Current Drug Metabolism - Volume 18, Issue 7, 2017

Background: The Direct Oral Anticoagulants (DOACs) represent a new generation of antithrombotic agents, providing direct inhibition of either thrombin (factor IIa; FIIa) or activated factor X (FXa). Around the globe, their use is progressively rising, as these new agents replace the historical anticoagulants (heparin and vitamin K antagonists including warfarin) for various clinical conditions in medical practice. Other acronyms used to designate DOACs include TSOAC (target specific oral anticoagulants) and NOAC (novel; or non-vitamin K antagonist oral anticoagulants). Currently available DOACS include dabigatran (FIIa inhibitor), along with rivaroxaban, apixaban, edoxaban and betrixaban (FXa inhibitors). Objective: This narrative review aims to briefly summarise the evidence concerning utility of different laboratory assays for qualitative or quantitative assessment of DOACs, emphasizing the difference between ‘drug monitoring’ and ‘drug measurement’ and ultimately discussing advantages and limitations of these processes. Results and Conclusion: Recently, the dogma that these innovative anticoagulant agents will not necessitate laboratory testing has been challenged with the recognition that assessment of drug concentration or activity may be required in some circumstances, although this does not immediately translate to the concept of ‘drug monitoring’.

Background: Apixaban is an oral, potent, highly selective, reversible and direct inhibitor of activated coagulation factor X, that is the end point of the intrinsic and extrinsic coagulation pathway. Additionally, apixaban has the capacity to indirectly inhibit thrombin-induced platelet aggregation. This new oral anticoagulant represents an immediate-release form of peroral drug with quick dissolution, linear pharmacokinetics, good bioavailability and rapid onset and offset of action. No clinically relevant age- or sex-dependent difference in the apixaban pharmacokinetics and pharmacodynamics which would lead to the modification of the dose exists, apixaban may even be administered with or without food. Its elimination is mediated by metabolism, renal elimination of unmodified drug and excretion in the gastrointestinal tract. Objective: The authors aim to provide a review of currently available literature about apixaban. Method: The authors summed-up the data from the scientific journals related to thrombosis and hemostasis and searched the available databases. Results and Conclusion: Apixaban has many advantages including predictable pharmacokinetics and pharmacodynamics, low number of drug and food interactions, and relatively wide therapeutic window.

Background: The superiority of dabigatran has been well proven in the standard dosing regimen in prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) and extended venous thromboembolism (VTE) treatment. Dabigatran, an anticoagulant with a good safety profile, reduces intracranial bleeding in patients with atrial fibrillation and decreases major and clinically relevant non-major bleeding in acute VTE treatment. However, several important clinical issues are not fully covered by currently available directions with regard to dabigatran administration. The prominent one is reflected in the fact that dynamic impairment in renal function due to dehydratation may lead to haemorragic complications on the one hand, while on the other hand glomerular hyperfiltration may be a possible cause of dabigatran subdosing, hence reducing the drug's efficacy. Furthermore, limitations of the Cockcroft-Gault formula, considered a standard equation for assessing the renal function, may imply that other calculations are likely to obtain more accurate estimates of the kidney function in specific patient populations. Method and Conclusions: Although not routinely recommended, a possibility of monitoring dabigatran in special clinical settings adds to optimization of its dosage regimens, timely perioperative care and administration of urgently demanded thrombolytic therapy, therefore significantly improving this drug’s safety profile. Despite the fact that dabigatran has fewer reported interactions with drugs, food constituents, and dietary supplements, certain interactions still remain, requiring considerable caution, notably in elderly, high bleeding risk patients, patients with decreased renal function and those on complex drug regimens. Additionally, upon approval of idarucizumab, an antidote to dabigatran solution, hitherto being a major safety concern, has been finally reached, which plays a vital role in life-threatening bleeding and emergency interventions and surgery.

Background: Rivaroxaban represents a selective direct inhibitor of activated coagulation factor X (FXa) having peroral bioavailability and prompt onset of action. Objective: The absorbtion of rivaroxaban is quick, reaching maximum plasma concentration 2-4 hours following its administration. Peroral bioavailability is high (80-100 %) and pharmacokinetic variability is considered to be moderate (coefficient of variation 30-40 %). This review discusses the properties, drug interactions, pharmacokinetics and clinical indications of rivaroxaban. Method: Dosing regimen of rivaroxaban was derived from pharmacologic data of the development program aimed to gain strong antithrombotic drug and balance between efficacy and risk of bleeding in patients. Results of doseranging trials, pharmacokinetic models and randomised studies of phase III advocate the use of such schemes in everyday practice. Results: The drug has been manufactured to fulfill clinical requirements in a variety of indications in adults: prophylaxis of venous thromboembolism (VTE) following elective knee or hip replacement surgical intervention, therapy and secondary prophylaxis of VTE, prophylaxis of ischemic stroke and embolism in individuals diagnosed with nonvalvular atrial fibrillation (NVAF) with risky characteristics, and in Europe the prophylaxis of atherothrombotic episodes following an acute coronary syndrome in subjects with increased levels of cardiac biomarkers. Conclusion: Rivaroxaban may offer benefit in many clinical situations. In comparison with low molecular weight heparin and fondaparinux requiring subcutaneous way of administration, and with vitamin K antagonists (VKAs), which require regular monitoring of international normalized ratio, rivaroxaban is relatively easy to use. However, adjustments of dose are needed in individuals with impaired renal functions.

