RESUMEN
BACKGROUND: German hospitals are legally obliged to implement digital patient portals within the next years. Systematic reviews show that the use of patient portals may be associated with improved patient-centeredness and workflows. However, mandatory digital healthcare innovations are sometimes not used by the target group as planned or even completely rejected. Based on Roger's theory of innovation diffusion, it can be assumed that the time factor is of particular importance for the adoption of the patient portal. The aim of the project is to assess determinants of patient portal adoption and to examine whether Roger's theory can be confirmed. METHODS: The project investigates the use of the patient portal in three different clinics of a large academic teaching hospital in Germany using a longitudinal study design with three cross-sectional time points (pre, post, post). Doctors and patients are surveyed about factors that predict the use of the patient portal and whether the strength of these factors changes over time. They are also interviewed about possible barriers they experience when using the patient portal or about the reasons why the patient portal is not used. Regression models and content analyses are used to answer the research questions. DISCUSSION: Determinants of patient portal use will be discussed under the light of the temporal component of Roger's theory. At the same time, it is expected that some determinants will remain unchanged over time. Identifying determinants independent of time allows targeting the groups, enabling specific communication strategies to empower these groups to use the patient portal, contributing to an equal health care system. TRIAL REGISTRATION: The study was prospectively registered in the German register of clinical trials (DRKS00033125) in May 2024.
RESUMEN
Pharmacokinetics and dose-finding studies on sorafenib were conducted on heterogeneous groups of patients with solid tumors. Portal hypertension, gut motility impairment and altered bile enterohepatic circulation may explain different sorafenib toxicological profile in cirrhotic patients. This study evaluated sorafenib plasma concentration in a homogeneous group of cirrhotic patients with hepatocellular carcinoma (HCC). Sorafenib concentrations were determined by liquid chromatography in 12 consecutive patients. Data have been evaluated by the generalized estimating equations method (p value statistical level was set at α = 0.05). (1) There were not significant differences between sorafenib concentrations in patients who tolerate the full dose versus patients with reduced dose due to toxicity; (2) the average sorafenib concentrations measured 3 h after the morning dosing were lower than those measured 12 h after the evening dosing (p = 0.005); (3) sorafenib concentrations decrease overtime (p < 10(-4)); (4) it has been found an association between the development of severe adverse reactions and sorafenib concentrations (p < 10(-5)). The relationship between dose and concentration of sorafenib in HCC patients is poor and not clinically predictable, confirming the variability both in the maximum tolerated dose and in plasma concentrations. Several factors may influence the pharmacokinetics in patients with liver disease. This may explain the inter-patient variability of concentrations and the lack of differences in concentration at different dosages. It could be interesting to extend the series of HCC patients to enhance information on the kinetics of the drug; furthermore, to establish a threshold of plasma sorafenib concentrations to predict severe adverse reactions would be clinically useful.
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Antineoplásicos/sangre , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Niacinamida/análogos & derivados , Compuestos de Fenilurea/sangre , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/sangre , Cromatografía Líquida de Alta Presión , Femenino , Humanos , Neoplasias Hepáticas/sangre , Masculino , Persona de Mediana Edad , Niacinamida/efectos adversos , Niacinamida/sangre , Niacinamida/farmacocinética , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/farmacocinética , Proyectos Piloto , SorafenibRESUMEN
Diurnal changes in the activity of drug metabolizing enzymes may contribute to the variability in drug disposition and drug effects. The aim of this study was to quantify the circadian rhythmicity exhibited by hepatic CYP3A. A 10 µg/kg intravenous bolus dose, followed by a 30-hour 4 µg/kg/h intravenous infusion of midazolam, used as a probe substrate for hepatic CYP3A activity, was administered to 16 healthy volunteers (8 males and 8 females). Blood samples were drawn hourly for 24 hours after achieving steady state, and plasma concentrations of midazolam and its main metabolite 1-OH midazolam were determined. Population pharmacokinetic analysis was performed using nonlinear mixed effects modeling. One-compartment pharmacokinetic models best described midazolam and 1-OH midazolam pharmacokinetic disposition. An unequivocal but minor diurnal pattern was identified in the midazolam plasma concentration profiles, which was described using a cosine function with a 24-hours period. The fluctuation in the relative CYP3A activity ranged between 10% above average around 15:00, and 10% below average around 03:00. None of the covariates tested had a significant impact on the parameters estimated. Although a diurnal pattern in hepatic CYP3A activity was identified, its magnitude suggests that it is small and without clinical significance for drug therapy.
