Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C9 and HLA-B Genotype and Phenytoin Dosing

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large inter-patient variability partly due to genetic variations in CYP2C9. Furthermore, the variant allele HLA-B*15:02 is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotype (also available on PharmGKB: www.pharmgkb.org)

Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing.

Phenytoin is a widely used antiepileptic drug with a narrow therapeutic index and large interpatient variability, partly due to genetic variations in the gene encoding cytochrome P450 (CYP)2C9 (CYP2C9). Furthermore, the variant allele HLA-B*15:02, encoding human leukocyte antigen, is associated with an increased risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in response to phenytoin treatment. We summarize evidence from the published literature supporting these associations and provide recommendations for the use of phenytoin based on CYP2C9 and/or HLA-B genotype (also available on PharmGKB: http://www.pharmgkb.org). The purpose of this guideline is to provide information for the interpretation of HLA-B and/or CYP2C9 genotype tests so that the results can guide dosing and/or use of phenytoin. Detailed guidelines for the use of phenytoin as well as analyses of cost-effectiveness are out of scope. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines are periodically updated at http://www.pharmgkb.org

Pharmacogenetics to Avoid Adverse Drug Reactions

Adverse drug reactions are one of the major constraints when using drugs. These adverse reactions can impact healthcare systems as strongly as many prevalent diseases. Identifying DNA variants associated with adverse drug reactions can help personalize medicine and sustain healthcare systems. This book delves into new advances in pharmacogenetics of cardiovascular, cancer, and nervous system drugs. It may be useful for clinicians and patients to understand the basics of pharmacogenetics

Direct Oral Anticoagulants (DOACs) Use in Patients with Renal Insufficiency and Obesity

The popularity of Direct Oral AntiCoagulants (DOACs) for approved indications has risen dramatically following their introduction to the UK’s National Health Service (NHS) due to their convenience of dosing surpassing warfarin. However, prescribing these medications to high-risk patients has been challenging since mainly due to uncertainties around limited clinical trial data. Patients with chronic kidney disease and obesity pose a risk in particular as DOAC dosing was significantly affected by the variables such as, body weight and renal function. Due to the increased prevalence of CKD and obesity among the NHS patient population, the cost savings of preferring DOACs over warfarin was no longerbeneficial due to higher costs of mortalities and consequential morbidities (e.g., strokes and bleeding events). There are very limited interventional studies to rationalise the sample sizes to generalise findings. Therefore, a retrospective real-world data-driven approach was used in this thesis in an attempt to optimise the DOACs dosing regimen for patients with renal impairment and obesity.The main data-driven techniques used in the thesis employed machine learning and multivariate logistic regression (The systematic review in Chapter 6 describes the potential of in-silico modelling). These were applied to a pre-processed dataset, carefully collected from Calderdale and Huddersfield NHS Foundation Trust Hospitals, and profiled accordingly. The methodology was executed in three phases: overall analysis of the full dataset, comprising different BMI categories (Chapter 3), the data analyses comprising patients with morbid obesity only (Chapter 4), and the analyses of the overall dataset comprising patients with different categories of renal impairment (Chapter 5).The factors that influenced the clinical outcomes (such as mortality, ischaemic stroke, clinically relevant non-major bleeding (CRNMB), thromboembolism, length of stay, and emergency visits) in renal impairment and obesity were then determined following data analysis. Some of these factors, which included the individual DOACs administered, exerted a protective effect, while others worsened the safety and, or efficacy indicators. Also, it was found that some of the machine learning models employed in the thesis predicted the target (i.e., DOAC dose regimen) more accurately than others. Chapter 7 provides a discussion of the findings and makes reference and comparison with the existing evidence in the literature. More importantly, the results from patients with renal impairment and obesity were compared. Overall, the aim of generating real-world evidence for optimising DOACs safety and effectiveness in obesity and renal impairment was achieved. Our findings would support clinicians’ decision-making by reducing the uncertainty in DOACs prescribing.There is a need to validate the thesis findings with well-designed prospective studies. There is also a need to explore pharmacometrics analyses and advanced data-driven techniques such as reinforcement learning to arrive at more precise DOAC dosing estimates for patients with renal impairment and obesity