Background: Direct oral anticoagulants (DOACs) offer consistent and predictable anticoagulation, oral administration with good patient compliance and a good safety profile. Dabigatran - a direct thrombin inhibitor, apixaban and rivaroxaban - direct factor Xa inhibitors are now largely used for anticoagulation in patients with nonvalvular atrial fibrillation and in patients with venous thromboembolism. These agents have emerged as an expediential clinical choice in long-term anticoagulation for an increasing number of patients. Despite their advantages, concerns persist about a lack of rapid reversal agents in urgent clinical situations. Methods: This review is focused on the pharmacology of nonspecific and target-specific reversal agents for DOACs-induced anticoagulation. A systemic review of preclinical and clinical studies published in peer-reviewed scientific journals was performed. Results and Conclusions: Fresh frozen plasma and coagulation factors concentrates might be considered in bleeding emergencies; however, there is a lack of larger studies confirming the efficacy of coagulation factors concentrates for the reversal of DOACs-induced anticoagulation, and a particular risk of coagulation factors concentrates-induced thrombosis. Recently, idarucizumab has been approved commercially for acute reversal of dabigatran in emergencies as a first target-specific reversal agent. Moreover, andexanet alpha and aripazine are being extensively studied in several phase II and III clinical studies. It is likely that more target-specific agents for reversal of DOACs-induced anticoagulation will be introduced to clinical practice in near future.

Background: The 10th edition of the CHEST Guideline and Expert Panel Report for the treatment of venous thromboembolism (VTE) was recently updated with recommendations on both the choice of anticoagulants and the duration of treatment in diverse clinical scenarios. Method: In this paper, we focus on news in the use of direct oral anticoagulants (DOACS), a group of synthetic low molecular weight drugs capable of directly and specifically inhibiting either activated factor X or both free and fibrin- bound thrombin. Results: New to the guidelines is the recommendation of the use of DOACS over vitamin K-antagonists (VKA´s) in individuals without cancer who develop VTE. The choice and intensity of anticoagulants is the same for lower and upper extremity thrombosis or for pulmonary embolism. For cancer-related thrombosis low molecular weight heparin is still recommended over the use of VKA´s or DOACS, though high quality evidence for this choice is lacking. If therapy is given beyond three months, remaining on the same anticoagulant is suggested. Re-thrombosis while on regular use of DOACs requires switching to low molecular weight heparins at least for one month. Conclusion: Ultimately the choice of anticoagulant will depend on patient–specific factors such as comorbidities, compliance, patient preferences, availability and costs. We address the news in DOAC use in VTE from the perspective of an upper-middle income economy.

Background: Tumor recurrence is the most expected clinical event after the resection of non-muscle invasive bladder cancer, depending on histological findings of the initial lesion. In patients with low and intermediate risk of disease, the intravesical instillation of chemotherapy agents is recommended as a standard treatment to reduce recurrences. Methods: A comprehensive review covering various aspects of different treatments with intravesical drugs is presented. Results: Drugs may be instilled into the bladder starting with a single, ‘early’ postoperative administration or, after tumor resection with adjuvant intent or, before tumor resection under a neo-adjuvant regimen. Both latter protocols would consist of weekly treatments followed by monthly maintenance treatments. Different methods of administering drugs intravesically have been proposed to enhance the depth of drug penetration and its absorption into the bladder wall thus increasing the rate of drug-DNA reaction. These device-assisted therapies therefore have set a goal to potentiate the drug’s effect and efficaciousness. The Radiofrequency-Induced Thermochemotherapeutic Effect (RITE) and the Electromotive-Drug Administration (EMDA) are the two most relevant modalities used to increase the activity of intravesical chemotherapy. Despite the widely adopted international guidelines’ recommendations, and recent clinical trials of device-assisted chemotherapy instillations showing markedly enhanced recurrence-free survival compared even to the standard of care, clinicians and pharmacologists are not familiar with the in-depth physical aspects, pharmacokinetics and systemic absorption of chemotherapeutic drugs following their intravesical administration. Conclusion: Knowledge of drug diffusion mechanisms into the tissue and cellular cytoplasm following bladder instillation is a key to understand the safety profile and clinical activity of chemotherapy.

Background: Inflammatory bowel diseases are chronic bowel disorders the causes of which have not been fully elucidated, though they all sharean immunological basis. They have an important impact on both quality of life of the patient and on healthcare services. Method: The incorporation of biological agents against tumour necrosis factor (TNF) alpha some 15 years ago represented a revolution in the management of patients with disease that did not respond to conventional treatment, enabling an overall improvement in the quality of life of many of these patients. Results: Nonetheless, these agents are not effective in an appreciable percentage of patients (primary lack of response), can lose their efficacy over time even though they were initially effective (loss of secondary response), and can also be burdened by varied and sometimes severe adverse effects (e.g., infusion reactions, infections, neoplasms). Consequently, basic research over recent years has provided us with promising new pharmacological agents aimed at targets other than TNF alpha (IL12/23, anti-adhesion molecules, Janus kinase inhibitors, anti- Smad7, blockade of sphingosine-1-phosphate receptors). Conclusion: This paper reviews some of the key aspects of these new drugs, including their mechanism of action, some incipient pharmacokinetic and metabolic data, their efficacy and their safety. These new agents will take on an important role in the coming years in the management of patients with moderate-to-severe forms of inflammatory bowel disease.

Background: Vitamin D deficiency is one determinant of secondary hyperparathyroidism in the course of Chronic Kidney Disease (CKD). However, numerous studies support the notion that vitamin D may exert pleiotropic effects aside of mineral metabolism control. Indeed, vitamin D receptor has been identified in a great variety of tissues and its activation contributes to the parathyroid, intestine, cardiovascular and immune system regulation. Conclusion: We herein review vitamin D metabolism and effects with a specific emphasis on the potential impact of vitamin D receptor modulation aside from parathyroid hormone control.