutic dose before the international normalized ratio (INR) is measured. To determine genotypic relevance after INR becomes available, we derived clinical and pharmacogenetic refinement algorithms on the basis of INR values (on day 4 or 5 of therapy), clinical factors, and genotype. After adjusting for INR, CYP2C9 and VKORC1 genotypes remained significant predictors (P < 0.001) of warfarin dose. The clinical algorithm had an R(2) of 48% (median absolute error (MAE): 7.0 mg/week) and the pharmacogenetic algorithm had an R(2) of 63% (MAE: 5.5 mg/week) in the derivation set (N = 969). In independent validation sets, the R(2) was 26-43% with the clinical algorithm and 42-58% when genotype was added (P = 0.002). After several days of therapy, a pharmacogenetic algorithm estimates the therapeutic warfarin dose more accurately than one using clinical factors and INR response alone.
Assuntos
Variação Genética/genética , Coeficiente Internacional Normatizado/normas , Integração de Sistemas , Varfarina/administração & dosagem , Idoso , Hidrocarboneto de Aril Hidroxilases/genética , Estudos de Coortes , Citocromo P-450 CYP2C9 , Relação Dose-Resposta a Droga , Feminino , Genótipo , Humanos , Coeficiente Internacional Normatizado/métodos , Masculino , Pessoa de Meia-Idade , Oxigenases de Função Mista/genética , Farmacogenética/métodos , Vitamina K Epóxido Redutases , Varfarina/farmacocinéticaRESUMO
BACKGROUND: Tacrolimus, an immunosuppressive drug discovered in 1984, is used to decrease the risk of organ rejection. The 2007 European Consensus Conference on Tacrolimus Optimization recommended the use of methods with a limit of quantitation at < or =1ng/ml for monitoring low dose tacrolimus therapy. METHODS: The performance characteristics of the Abbott i2000 Tacrolimus assay were evaluated and compared to LC-MS/MS and Abbott IMx methods. RESULTS: The limit of detection of the Abbott i2000 method was 0.21ng/ml. Total imprecision was 6.9, 5.8 and 4.2% at three target concentrations of tacrolimus (3.2, 8.5 and 15.9ng/ml) respectively. The method was linear up to 30ng/ml. The limit of quantitation (LOQ) was 0.5ng/ml. Correlation of patient specimen results between the Abbott i2000 method and LC-MS/MS yielded a Deming slope of 1.072ng/ml (CI 1.005 to 1.140), r=0.952 and an intercept of -0.491ng/ml (CI -1.387 to 0.405). The mean bias, as determined by Bland-Altman analysis, was 0.36ng/ml. Comparing results generated by the widely used Abbott IMx assay with LC-MS/MS and Architect i2000 methods yielded Deming slopes of 1.062 and 0.973, with intercepts of -0.214ng/ml and -0.01ng/ml respectively. For both comparisons, r=0.97. The corresponding mean bias of results generated by the Abbott IMx assay (Bland-Altman plots) was 0.53ng/ml vs LC-MS/MS and -0.38ng/ml vs the Architect i2000. CONCLUSIONS: The Architect i2000 method is a sensitive and highly precise method that achieves a LOQ of <1.0 ng/ml and demonstrated overall accuracy of tacrolimus measurements within 0.4ng/ml.