Thrombotic and cardiac disease in the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is a highly heterogeneous disease that presents with obstetric complications and/or thromboembolic events that can hit any side of the vascular tree in an unpredictable way. The common trait among all patients affected by the syndrome is the persistent presence of the antiphospholipid antibodies (aPL) and/or a prolonged coagulation time in vitro, the lupus anticoagulant (LA) test. The pathogenesis of APS has not yet been clearly defined. Many molecules are involved in the maintenance of the equilibrium called hemostasis, interacting and cross-reacting in an incredibly perfect orchestrated balance that somehow, in APS, is broken. The aim of this thesis has been to try to shed some light on the complex mechanisms behind APS, by focusing on some of the many pieces of the puzzle that characterize the disease. The complement, coagulation and fibrinolytic systems have been the subjects of this fascinating journey, and two proteins in particular have been on focus: C4b-binding protein (C4BP) and Thrombin activatable fibrinolysis inhibitor (TAFI). These are both regulators of complement activation that at the same time play a role in coagulation. Moreover, the link between myocardial infarction (MI) and aPL/LA has been explored. Paper I: TAFI and its activated form, TAFIa, were studied in patients affected by mainly primary APS (i.e. without other autoimmune diseases) and compared with a healthy control group. Moreover, C5a, a marker of complement activation, and markers of fibrinolysis were investigated and correlated with TAFI and TAFIa. Both TAFI and TAFIa are significantly higher in APS compared to controls. TAFIa is increased in APS patients affected by arterial thrombosis compared to other clinical manifestations, independently of traditional cardiovascular risk factors. TAFI is positively correlated with C5a, confirming its increase upon inflammation. TAFIa positively correlates with thrombomodulin, marker of endothelial damage/activation. The values of the clot lysis time (CLT) and of the permeability coefficient confirm impaired fibrinolysis in APS, with clots more resistant to lysis. Paper II: we investigated the prevalence of aPL in a large and well-characterized cohort of patients after 6-10 weeks from a first MI, and compared it with age, gender and region matched controls. We demonstrated ten times higher prevalence of aPL of the IgG isotype in patients versus controls, independently of traditional cardiovascular risk factors, suggesting that IgG aPL positivity may be considered a potential risk factor for MI in the general population. No significant differences were observed for IgM and IgA isotypes. Paper III: C4BP was investigated in a large cohort of patients affected by systemic lupus erythematosus (SLE), in primary APS and in controls. C4BP is lower in patients persistently positive for aPL and in patients treated with warfarin. C4BP correlates with markers of complement activation. Both persistent aPL positivity and warfarin are associated with C4BP reduction, and by means of a mediation analysis we were able to assess the relative contribution of these two variables: aPL have a direct reducing effect on C4BP of 11%, while warfarin contributes to 9% of the observed reduction. Paper IV: After the results of paper III, we decided to study the effect of warfarin on complement and C4BP in the general population, comparing it with the direct oral anticoagulants (DOACs), during and after treatment discontinuation. Warfarin, as opposed to DOACs, is associated with increased markers of complement activation, which persist for at least three weeks after withdrawal. Higher C4BP levels characterize the patients after warfarin discontinuation, as a rebound effect. DOACs have no effect on complement, but, in contrast, we demonstrate that warfarin is associated with complement activation, partly but probably not only through inhibition of C4BP. This study is of relevance in the context of APS, since different anticoagulant mechanisms have been subjects of debate in recent years. In conclusion, as also Ames stated regarding paper I , this thesis has tried to insert other linking pieces in the puzzle of APS. We confirm the presence of impaired fibrinolysis and complement activation in APS, and we have opened the path for a new era of research in the syndrome, where also the treatment with anticoagulants has to be considered for its potential impact on complement activation. Moreover, although causality could not be proven, we demonstrate that the prevalence of aPL after myocardial infarction in the general population is considerable and higher than generally anticipated

Venous Thrombosis

According to Virchow's triad, venous thrombosis can occur as a result of one or more of three factors: changes in the dynamics of the blood flow, endothelial injury/dysfunction of the blood vessel and hypercoagulability. The blood in the veins is constantly forming microscopic thrombi that are routinely broken down by the body, and significant clotting can occur only when the balance of thrombus formation and resolution is altered. This book is a fresh synthesis of venous thromboembolism care and considers the opinions and studies from different fields of medicine. As venous thrombosis spectrum is wide and can affect many organ systems, from deep veins of the leg to the cerebral venous system, our intent is for this to be a comprehensive, up-to-date and readable book. We tried to present a synthesis of existing material infused with new ideas and perspectives and authors own clinical studies and even case-reports

Personalised warfarin dosing in children after congenital heart surgery using the model-based approach

