RESUMEN
AIMS: Clopidogrel is a prodrug that needs to be activated to inhibit platelet aggregation. The objective of this study was to evaluate the prevalence and clinical consequences of potential drug-drug interactions of clopidogrel with drugs affecting CYP3A4 activity. METHODS: Co-administrations of clopidogrel together with well-established CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin were investigated in a population-based pharmacoepidemiological study utilizing data from the national healthcare registers and in more detail from a university hospital register in Finland. The main outcome measures were all-cause mortality and mortality and morbidity related to thrombosis or bleeding. RESULTS: In the nationwide analysis, 6.1%, 1.0%, and 20.8% of the clopidogrel-treated patients were exposed to concomitant use of CYP3A4 inhibitors, CYP3A4 inducers, and atorvastatin, respectively. In the survival analysis, the adjusted hazard ratio for overall mortality was 2.29 (P < 0.001) for CYP3A4 inducer users and 0.74 (P = 0.003) for atorvastatin users compared with controls (patients receiving clopidogrel without interacting medication). CYP3A4 inhibitor use seemed to prevent from thrombosis: HR 0.67, P < 0.001. The hospitalizations due to bleedings were rarer in atorvastatin and CYP3A4 inhibitor groups compared with controls. Thrombosis complications leading to hospitalizations were more often seen in the atorvastatin group than in the control group. CONCLUSIONS: No uniform untoward effect of concomitant CYP3A4 inhibitor use on the clinical efficacy of clopidogrel was found. In patients receiving concomitant atorvastatin and clopidogrel, the antithrombotic effect of clopidogrel was moderately attenuated, but the combination significantly reduced the overall mortality. CYP3A4 inhibitors and atorvastatin may reduce bleedings in clopidogrel users.
Asunto(s)
Citocromo P-450 CYP3A/fisiología , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Agregación Plaquetaria/farmacología , Pirroles/farmacología , Ticlopidina/análogos & derivados , Anciano , Atorvastatina , Clopidogrel , Inhibidores del Citocromo P-450 CYP3A , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ticlopidina/farmacologíaRESUMEN
BACKGROUND: Bleeding is a serious adverse drug reaction associated with warfarin therapy, often induced by interacting co-medication. METHODS: We investigated the frequency and clinical consequences of warfarin drug interactions utilizing medical records of 6,772 warfarin-treated in-patients of Turku University Hospital. RESULTS: A total of 48% of warfarin-treated in-patients were exposed to interacting co-medication. Adjusted odds ratio (OR) for bleeding was highest for cytochrome P450 2C9 (CYP2C9) inhibitors (OR 3.6; 95% confidence interval (CI) 2.4-5.6). Non-selective non-steroidal anti-inflammatory drugs (NSAID) and coxibs were associated with a bleeding risk of a similar magnitude (OR 2.6; 95% CI 1.6-4.2 and OR 3.1; 95% CI 1.4-6.7, respectively). Selective serotonin re-uptake inhibitors (SSRI) were associated with a remarkably higher bleeding risk than non-SSRIs (OR 2.6; 95% CI 1.5-4.3 and OR 1.2; 95% CI 0.3-4.3, respectively). Odds ratio for bleeding in the platelet aggregation inhibitor group was 1.6 (95% CI 0.8-3.1). CONCLUSION: We conclude that co-medication in warfarin-treated in-patients is common and should be carefully evaluated to decrease the bleeding risk associated with warfarin therapy.
Asunto(s)
Anticoagulantes/efectos adversos , Hemorragia/inducido químicamente , Warfarina/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Anticoagulantes/farmacocinética , Antidepresivos/efectos adversos , Antidepresivos/farmacología , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Estudios de Casos y Controles , Citocromo P-450 CYP2C9 , Bases de Datos Factuales , Interacciones Farmacológicas , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacología , Femenino , Finlandia , Hospitalización , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/farmacología , Warfarina/farmacocinética , Adulto JovenRESUMEN
OBJECTIVE: The aim was to develop a drug-drug interaction database (SFINX) to be integrated into decision support systems or to be used in website solutions for clinical evaluation of interactions. METHODS: Key elements such as substance properties and names, drug formulations, text structures and references were defined before development of the database. Standard operating procedures for literature searches, text writing rules and a classification system for clinical relevance and documentation level were determined. ATC codes, CAS numbers and country-specific codes for substances were identified and quality assured to ensure safe integration of SFINX into other data systems. Much effort was put into giving short and practical advice regarding clinically relevant drug-drug interactions. RESULTS: SFINX includes over 8,000 interaction pairs and is integrated into Swedish and Finnish computerised decision support systems. Over 31,000 physicians and pharmacists are receiving interaction alerts through SFINX. User feedback is collected for continuous improvement of the content. CONCLUSION: SFINX is a potentially valuable tool delivering instant information on drug interactions during prescribing and dispensing.
