pyrimidinones and Hemorrhage

About 50% of patients with meta- static or inoperable melanoma carry a tumour with BRAF V600 mutation.The drug of first choice for these patients is vemurafenib, a BRAF inhibitor, which appears to prolong survival by a few months. Dabrafenib is a vemurafenib me-too with a slightly different known profile of adverse effects. Trametinib, a MEK inhibitor, is now authorised in the European Union for use in this setting, either as monotherapy or in combination with dabrafenib (marketed by the same company). Trametinib monotherapy has not been compared to BRAF inhibitor monotherapy. In a randomised, unblinded trial versus cytotoxic drugs in 322 patients, the median survival time did not differ statistically between the groups (15.6 versus 11.3 months; p = 0.09), but 65% of patients in the chemotherapy group received trametinib after disease pro- gression, making it more difficult to detect a difference between the groups. In an unblinded randomised controlled trial in 704 patients who had never received treatment for metastatic or inoperable disease, the trametinib + dabrafenib combination prolonged median survival by about 8 months more than vemurafenib. In another double-blind randomised controlled trial in 423 patients, median survival was about 6 months longer with trametinib + dabrafenib than with placebo + dabrafenib. The trametinib+ dabrafenibcombination was poorly effective after BRAF inhibitor failure in non-comparative trials including a few dozen patients in which the only endpoint was tumour response. Trametinib has many adverse effects, some of which can be life-threatening, such as heart failure, deep vein thrombosis, bleeding (including intracranial haemorrhage), neutropenia, and gastrointestinal perforation. Trametinib also causes retinal disorders and pneumonitis. Combining trametinib with dabrafenib reduces the risk of hyperkeratosis and skin cancer associated with dabrafenib, but increases the frequency of fever (including very high fever). Trametinib interactions mainly involve additive effects or antagonism. In practice, when a patient with metastatic or inoperable BRAF V600-positive melanoma is willing to accept the significant toxicity of trametinib in the hope of gaining several extra months of life, the trametinib + dabrafenib combination is a first-line option.

Topics: Heart Failure; Hemorrhage; Humans; Imidazoles; Intestinal Perforation; Intracranial Hemorrhages; MAP Kinase Kinase 1; Melanoma; Neutropenia; Oximes; Pneumonia; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Diseases; Skin Neoplasms; Survival Rate; Venous Thrombosis

Based on animal and human data, phosphoinositide 3-kinase (PI3K)β is a promising antithrombotic target. However, the relation between efficacy and bleeding when combined with current antiplatelet therapies is unclear.. To strengthen the PI3Kβ target validation using the short-acting inhibitor AZD6482 alone and in different combinations with P2Y12 and cyclooxygenase (COX)-1 inhibition in vitro (human platelets), in vivo (dog), and in healthy subjects.. Evaluation of complete target inhibition of PI3Kβ (by AZD6482), P2Y12 (by ticagrelor), and COX-1 (by aspirin) alone and in the different combinations vs. concentration responses for a panel of platelet agonists in vitro (adenosine diphosphate, collagen, thrombin receptor activating peptide) indicates that the rank order of antiplatelet efficacy is P2Y12  > PI3Kβ > COX-1 as monotherapy and P2Y12 plus PI3Kβ > P2Y12 plus COX-1 > PI3Kβ plus COX-1 as dual therapy, with little additional effect with triple therapy. Use of a conscious dog model to assess ex vivo antiplatelet effect in parallel with bleeding time prolongation (standard incision in the ear) confirms the wide separation of efficacy vs. bleeding for PI3Kβ inhibition and that this separation is reduced when combined with aspirin and more reduced when combined with clopidogrel. In healthy subjects, AZD6482, in combination with aspirin, shows a potential for greater antiplatelet potency but less bleeding potential compared with clopidogrel plus aspirin.. PI3Kβ inhibition, in comparison with P2Y12 and COX-1, delivers medium antiplatelet effect but with minimal bleeding. PI3Kβ inhibition, in combination with aspirin, in healthy subjects, provides a potential for greater overall antiplatelet effect compared with clopidogrel plus aspirin, but with significantly less bleeding potential.

