Pharmacogenetic-guided dosing of coumarin anticoagulants : Algorithms for warfarin, acenocoumarol and phenprocoumon

Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials

Pharmacogenetic-guided dosing of coumarin anticoagulants : Algorithms for warfarin, acenocoumarol and phenprocoumon

Coumarin derivatives, such as warfarin, acenocoumarol and phenprocoumon are frequently prescribed oral anticoagulants to treat and prevent thromboembolism. Because there is a large inter-individual and intra-individual variability in dose-response and a small therapeutic window, treatment with coumarin derivatives is challenging. Certain polymorphisms in CYP2C9 and VKORC1 are associated with lower dose requirements and a higher risk of bleeding. In this review we describe the use of different coumarin derivatives, pharmacokinetic characteristics of these drugs and differences amongst the coumarins. We also describe the current clinical challenges and the role of pharmacogenetic factors. These genetic factors are used to develop dosing algorithms and can be used to predict the right coumarin dose. The effectiveness of this new dosing strategy is currently being investigated in clinical trials

Pharmacogenetics of coumarin anticoagulant therapy

Coumarins are effective drugs for treatment and prevention of thromboembolic events. However, their use requires a balancing act between the chance of underdosing which increases the risk of thromboembolic events and the chance of overdosing which increases the risk of haemorrhages. It has been shown that polymorphisms in VKORC1 and CYP2C9 explain 35-50% of the dose variability, although patient characteristics and environmental factors also play a role. In this book chapter we discuss the pharmacogenetics of coumarin derivatives, clinical trials investigating the effectiveness of pre-treatment genotyping and the cost-effectiveness of pharmacogenetic-guided dosing

Pharmacogenetics of coumarin anticoagulant therapy

Coumarins are effective drugs for treatment and prevention of thromboembolic events. However, their use requires a balancing act between the chance of underdosing which increases the risk of thromboembolic events and the chance of overdosing which increases the risk of haemorrhages. It has been shown that polymorphisms in VKORC1 and CYP2C9 explain 35-50% of the dose variability, although patient characteristics and environmental factors also play a role. In this book chapter we discuss the pharmacogenetics of coumarin derivatives, clinical trials investigating the effectiveness of pre-treatment genotyping and the cost-effectiveness of pharmacogenetic-guided dosing

Immunological Risk of Injectable Drug Delivery Systems

Injectable drug delivery systems (DDS) such as particulate carriers and water-soluble polymers are being used and developed for a wide variety of therapeutic applications. However, a number of immunological risks with serious clinical implications are associated with administration of DDS. These immunological events can compromise the efficacy and safety of these systems by changing the pharmacokinetics, biodistribution and targeting capability of DDS, and by inducing hypersensitivity reactions. Antibodies induced by administration of DDS can be directed against the carrier material, the drug and/or targeting ligands associated with the DDS. Complement activation and opsonization of DDS, which may or may not be associated with antibody formation, may lead to accelerated clearance, hypersensitivity reactions and formation of membrane attack complexes resulting in premature release of the drug. Also platelets have been reported to play a role in DDS immunogenicity. Despite our curtailed understanding of the relationships between physicochemical characteristics and immunogenicity of DDS, several risk factors have been identified. Insight into these factors should be employed in the development of novel DDS with low immunological risk