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Ritmo Circadiano/fisiología , Citocromo P-450 CYP3A/metabolismo , Midazolam/farmacocinética , Modelos Biológicos , Adulto , Citocromo P-450 CYP3A/fisiología , Femenino , Humanos , Infusiones Intravenosas , Hígado/metabolismo , Masculino , Midazolam/análogos & derivados , Dinámicas no Lineales , Adulto JovenRESUMEN
The 4-anilinoquinazolines (gefitinib, erlotinib and lapatinib) are members of a class of potent and selective inhibitors of the human epidermal growth factor receptor (HER) family of tyrosine kinases that have been developed to treat patients with tumours with defined genetic alterations of the HER tyrosine kinase domain. They are characterized by a moderate rate of absorption after oral administration with peak plasma concentrations at several hours post-dose. Absolute bioavailability of gefitinib and erlotinib is about 60%. Low bioavailability is assumed for lapatinib. The drugs are extensively distributed in human tissues, including tumour tissues, have a large volume of distribution at least 3-fold exceeding the volume of body water and are extensively (about 95%) protein bound to α(1)-acid glycoprotein and albumin. Existing human data for gefitinib and erlotinib indicate that these substances penetrate into the central nervous system and accumulate in brain tumours, possibly due to leaks in the blood-brain barrier. Gefitinib, erlotinib and the absorbed fraction of lapatinib undergo extensive metabolism - mainly via hepatic and intestinal cytochrome P450 (CYP) 3A4 and also via CYP2D6 (gefitinib) and CYP1A2 (erlotinib) - and are primarily eliminated by biotransformation. The excretion of unchanged gefitinib, erlotinib, lapatinib and their metabolites occurs predominantly in the faeces and only a minor fraction is excreted in the urine. No relevant effects of age, sex, bodyweight or race on their pharmacokinetics have been reported to date. Limited available data indicate that genetic polymorphisms in enzymes and transporters involved in the pharmacokinetics of gefitinib (CYP2D6) and erlotinib (CYP3A4, CYP3A5 and ABCG2 [breast cancer resistance protein]) alter the exposure to these drugs. Modification of drug dose should be considered in patients with severe hepatic impairment receiving these tyrosine kinase inhibitors and in current smokers receiving erlotinib. Existing recommendations for dose adjustment (i.e. a dose decrement or increment for gefitinib, erlotinib and lapatinib in the presence of CYP3A4 inhibitors or inducers, respectively; a dose increase for erlotinib in smoking patients) need to be validated in clinical studies. Further investigations are required to explain the large interindividual variability in the pharmacokinetics of these drugs and to assess the clinical relevance of interaction potential and inhibitory effects on the metabolizing enzymes and transporters.
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Antineoplásicos/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Quinazolinas/farmacocinética , Animales , Interacciones Farmacológicas , Clorhidrato de Erlotinib , Gefitinib , Humanos , Lapatinib , Farmacogenética , Distribución TisularRESUMEN
Pyrimidine (imatinib, dasatinib, nilotinib and pazopanib), pyridine (sorafenib) and pyrrole (sunitinib) tyrosine kinase inhibitors (TKIs) are multi-targeted TKIs with high activity towards several families of receptor and non-receptor tyrosine kinases involved in angiogenesis, tumour growth and metastatic progression of cancer. These orally administered TKIs have quite diverse characteristics with regard to absorption from the gastrointestinal tract. Absolute bioavailability in humans has been investigated only for imatinib (almost 100%) and pazopanib (14-39%; n = 3). On the basis of human radioactivity data, dasatinib is considered to be well absorbed after oral administration (19% and 0.1% of the total radioactivity were excreted as unchanged dasatinib in the faeces and urine, respectively). Quite low absolute bioavailability under fasted conditions is assumed for nilotinib (31%), sorafenib (50%) and sunitinib (50%). Imatinib, dasatinib and sunitinib exhibit dose-proportional increases in their area under the plasma concentration-time curve values over their therapeutic dose ranges. Less than dose-proportional increases were observed for nilotinib at doses ≥400 mg/day and for sorafenib and pazopanib at doses ≥800 mg/day. At steady state, the accumulation ratios are 1.5-2.5 (unchanged imatinib), 2.0 (nilotinib once-daily dosing), 3.4 (nilotinib twice-daily dosing), 1.2-4.5 (pazopanib), 5.7-6.4 (sorafenib) and 3.0-4.5 (sunitinib). Concomitant intake of a high-fat meal does not alter exposure to imatinib, dasatinib and sunitinib but leads to considerably increased bioavailability of nilotinib and pazopanib and decreased bioavailability of sorafenib. With the exception of pazopanib, the TKIs described here have large apparent volumes of distribution, exceeding the volume of body water by at least 4-fold. Very low penetration into the