Topics: Adenosine; Adult; Animals; Aspirin; Blood Platelets; Cross-Over Studies; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Dogs; Dose-Response Relationship, Drug; Drug Therapy, Combination; Hemorrhage; Humans; Male; Models, Animal; ortho-Aminobenzoates; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Function Tests; Protein Kinase Inhibitors; Purinergic P2Y Receptor Antagonists; Pyrimidinones; Receptors, Purinergic P2Y12; Sweden; Ticagrelor; Young Adult

TAK-442 is an oral direct factor Xa inhibitor. We sought to determine the dose-dependent effect of TAK-442 on major bleeding when added to standard treatment in stabilised patients with acute coronary syndrome (ACS). In this phase II double-blind study, 2,753 ACS patients were randomised to TAK-442 or placebo in addition to usual care using a three-stage adaptive design. Patients were randomised to placebo in all stages, but doses of TAK-442 escalated from 10 mg BID, 20 mg twice-daily (BID), or 40 mg once-daily (QD) in stage 1; to 40 mg BID, 80 mg QD, or 80 mg BID in stage 2; and to 160 mg QD or 120 mg BID in stage 3. Study drug was started 36 hours after emergent treatment of ACS and within seven days of admission, and continued for 24 weeks. The primary endpoint was incidence of TIMI (thrombolysis in myocardial infarction) major bleeding. TIMI major bleeding incidence was low, but higher with the pooled TAK-442 doses than with placebo (17 [0.9%] vs 4 [0.5%]; p=0.47), although the difference was neither significant nor dose-dependent. However, a dose response was evident when using the modified ISTH scale. The incidence of cardiovascular events was similar among TAK-442 dose groups and placebo. When administered over a wide range of doses after an ACS event, TAK-442 treatment did not result in a dose-dependent increase in TIMI major bleeding, but increased bleeding was observed when a more sensitive bleeding scale was used. There was no evidence for efficacy.

Topics: Acute Coronary Syndrome; Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Male; Middle Aged; Pyrimidinones; Sulfones; Treatment Outcome

This multicentre dose-finding study compared TAK-442, an oral factor Xa inhibitor, with enoxaparin for thromboprophylaxis after knee arthroplasty. In this parallel group study, patients were randomised to oral TAK-442 (40 or 80 mg once-daily [QD] or 10, 20, 40, or 80 mg twice-daily [BID] started 6-8 hours postoperatively), which was blinded as to dose, or to open-label subcutaneous enoxaparin (30 mg BID starting 12-24 hours postoperatively) for 10 days. Treatments were continued until bilateral venography was performed (maximum of 14 days). The primary efficacy endpoint was the composite of any deep-vein thrombosis, non-fatal pulmonary embolism or all-cause mortality, while the primary safety endpoint was major bleeding. Of 1,038 patients randomised who received at least one dose of study drug, 949 completed the study and 730 (76.9%) were evaluable for the primary efficacy analysis. Recruitment into the 10 and 20 mg BID dose groups was stopped early because the incidences of the primary efficacy endpoint were significantly higher than that with enoxaparin. The primary efficacy endpoint occurred in 22.0% of patients given enoxaparin and in 39.0%, 38.4%, 23.5%, 21.4%, 26.8%, and 14.3% of those receiving TAK-442 10 mg BID, 20 mg BID, 40 mg QD, 40 mg BID, 80 mg QD, and 80 mg BID, respectively. The incidences of major and clinically relevant non-major bleeding with TAK-442 were not dose-dependent or different from that with enoxaparin. All TAK-442 doses except 10 and 20 mg BID displayed similar efficacy and safety profiles to enoxaparin.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anticoagulants; Arthroplasty, Replacement, Knee; Canada; Dose-Response Relationship, Drug; Double-Blind Method; Elective Surgical Procedures; Enoxaparin; Factor Xa Inhibitors; Female; Hemorrhage; Humans; Logistic Models; Male; Middle Aged; Phlebography; Pulmonary Embolism; Pyrimidinones; Risk Assessment; Risk Factors; Sulfones; Time Factors; United States; Venous Thromboembolism; Venous Thrombosis

