Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Farmacovigilancia , Humanos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Bases de Datos Factuales , Factores de Riesgo , Sistemas de Registro de Reacción Adversa a MedicamentosRESUMEN
The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.
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Genómica , Medicina de Precisión , Atención a la Salud , Enfermedad , HumanosRESUMEN
This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.
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Anticoagulantes/administración & dosificación , Citocromo P-450 CYP2C9/genética , Familia 4 del Citocromo P450/genética , Vitamina K Epóxido Reductasas/genética , Warfarina/administración & dosificación , Adulto , Niño , Relación Dosis-Respuesta a Droga , Genotipo , Humanos , Farmacogenética , Guías de Práctica Clínica como AsuntoRESUMEN
OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a potentially severe adverse effect of bisphosphonates (BP). Although the risk of ONJ increases with increasing duration of BP treatment, there are currently no reliable estimates of the ONJ time to onset (TTO). The objective of this study was to estimate the TTO and associated risk factors in BP-treated patients. SUBJECTS AND METHODS: Retrospective analysis of data from 22 secondary care centres in seven countries relevant to 349 patients who developed BP-related ONJ between 2004 and 2012. RESULTS: The median (95%CI) TTO was 6.0 years in patients treated with alendronate (n = 88) and 2.2 years in those treated with zoledronate (n = 218). Multivariable Cox regression showed that dentoalveolar surgery was inversely associated, and the use of antiangiogenics directly associated, with the TTO in patients with cancer treated with zoledronate. CONCLUSIONS: The incidence of ONJ increases with the duration of BP therapy, with notable differences observed with respect to BP type and potency, route of administration and underlying disease. When data are stratified by BP type, a time of 6.0 and 2.2 years of oral alendronate and intravenous zoledronate therapy, respectively, is required for 50% of patients to develop ONJ. After stratification by disease, a time of 5.3 and 2.2 years of BP therapy is required for 50% of patients with osteoporosis and cancer, respectively, to develop ONJ. These findings have significant implications for the design of future clinical studies and the development of risk-reduction strategies aimed at either assessing or modulating the risk of ONJ associated with BP.
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Osteonecrosis de los Maxilares Asociada a Difosfonatos/etiología , Conservadores de la Densidad Ósea/administración & dosificación , Difosfonatos/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Osteonecrosis de los Maxilares Asociada a Difosfonatos/epidemiología , Conservadores de la Densidad Ósea/efectos adversos , Estudios Transversales , Difosfonatos/efectos adversos , Esquema de Medicación , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
We aimed to assess the cost-effectiveness of pharmacogenetic-guided dosing of warfarin in patients with atrial fibrillation (AF) in the United Kingdom and Sweden. Data from EU-PACT, a randomized controlled trial in newly diagnosed AF patients, were used to model the incremental costs per quality-adjusted life-year (QALY) gained by pharmacogenetic-guided warfarin dosing versus standard treatment over a lifetime horizon. Incremental lifetime costs were £26 and 382 Swedish kronor (SEK) and incremental QALYs were 0.0039 and 0.0015 in the United Kingdom and Sweden, respectively. The corresponding incremental cost-effectiveness ratios (ICERs) were £6 702 and 253 848 SEK per QALY gained. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 93% of the simulations in the United Kingdom and below 500 000 SEK in 67% of the simulations in Sweden. Our data suggest that pharmacogenetic-guided dosing of warfarin is a cost-effective strategy to improve outcomes of patients with AF treated with warfarin in the United Kingdom and in Sweden.