central nervous system in humans has been reported for imatinib and dasatinib, but there are currently no published human data for nilotinib, pazopanib, sorafenib or sunitinib. All TKIs that have been described are more than 90% bound to the plasma proteins: α(1)-acid glycoprotein and/or albumin. They are metabolized primarily via cytochrome P450 (CYP) 3A4, the only exception being sorafenib, for which uridine diphosphate glucuronosyltransferase 1A9 is the other main enzyme involved. Active metabolites of imatinib and sunitinib contribute to their antitumour activity. Although some patient demographics have been identified as significant co-factors that partly explain interindividual variability in exposure to TKIs, these findings have not been regarded as sufficient to recommend age-, sex-, bodyweight- or ethnicity-specific dose adjustment. Systemic exposure to imatinib, sorafenib and pazopanib increases in patients with hepatic impairment, and reduction of the initial therapeutic dose is recommended in this subpopulation. The starting dose of imatinib should also be reduced in renally impaired subjects. Because the solubility of dasatinib is pH dependent, co-administration of histamine H(2)-receptor antagonists and proton pump inhibitors with dasatinib should be avoided. With the exception of sorafenib, systemic exposure to TKIs is significantly decreased/increased by co-administration of potent CYP3A4 inducers/inhibitors, and so it is strongly recommended that the TKI dose is adjusted or that such co-administration is avoided. Caution is also recommended for co-administration of CYP3A4 substrates with TKIs, especially for those with a narrow therapeutic index. However, current recommendations with regard to dose adjustment of TKIs need to be validated in clinical studies. Further investigations are needed to explain the large interindividual variability in the pharmacokinetics of these drugs and to assess theclinical relevance of their interaction potential and inhibitory effects on metabolizing enzymes and transporters.
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Inhibidores de Proteínas Quinasas/farmacocinética , Piridinas/farmacocinética , Pirimidinas/farmacocinética , Pirroles/farmacocinética , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Inhibidores de Proteínas Quinasas/sangre , Inhibidores de Proteínas Quinasas/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Piridinas/sangre , Piridinas/metabolismo , Piridinas/farmacología , Pirimidinas/sangre , Pirimidinas/metabolismo , Pirimidinas/farmacología , Pirroles/sangre , Pirroles/metabolismo , Pirroles/farmacologíaRESUMEN
BACKGROUND: Dexamethasone is a glucocorticoid used widely worldwide for immunosuppressive treatment, allergies, bronchiolitis, and croup, among others. For children, liquid formulations are especially suitable because, compared with other dosage forms, both exact dosing and proper intake are facilitated. OBJECTIVE: The objective was to evaluate the pharmacokinetics, pharmacodynamics, and comparative bioavailability of a commercial liquid oral dexamethasone formulation intended for pediatric use relative to those of a tablet. METHODS: In a randomized, controlled, crossover study in 24 healthy adult volunteers, we administered single doses of the liquid and tablet formulation, containing 2 mg of dexamethasone each. Blood samples were taken up to 24 hours postdose. Quantification was carried out using a validated specific and sensitive high-pressure liquid chromatography with UV detector method. Noncompartmental pharmacokinetic parameters were compared between treatments according to European Medicines Agency (EMA) bioequivalence guidelines. For AUC(0-t) and C(max), the 90% CI for the ratio of the test and reference products should be contained within the predetermined acceptance interval of 80% to 125%. As a pharmacodynamic variable, we measured suppression of endogenous cortisol (predose and postdose). RESULTS: Both preparations showed similar pharmacokinetic and pharmacodynamic profiles but high between-subject variability of pharmacokinetic key parameters and endogenous cortisol concentrations (>30%). Mean AUC(0-t), AUC(0-∞), and C(max) were 37.8 ng/mL/h, 46.0 ng/mL/h, and 9.35 ng/mL, respectively, for the liquid and 41.3 ng/mL/h, 48.1 ng/mL/h, and 9.17 ng/mL, respectively, for the tablet formulation. T(max) was 0.89 hour (liquid) and 0.97 hour (tablet). The point estimates and 90% CIs for AUC(0-t), AUC(0-∞), and C(max) ratios (liquid vs tablet) were 91.42% (82.05%-101.86%), 95.72% (84.46%-108.5%), and 102.04% (86.94%-119.76%), respectively. Thus, point estimates and 90% CIs were within the bioequivalence range of 80% to 125% for all relevant parameters, including the pharmacodynamic parameter AUEC (area under the effect curve). CONCLUSIONS: This single-dose study suggests that the test and reference products met the EMA regulatory criteria to assume bioequivalence in these fasting healthy male and female volunteers. German Register of Clinical Trials registration number: DRKS00000785.