Oral anticoagulation with warfarin represents a major challenge to successful drug therapy in children. The aims of this study was to investigate the implementation in routine clinical practice, personalised warfarin dosing using a PK/PD model, in children after congenital heart surgery and to explore the experience of patients/parents and health care professionals with managing long-term warfarin treatment as well as their experience with the model-based dosing approach. The predictive performance of the PK/PD model was first validated using retrospectively collected data from a cohort of 60 children on long-term warfarin treatment. Seventy percent of the predicted doses were ideal with bias of -0.10 and precision of 0.19. A prospective interventional quantitative study was then conducted in two groups of children. Group 1 included 5 patients who started warfarin treatment for the first time after cardiac surgery. For the case subjects compared to the controls, the median time to achieve the first therapeutic INR values was longer (5 vs 2 days), the median time to stable anticoagulation was shorter (29.0 vs 96.5 days), the median time to over-anticoagulation was longer (15.0 vs 4.0 days), the median percentage of the INR observations within the target range (%ITR) was higher (70% vs 47.4%), the median percentage of time in therapeutic range (%TTR) was higher (83.4% vs 62.3%), the median frequency of INR measurements per month was comparable (5.0 vs 6.3) and the median frequency of dose alterations was also comparable (20.0 vs 21.0). Group 2 included 26 patients who were established on maintenance warfarin therapy. For the model-based dosing phase compared to the traditional dosing phase, the mean %ITR was 68.82% compared to 67.9% (p=0.84) and the mean %TTR was 85.47% compared to 80.2% (p=0.09). After excluding 5 patients who experienced medical issues during either phases of treatment, the mean %ITR was 71.28% compared to 65.51% (p=0.22) and the median %TTR was 91.8% compared to phase 77.3 % (p=0.03). The median frequency of INR measurements per month was 2.3 compared to 1.9 (p=0.08) and the median frequency of dose alteration was 6.5 compared to 2.5 (p=0.02). Patients with Fontan circulation had significantly higher %TTR during the model-based dosing phase than during the traditional dosing phase after excluding the 5 patients with medical issues (p=0.02). Semi-structured interviews were conducted with 3 doctors, 2 cardiac liaison nurses and four family representatives. Three thematic areas emerged from the doctors’ interviews; ‘medical and clinical knowledge’, ‘INR monitoring’ and ‘dose decision’. Four thematic areas emerged from the nurses’ interviews; ‘role of the cardiac liaison nurses in managing warfarin treatment’, ‘INR monitoring’, ‘dose decision’ and ‘adherence to the prescribed regimen’. Three thematic areas emerged from the families’ interviews; ‘managing warfarin treatment and the coping mechanism’, ‘warfarin dose decision’ and ‘adherence to warfarin treatment’. Both doctors and nurses found the new dosing approach useful and acceptable in patients with stable medical condition. Additionally, three of the families favoured that dosing be performed by a professional experienced with warfarin treatment regardless of the method used. This study has shown that model-based dosing can improve the anticoagulation control of warfarin and hence reduce its adverse events in children after congenital heart surgery. Further work is required to establish the clinical effectiveness and cost-effectiveness of the new dosing approach in this group of children.University of Baghdad/Ira

Pharmacogenetic Aspects and Drug Interactions in Anticoagulation Therapy with Coumarins

The mysterious ability of blood to clot has fascinated people over millennia. In the beginning of the 20th century, the mechanisms became better understood. In 1922, the development of hemorrhagic disease in cattle caused by mouldy sweet clover was described by Schofield. The absence or delay of blood clotting was correlated to a greatly diminished quantity of prothrombin. This discovery remained unnoticed until twenty years later the ‘hemorrhagic agent’ was identified as dicoumarol, 3,3-methylene-bis. It was promptly made available for clinical studies and already one year later first experiences on the effectiveness in deep vein thrombosis as well as its hemorrhagic complications were published. From the coumarin derivates synthesized, the most potent one was warfarin, an acronym for the Wisconsin Alumni Research Foundation (WARF). As it was used successfully to fight rats, its name may also contribute to that ‘warfare’. It was patented in 1948 and is since then the most frequently used coumarin worldwide. In 1929, Dam observed haemorrhage and markedly prolonged coagulation times in chickens fed with diets from which fat was completely extracted. He concluded that the substance whose absence in the diet was responsible for the coagulation and bone growth pathologies should be a new fat-soluble vitamin which he named vitamin K (“Koagulation”). For the discovery of vitamin K and the purification, characterization and synthesis of the vitamin, Dam and Doisy were awarded the Nobel Prize in Medicine in 1943. It was known then empirically that vitamin K reversed the bleeding problem of mouldy sweet clover poisoning. However, it took three more decades until the vitamin K cycle was proposed in 1974. After another three decades, in 2004, the complex biochemical relationship between vitamin K, its epoxide, and coumarins was enlightened by identifying the VKORC1 gene. This gene encodes the protein which is the target of the coumarins. Genetically mutated variants of the gene have been shown to cause warfarin-resistance phenotypes as well as pathogenic deficiency of all vitamin K-dependent coagulation factors