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Anticoagulantes/administración & dosificación , Anticoagulantes/economía , Fibrilación Atrial/tratamiento farmacológico , Fibrilación Atrial/economía , Costos de los Medicamentos , Farmacogenética/economía , Pruebas de Farmacogenómica/economía , Warfarina/administración & dosificación , Warfarina/economía , Anciano , Anticoagulantes/efectos adversos , Fibrilación Atrial/diagnóstico , Fibrilación Atrial/genética , Análisis Costo-Beneficio , Citocromo P-450 CYP2C9/genética , Cálculo de Dosificación de Drogas , Monitoreo de Drogas/economía , Femenino , Humanos , Relación Normalizada Internacional/economía , Masculino , Cadenas de Markov , Modelos Económicos , Selección de Paciente , Variantes Farmacogenómicas , Medicina de Precisión/economía , Valor Predictivo de las Pruebas , Calidad de Vida , Años de Vida Ajustados por Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Suecia , Resultado del Tratamiento , Reino Unido , Vitamina K Epóxido Reductasas/genética , Warfarina/efectos adversosRESUMEN
Observational studies have overwhelmingly shown that variants in the genes CYP2C9 and VKORC1 are significant determinants of individual dose of coumarin anticoagulants needed to maintain a therapeutic international normalized ratio (INR).(1) Until recently, however, few randomized clinical trials had been performed relating to the use of genetic data to predict dosing. Three sucsh clinical trials have now reported their findings.
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Acenocumarol/administración & dosificación , Acenocumarol/farmacocinética , Algoritmos , Anticoagulantes/administración & dosificación , Anticoagulantes/farmacocinética , Hidrocarburo de Aril Hidroxilasas/genética , Coagulación Sanguínea/efectos de los fármacos , Genotipo , Oxigenasas de Función Mixta/genética , Fenprocumón/administración & dosificación , Vitamina K Epóxido Reductasas/genética , Warfarina/administración & dosificación , Femenino , Humanos , MasculinoRESUMEN
Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Enfermedades Musculares/inducido químicamente , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/clasificación , Humanos , Enfermedades Musculares/clasificación , Mialgia/inducido químicamente , Mialgia/clasificación , Miositis/inducido químicamente , Miositis/clasificación , Fenotipo , Rabdomiólisis/inducido químicamente , Rabdomiólisis/clasificación , Factores de Riesgo , Terminología como Asunto , Factores de TiempoRESUMEN
Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient heterogeneity, we have standardized the phenotype. In brief, it comprises swelling in the head and neck region that first occurs during treatment. It should not coincide with urticaria or have another likely cause such as hereditary angioedema.
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Angioedema/inducido químicamente , Antagonistas de Receptores de Angiotensina/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Angioedema/clasificación , Angioedema/epidemiología , Bradiquinina/metabolismo , Cabeza , Humanos , Cuello , Fenotipo , Factores de RiesgoRESUMEN
Simvastatin is among the most commonly used prescription medications for cholesterol reduction. A single coding single-nucleotide polymorphism, rs4149056T>C, in SLCO1B1 increases systemic exposure to simvastatin and the risk of muscle toxicity. We summarize evidence from the literature supporting this association and provide therapeutic recommendations for simvastatin based on SLCO1B1 genotype. This article is an update to the 2012 Clinical Pharmacogenetics Implementation Consortium guideline for SLCO1B1 and simvastatin-induced myopathy.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Enfermedades Musculares/inducido químicamente , Transportadores de Anión Orgánico/genética , Simvastatina/uso terapéutico , Interacciones Farmacológicas , Genotipo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Transportador 1 de Anión Orgánico Específico del Hígado , Farmacogenética , Polimorfismo Genético , Simvastatina/efectos adversos , Simvastatina/farmacocinéticaRESUMEN
To date, studies of irinotecan pharmacogenetics have mostly focused on the effect of the UGT1A1*28 allele on irinotecan-related toxicity. However, the clinical utility of routine UGT1A1*28 genotyping to pre-emptively adjust irinotecan dosage is dependent upon whether UGT1A1*28 also affects patient survival following irinotecan therapy. Previous observational studies evaluating the influence of UGT1A1*28 on survival have shown contradictory results. A systematic review and meta-analysis of both published and unpublished data were performed to summarize the available evidence of the relationship between the UGT1A1*28 allele and patient survival related to irinotecan therapy. Overall and progression-free survival meta-analysis data were available for 1524 patients and 1494 patients, respectively. The difference in the survival between patients of different UGT1A1*28 genotypes (homozygous, heterozygous or wild-type) who had received irinotecan was not found to be statistically significant. There was also no evidence of irinotecan dose, regimen or line of therapy having an impact on this association.
