Background: Whether concomitant administration of anticancer agents influences the efficacy and safety of oral anticoagulants in patients treated for cancer-associated venous thromboembolism (VTE)... Show moreBackground: Whether concomitant administration of anticancer agents influences the efficacy and safety of oral anticoagulants in patients treated for cancer-associated venous thromboembolism (VTE) is undefined. The pharmacological interaction between anticancer agents and direct oral anticoagulants is perceived as a concern.Methods: We evaluated the effects of concomitant administration of anticancer agents on recurrent VTE, major bleeding and death in patients with cancer-associated VTE randomised to receive apixaban or dalteparin in the Caravaggio study.Results: Anticancer agents were concomitantly given to 336 patients (58.3%) treated with apixaban and to 332 patients (57.3%) treated with dalteparin. In patients treated with apixaban, recurrent VTE occurred in 20 (6.0%) and 12 (5.0%) among patients treated or not treated with anticancer agents, respectively (hazard ratio [HR] = 1.14; 0.55-2.38); major bleeding occurred in 12 (3.6%) and 10 (4.2%) patients , respectively (HR = 0.79; 0.34-1.82), and death occurred in 74 (22.0%) and 61 (25.4%) patients , respectively (HR = 0.71; 0.51-1. 00). In patients treated with dalteparin, recurrent VTE occurred in 24 (7.2%) and 22 (8.9%) among patients treated or not treated with anticancer agents, respectively (HR = 0.71; 0.40-1.28); major bleeding occurred in 16 (4.8%) and 7 (2.8%) patients, respectively (HR = 1.78; 0.66-4.79 ), and death occurred in 87 (26.2% ) and 66 (26.7 %) patients, respectively (HR = 0.85; 0.62-1.18). The comparative efficacy and safety of apixaban and dalteparin was not different in patients treated or not treated with anticancer agents. No effect on recurrent VTE, major bleeding or death was observed with inhibitors or inducers of P-glycoprotein and/or CYP3A4.Conclusion: In our study, concomitant administration of anticancer agents had no effect on the risk of VTE recurrence or major bleeding in patients treated with apixaban or dalteparin for cancer-associated VTE.(c) 2021 Elsevier Ltd. All rights reserved. Show less
The objective of this thesis was the development of a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the electro-encephalogram (EEG) effects of opioids, with emphasis on biophase... Show moreThe objective of this thesis was the development of a mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) model for the electro-encephalogram (EEG) effects of opioids, with emphasis on biophase distribution and target interaction kinetics. Several in vitro and in vivo studies have been performed to characterize the transport to the site of action in the brain, the receptor interaction and EEG effects. From the transport studies it could be concluded that the efflux transporter P-glycoprotein is involved in the transport of morphine, whereas for the other opioids no interaction could be identified, which was mainly due to the high passive permeability. Population modeling showed that the predicted morphine biophase concentration-time profiles in vivo were distinctly different from the brain ECF concentration-time profiles, as estimated by intracerebral microdialysis. In addition, for morphine, a complex biophase distribution model was required to describe the hysteresis between blood concentration and EEG effect whereas for the other opioids a simple one-compartment distribution model was sufficient. Investigation of the role of target interaction showed that based on the correlation between in vitro and in vivo receptor binding characteristics, two subpopulations existed. In conclusion, for the development of a predictive PK-PD model, the underlying processes should be investigated in great detail and supportive data are essential for model validation and prediction. Show less