Asunto(s)
Sistemas de Administración de Bases de Datos , Sistemas de Apoyo a Decisiones Clínicas , Interacciones FarmacológicasRESUMEN
BACKGROUND: Concomitantly used cytochrome P450 (CYP) 3A4 inhibitors and inducers have been shown to alter the plasma concentrations of the HMG-CoA reductase inhibitors ('statins') lovastatin and simvastatin. Myopathy is a serious adverse effect of statins. Concurrent use of statins with fibrates in particular seems to increase the risk of this adverse effect. OBJECTIVE: To evaluate the incidence and clinical consequences of the use of lovastatin or simvastatin with concomitant CYP3A4 inhibitors and inducers, and with fibrates. METHODS: An observational database study of hospitalized patients treated in Turku University Hospital, Turku, Finland, covering the period 1 July 1996 to 30 June 2003, and of nationwide community data from the Finnish Prescription Register over the period 1 April to 30 June 2001 was conducted. In the hospital setting, the study population comprised 71 025 patients (93 467 treatment periods) over 7 years, with a total of 5320 treatment periods of lovastatin or simvastatin. The community-based, nationwide survey included all reimbursed prescriptions of lovastatin and simvastatin (n = 91 656) in Finland during a 3-month period. The frequency of drug-drug interactions involving lovastatin or simvastatin was studied. The efficacy and safety of the various statin/concomitant drug combinations was estimated by evaluating patients' laboratory data. RESULTS: Concomitant use of lovastatin or simvastatin with interacting medication was detected in 13.3% (704) and 6.9% (6338) of patients in hospital and community settings, respectively. Co-administration of lovastatin or simvastatin with CYP3A4 inhibitors or inducers did not have a clinically significant effect on serum lipid values. Plasma creatine kinase (CK) activity was significantly higher in patients receiving a statin and a fibrate compared with a statin only (433 U/L vs 209 U/L, p = 0.053). Co-administration of a statin and a CYP3A4 inhibitor did not increase CK activity. CONCLUSION: Although the pharmacokinetic interactions between lovastatin or simvastatin and CYP3A4 inhibitors and inducers are substantial, their clinical relevance seems to be limited, at least with lower statin doses. However, combining statins with fibrates, especially gemfibrozil, clearly increases the potential for muscular toxicity.
Asunto(s)
Anticolesterolemiantes/farmacocinética , Citocromo P-450 CYP3A/efectos de los fármacos , Lovastatina/farmacocinética , Simvastatina/farmacocinética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticolesterolemiantes/administración & dosificación , Creatina Quinasa/efectos de los fármacos , Creatina Quinasa/metabolismo , Citocromo P-450 CYP3A/metabolismo , Bases de Datos Factuales , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inducción Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Femenino , Finlandia , Hospitales Universitarios , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacocinética , Lovastatina/administración & dosificación , Masculino , Persona de Mediana Edad , Simvastatina/administración & dosificaciónRESUMEN
OBJECTIVE: Our objective was to investigate the frequency of potential drug-drug interactions between the prodrugs losartan, codeine, and tramadol and drugs known to inhibit their activation in hospitalized patients. METHODS: The frequency of coadministration between losartan and well-established cytochrome P450 (CYP) 2C9 inhibitors, as well as codeine and tramadol and CYP2D6 inhibitors, was studied by use of data from a university hospital medication database. The study population comprised all patients treated in internal medicine, pulmonary medicine, oncology, and neurology wards (105,533 treatment periods and 65,526 patients) between July 1, 1996, and June 30, 2002 (6 years). RESULTS: Every fifth patient receiving losartan, codeine, or tramadol was concomitantly taking another drug that has the potential to inhibit the activation of these drugs. During the 6-year time period, 1999 patients were exposed to a potential interaction. Interactions occurred more commonly in internal medicine wards (odds ratio, 2.3; 95% confidence interval, 2.1-2.5) and in women (odds ratio, 1.5; 95% confidence interval, 1.4-1.7). CONCLUSIONS: Coadministration of drugs that potentially result in inhibition of prodrug activation present a common and unrecognized source of irrational prescribing.