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Alelos , Camptotecina/análogos & derivados , Glucuronosiltransferasa/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/uso terapéutico , Progresión de la Enfermedad , Genotipo , Humanos , Irinotecán , Análisis de SupervivenciaRESUMEN
Cholesterol reduction from statin therapy has been one of the greatest public health successes in modern medicine. Simvastatin is among the most commonly used prescription medications. A non-synonymous coding single-nucleotide polymorphism (SNP), rs4149056, in SLCO1B1 markedly increases systemic exposure to simvastatin and the risk of muscle toxicity. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A) and clinical outcome for all statins. The strength of the evidence is high for myopathy with simvastatin. We limit our recommendations accordingly.
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Inhibidores de Hidroximetilglutaril-CoA Reductasas , Enfermedades Musculares , Transportadores de Anión Orgánico/genética , Polimorfismo de Nucleótido Simple , Simvastatina , Prescripciones de Medicamentos , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Transportador 1 de Anión Orgánico Específico del Hígado , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/genética , Farmacogenética , Medicina de Precisión , Medición de Riesgo , Factores de Riesgo , Simvastatina/administración & dosificación , Simvastatina/efectos adversos , Simvastatina/farmacocinéticaRESUMEN
A significant proportion of the interindividual variability in warfarin dose requirements can be explained on the basis of CYP2C9 and VKORC1 genotypes. We report the development of a novel pharmacogenetics-based 3-day warfarin initiation dose (ID) algorithm based on the International Warfarin Pharmacogenetics Consortium (IWPC) maintenance dose algorithm and the CYP2C9 genotype-based variance in warfarin half-life. The predictive value of the pharmacogenetics-based ID was assessed in a large cohort of 671 newly diagnosed patients with thromboembolic disorders who were about to commence anticoagulation therapy in accordance with standard induction regimens. In patients with mean international normalized ratio (INR)days 4-7>4.0 (n=63) after warfarin initiation, the pharmacogenetics-based ID algorithm predicted a markedly lower dose requirement (median reduction=4.2 mg), whereas in those with mean INRdays 4-7<2.0 (n=145), the predicted dose requirement was very similar to that in the standard regimen. The use of a pharmacogenetics-based ID may avoid overshooting of INR in warfarin-sensitive patients without unduly affecting the time taken to reach target range in the majority of patients.
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Anticoagulantes/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Tromboembolia/tratamiento farmacológico , Warfarina/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Anticoagulantes/farmacocinética , Anticoagulantes/uso terapéutico , Estudios de Cohortes , Citocromo P-450 CYP2C9 , Relación Dosis-Respuesta a Droga , Femenino , Semivida , Humanos , Relación Normalizada Internacional , Masculino , Persona de Mediana Edad , Farmacogenética/métodos , Estudios Prospectivos , Warfarina/farmacocinética , Warfarina/uso terapéutico , Adulto JovenRESUMEN
Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the dose required to achieve target anticoagulation. Common genetic variants in the cytochrome P450-2C9 (CYP2C9) and vitamin K-epoxide reductase complex (VKORC1) enzymes, in addition to known nongenetic factors, account for ~50% of warfarin dose variability. The purpose of this article is to assist in the interpretation and use of CYP2C9 and VKORC1 genotype data for estimating therapeutic warfarin dose to achieve an INR of 2-3, should genotype results be available to the clinician. The Clinical Pharmacogenetics Implementation Consortium (CPIC) of the National Institutes of Health Pharmacogenomics Research Network develops peer-reviewed gene-drug guidelines that are published and updated periodically on http://www.pharmgkb.org based on new developments in the field.(1).