Published evidence suggests that phosphoinositide 3 kinase-β (PI3K-β) plays an important role in platelet aggregation and shear activation. TGX-221 is a selective PI3K-β inhibitor with a good separation of anti-thrombotic efficacy and bleeding (therapeutic index) in rats. Our goal was to further evaluate potential of a PI3K-β inhibitor as an anti-thrombotic agent by determining the therapeutic index in another species and efficacy model. Reported effects of TGX-221 in rats were also confirmed.. TGX-221 (0.3 + 0.3, 1 + 1, 3 + 3 mg/kg + mg/kg/hr, i.v.) or vehicle was given to mice starting 15 min prior to FeCl(3) arterial thrombosis (AT), tail or kidney bleeding time (BT) procedures.. Integrated blood flow over 30 min (%baseline mean ± SEM) improved (p < 0.05) with TGX-221 doses 1 + 1 (49 ± 13.9%) and 3+3 (88 ± 10.6%) versus 0.3 + 0.3 (10 ± 0.8%) and vehicle (10 ± 0.6%). Vascular patency (non-occluded/total arteries) improved (p < 0.01) with TGX-221 doses of 3 + 3 (7/8), but not 0.3 + 0.3 (0/8) or 1 + 1 (4/8) versus vehicle (0/8). Tail BT (sec) increased (p < 0.05) with TGX-221 doses of 3 + 3 (median 1560) and 1 + 1 (1305) versus vehicle (225). Mean renal BT (sec) increased (p < 0.05) in all TGX-221 groups (3 + 3: 510 + 26; 1 + 1: 478 + 41; 0.3 + 0.3: 246 + 37) versus vehicle (123 + 9). For comparison, a reference agent, aspirin (30 mpk, i.p.) increased tail BT 1.9X and renal BT 2.6X.. The novel finding of a clear impact on hemostasis by TGX-221 was demonstrated by increased bleeding in two models in mice at anti-thrombotic doses. The results suggest a narrower therapeutic index for this PI3K-β inhibitor than previously recognized, at least for this species.

Topics: Animals; Bleeding Time; Blood Platelets; Carotid Artery Thrombosis; Disease Models, Animal; Fibrinolytic Agents; Hemorrhage; Humans; Kidney; Male; Mice; Mice, Inbred C57BL; Morpholines; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Pyrimidinones; Rats; Rats, Sprague-Dawley; Tail

Thrombin amplifies the blood coagulation via factor V (FV)-mediated positive feedback loop. We hypothesised that factor Xa (FXa) inhibitors would interfere more gradually with this feedback activation loop than thrombin inhibitors, thereby achieving a better balance between haemostasis and prevention of thrombosis. In this study, we compared the effects of TAK-442, a novel FXa inhibitor, versus ximelagatran, a thrombin inhibitor, on FV-mediated positive feedback, venous thrombosis and bleeding. In normal plasma, TAK-442 delayed the onset of tissue factor-induced thrombin generation and prolonged prothrombin time (PT) with more gradual concentration-response curve than melagatran, the active form of ximelagatran. The effect of melagatran on the onset of thrombin generation decreased in an FVa-concentration-dependent manner in FV-deficient plasma supplemented with FVa. Furthermore, in FV-deficient plasma, the PT-prolonging potency of melagatran was markedly increased with a change in its concentration-response curve from steep to gradual. In the rat venous thrombosis model, TAK-442 (10 mg/kg, p.o.) prevented thrombus formation by 55% with 1.2 times prolongation of PT; a similar effect was observed in ximelagatran-treated (3 mg/kg, p.o.) rats. TAK-442 at 100 mg/kg prolonged PT by only 2.1 times with no change in bleeding time (BT), whereas ximelagatran at 10 mg/kg prolonged PT by 3.9 times and significantly increased BT. These results suggest that the differential effects of the two agents on FV-mediated amplification of thrombin generation may underlie the observation of a wider therapeutic window for TAK-442 than for ximelagatran.

Topics: Administration, Oral; Animals; Anticoagulants; Antithrombins; Azetidines; Benzylamines; Blood Coagulation; Disease Models, Animal; Dose-Response Relationship, Drug; Factor V; Factor Xa; Factor Xa Inhibitors; Feedback, Physiological; Hemorrhage; Humans; Male; Phospholipids; Prothrombin Time; Pyrimidinones; Rats; Rats, Sprague-Dawley; Risk Assessment; Sulfones; Thrombin; Thromboplastin; Venous Thrombosis

Topics: Administration, Oral; Anticoagulants; Arthroplasty, Replacement, Knee; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Elective Surgical Procedures; Enoxaparin; Evidence-Based Medicine; Factor Xa Inhibitors; Hemorrhage; Humans; Pulmonary Embolism; Pyrimidinones; Risk Assessment; Risk Factors; Sulfones; Time Factors; Venous Thromboembolism; Venous Thrombosis

Topics: Adolescent; Adult; Drug Combinations; Female; Hemophilia A; Hemorrhage; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lopinavir; Male; Pyrimidinones; Retrospective Studies; Ritonavir