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Anticoagulantes/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Oxigenasas de Función Mixta/genética , Farmacogenética/normas , Warfarina/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2C9 , Relación Dosis-Respuesta a Droga , Variación Genética/genética , Genotipo , Humanos , Oxigenasas de Función Mixta/metabolismo , Vitamina K Epóxido ReductasasRESUMEN
Irinotecan and 5-fluorouracil (5-FU) are used to treat metastatic colorectal cancer. Irinotecan's active metabolite is inactivated by UDP-glucuronosyltransferase 1A1 (UGT1A1), which is deficient in Gilbert's syndrome. Irinotecan and metabolites are transported by P-glycoprotein, encoded by ABCB1. 5-FU targets folate metabolism through inhibition of thymidylate synthase (TYMS). Methylenetetrahydrofolate reductase (MTHFR) generates active folate necessary for haematopoiesis. We retrospectively genotyped 140 Swedish and Norwegian irinotecan and 5-FU-treated colorectal cancer patients from the Nordic VI clinical trial for selected variants of UGT1A1, ABCB1, TYMS and MTHFR. We found an increased risk of clinically relevant early toxicity in patients carrying the ABCB1 3435 T/T genotype, Odds ratio (OR)=3.79 (95% confidence interval (CI)=1.09-13.2), and in patients carrying the UGT1A1(*)28/(*)28 genotype, OR=4.43 (95% CI=1.30-15.2). Patients with UGT1A1(*)28/(*)28 had an especially high risk of neutropenia, OR=6.87 (95% CI=1.70-27.7). Patients who had reacted with toxicity during the first two cycles were in total treated with fewer cycles (P<0.001), and less often responded to treatment (P<0.001). Genetic variation in ABCB1 was associated with both early toxicity and lower response to treatment. Carriers of the ABCB1 1236T-2677T-3435T haplotype responded to treatment less frequently (43 vs 67%, P=0.027), and survived shorter time, OR=1.56 (95% CI=1.01-2.45).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/administración & dosificación , Camptotecina/efectos adversos , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/enzimología , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/farmacocinética , Genotipo , Glucuronosiltransferasa/genética , Glucuronosiltransferasa/metabolismo , Haplotipos , Humanos , Irinotecán , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/genética , Estudios Retrospectivos , Tasa de Supervivencia , Timidilato Sintasa/antagonistas & inhibidores , Timidilato Sintasa/genética , Timidilato Sintasa/metabolismo , Resultado del TratamientoRESUMEN
The objective of the study was to update a previous NONMEM model to describe the relationship between warfarin dose and international normalized ratio (INR) response, to decrease the dependence of the model on pharmacokinetic (PK) data, and to improve the characterization of rare genotype combinations. The effects of age and CYP2C9 genotype on S-warfarin clearance were estimated from high-quality PK data. Thereafter, a temporal dose-response (K-PD) model was developed from information on dose, INR, age, and CYP2C9 and VKORC1 genotype, with drug clearance as a covariate. Two transit compartment chains accounted for the delay between exposure and response. CYP2C9 genotype was identified as the single most important predictor of required dose, causing a difference of up to 4.2-fold in the maintenance dose. VKORC1 accounted for a difference of up to 2.1-fold in dose, and age reduced the dose requirement by ~6% per decade. This reformulated K-PD model decreases dependence on PK data and enables robust assessment of INR response and dose predictions, even in individuals with rare genotype combinations.
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Anticoagulantes/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Oxigenasas de Función Mixta/genética , Modelos Biológicos , Warfarina/administración & dosificación , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Anticoagulantes/farmacocinética , Ensayos Clínicos como Asunto , Citocromo P-450 CYP2C9 , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Humanos , Relación Normalizada Internacional/métodos , Masculino , Persona de Mediana Edad , Dinámicas no Lineales , Estudios Retrospectivos , Factores de Tiempo , Vitamina K Epóxido Reductasas , Warfarina/farmacocinética , Adulto JovenRESUMEN
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.
Asunto(s)
Variación Genética/genética , Relación Normalizada Internacional/normas , Integración de Sistemas , Warfarina/administración & dosificación , Anciano , Hidrocarburo de Aril Hidroxilasas/genética , Estudios de Cohortes , Citocromo P-450 CYP2C9 , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Humanos , Relación Normalizada Internacional/métodos , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/genética , Farmacogenética/métodos , Vitamina K Epóxido Reductasas , Warfarina/farmacocinéticaRESUMEN
The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.
Asunto(s)
Anticoagulantes/uso terapéutico , Farmacogenética , Warfarina/uso terapéutico , Acenocumarol/uso terapéutico , Algoritmos , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Hidrocarburo de Aril Hidroxilasas/genética , Estudios de Cohortes , Análisis Costo-Beneficio , Citocromo P-450 CYP2C9 , Interacciones Farmacológicas/genética , Europa (Continente) , Femenino , Estudios de Seguimiento , Genotipo , Humanos , Relación Normalizada Internacional , Masculino , Oxigenasas de Función Mixta/genética , Fenprocumón/uso terapéutico , Polimorfismo Genético , Estudios Prospectivos , Años de Vida Ajustados por Calidad de Vida , Seguridad , Factores de Tiempo , Vitamina K Epóxido Reductasas , Warfarina/administración & dosificación , Warfarina/efectos adversosRESUMEN
BACKGROUND: The ATP-dependent drug-efflux pump, P-glycoprotein (P-gp) encoded by ABCB1 (MDR1), plays a crucial role in several tissues forming blood-tissue barriers. Absence of a normally functioning P-gp can lead to a highly increased tissue penetration of a number of clinically important drugs. METHODS: We have studied the dose-response effect of exogenous ATP on the placental transfer of the well-established P-gp substrate saquinavir in 17 dually perfused human term placentas. We have also studied the influence of the ABCB1 polymorphisms 2677G>T/A and 3435C>T on placental P-gp expression (n = 44) and the transfer (n = 16) of saquinavir. RESULTS: The present results indicate that the addition of exogenous ATP to the perfusion medium does not affect the function of P-gp as measured by saquinavir transfer across the human placenta. The variant allele 3435T was associated with significantly higher placental P-gp expression than the wild-type alleles. However, neither polymorphism affected placental transfer of saquinavir nor there was any correlation between P-gp expression and saquinavir transfer. CONCLUSIONS: Our results indicate that addition of exogenous ATP is not required for ATP-dependent transporter function in a dually perfused human placenta. Although the ABCB1 polymorphism 3435C>T altered the expression levels of P-gp in the human placenta, this did not have any consequences on P-gp-mediated placental transfer of saquinavir.
Asunto(s)
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Fármacos Anti-VIH/farmacocinética , Placenta/metabolismo , Saquinavir/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Adenosina Trifosfato/farmacología , Adulto , Alelos , Área Bajo la Curva , Análisis de los Gases de la Sangre , Western Blotting , Relación Dosis-Respuesta a Droga , Femenino , Genotipo , Semivida , Humanos , Técnicas In Vitro , Polimorfismo de Nucleótido Simple/genética , EmbarazoAsunto(s)
Farmacogenética/métodos , Warfarina/administración & dosificación , Anciano , Anciano de 80 o más Años , Algoritmos , Anticoagulantes/administración & dosificación , Sistema Enzimático del Citocromo P-450/genética , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Oxigenasas de Función Mixta/genética , Polimorfismo Genético , Suecia , Reino Unido , Vitamina K Epóxido ReductasasRESUMEN
The aim of this study was to characterize the relationship between warfarin concentrations and international normalized ratio (INR) response and to identify predictors important for dose individualization. S- and R-warfarin concentrations, INR, and CYP2C9 and VKORC1 genotypes from 150 patients were used to develop a population pharmacokinetic/pharmacodynamic model in NONMEM. The anticoagulant response was best described by an inhibitory E(MAX) model, with S-warfarin concentration as the only exposure predictor for response. Delay between exposure and response was accounted for by a transit compartment model with two parallel transit compartment chains. CYP2C9 genotype and age were identified as predictors for S-warfarin clearance, and VKORC1 genotype as a predictor for warfarin sensitivity. Predicted INR curves indicate important steady-state differences between patients with different sets of covariates; differences that cannot be foreseen from early INR assessments alone. It is important to account for CYP2C9 and VKORC1 genotypes and age to improve a priori and a posteriori individualization of warfarin therapy.