Hamim Zahir

Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex Concentrate

Background— The oral factor Xa inhibitor edoxaban has demonstrated safety and efficacy in stroke prevention in patients with atrial fibrillation and in the treatment and secondary prevention of venous thromboembolism. This study investigated the reversal of edoxaban’s effects on bleeding measures and biomarkers by using a 4-factor prothrombin complex concentrate (4F-PCC). Methods and Results— This was a phase 1 study conducted at a single site. This was a double-blind, randomized, placebo-controlled, 2-way crossover study to determine the reversal effect of descending doses of 4F-PCC on bleeding duration and bleeding volume following edoxaban treatment. A total of 110 subjects (17 in part 1, 93 in part 2) were treated. Intravenous administration of 4F-PCC 50, 25, or 10 IU/kg following administration of edoxaban (60 mg) dose-dependently reversed edoxaban’s effects on bleeding duration and endogenous thrombin potential, with complete reversal at 50 IU/kg. Effects on prothrombin time were partially reversed at 50 IU/kg. A similar trend was seen for bleeding volume. Conclusions— The 4F-PCC dose-dependently reversed the effects of edoxaban (60 mg), with complete reversal of bleeding duration and endogenous thrombin potential and partial reversal of prothrombin time following 50 IU/kg. Edoxaban alone and in combination with 4F-PCC was safe and well tolerated in these healthy subjects. A dose of 50 IU/kg 4F-PCC may be suitable for reversing edoxaban anticoagulation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02047565.

Pharmacokinetics, Safety, and Tolerability of Teduglutide, a Glucagon-Like Peptide-2 (GLP-2) Analog, Following Multiple Ascending Subcutaneous Administrations in Healthy Subjects

Teduglutide, a glucagon‐like peptide‐2 (GLP‐2) analog, is currently being evaluated for the treatment of short‐bowel syndrome, Crohns disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N =64) were assessed following daily subcutaneous administrations for 8 days in a double‐blinded, randomized, placebo‐controlled, ascending‐dose study. Teduglutide treatments were administered as a 50‐mg/mL (10, 15, 20, 25, 30, 50, and 80 mg) or 20‐mg/mL (20 mg) formulation. Blood samples were collected on days 1 and 8, and plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method. Mean systemic exposures to teduglutide were very similar on days 1 and 8, suggesting minimal, if any, accumulation following once‐daily repeated administrations. The apparent clearance of teduglutide following administration of the 50‐mg/mL formulation was constant over the dose range, with mean values in male and female subjects of 0.155 and 0.159 L/h/kg, respectively. Peak plasma concentrations and total exposure of teduglutide after subcutaneous injection of a 20‐mg/mL formulation (1.0 mL) were approximately 15% and 78% higher than those observed with the 50‐mg/mL formulation (0.4 mL), respectively. Teduglutide treatments were safe and well tolerated. All but 1 adverse event was assessed as mild or moderate in severity. No relationship between teduglutide treatments and frequency of adverse events was observed, with the exception of injection site pain, which increased as a function of dose and injected volume. Results from the current study will assist in the dose selection in future efficacy studies.

A Phase 1 Study of Efatutazone, an Oral Peroxisome Proliferator-Activated Receptor Gamma Agonist, Administered to Patients With Advanced Malignancies

Efatutazone (CS‐7017), a novel peroxisome proliferator‐activated receptor gamma (PPARγ) agonist, exerts anticancer activity in preclinical models. The authors conducted a phase 1 study to determine the recommended phase 2 dose, safety, tolerability, and pharmacokinetics of efatutazone.

Edoxaban administration following enoxaparin: A pharmacodynamic, pharmacokinetic, and tolerability assessment in human subjects

Edoxaban is an oral direct factor (F)Xa inhibitor in advanced stages of clinical development. The primary objective of the present study was to assess the pharmacodynamics (PD) and safety of enoxaparin 1 mg/kg followed 12 hours (h) post-dose by edoxaban 60 mg, which is the regimen being used in the phase III study of edoxaban for the treatment of venous thromboembolism (Hokusai-VTE). This was a phase I, open-label, randomised, four-period, four-treatment cross-over study. Treatments were edoxaban alone (EDOX), enoxaparin alone (ENOX), edoxaban plus enoxaparin (EDOX+ENOX), and enoxaparin followed by edoxaban 12 h later (ENOX12-EDOX). Serial blood samples were collected for PD (thrombin generation, anti-FXa) and pharmacokinetic (PK) variables (edoxaban and its principal metabolite M4 by LC-MS/MS, and anti-FIIa as a surrogate of enoxaparin). The highest effect on thrombin AUC (endogenous thrombin potential, or ETP), thrombin (peak), thrombin generation lag time, and velocity index was observed for EDOX+ENOX, followed by ENOX, ENOX12-EDOX, and EDOX. The greatest effect on anti-FXa activity was observed for EDOX+ENOX, followed by ENOX12-EDOX. As expected, neither edoxaban nor enoxaparin significantly altered the PK of the other drug. There were no serious adverse events during the study. It is concluded that a 60-mg dose of edoxaban can be safely administered 12 h following enoxaparin 1 mg/kg.

Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: Results from a 12-week, open-label pilot study in multiple sclerosis patients

CS-0777 is a selective sphingosine 1-phosphate receptor-1 modulator under investigation for treatment of multiple sclerosis (MS). We conducted an open-label, pilot study in 25 MS patients to assess the safety, pharmacokinetics, pharmacodynamics and exploratory efficacy of oral CS-0777 (0.1, 0.3 and 0.6 mg), administered once weekly or every other week for 12 weeks. CS-0777 resulted in a pronounced, dose-dependent decrease in lymphocytes and CD4 T cell subsets, which returned to baseline within 4 weeks after the last dose. Overall, CS-0777 was safe and well-tolerated. These results require confirmation in a double-blind, placebo-controlled and adequately powered phase 2 study in MS.

Edoxaban drug–drug interactions with ketoconazole, erythromycin, and cyclosporine

Aims Edoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P‐glycoprotein (P‐gp). Three edoxaban drug–drug interaction studies examined the effects of P‐gp inhibitors with varying degrees of CYP3A4 inhibition. Methods In each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P‐gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study. Results Coadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half‐life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9‐fold and peak exposure by 8.7‐fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed. Conclusions Administration of dual inhibitors of P‐gp and CYP3A4 increased edoxaban exposure by less than two‐fold. This effect appears to be primarily due to inhibition of P‐gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.

Pharmacological Modulation of Peripheral T and B Lymphocytes by a Selective Sphingosine 1‐Phosphate Receptor‐1 Modulator

CS‐0777 is a selective sphingosine 1‐phosphate receptor‐1 (S1P1) modulator under development for treatment of autoimmune conditions. A randomized, double‐blind, placebo‐controlled study was conducted to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CS‐0777 in escalating dose cohorts of healthy male participants (0.1, 0.3, 1.0, and 2.5 mg; 6 active, 2 placebo per cohort). Primary pharmacodynamic parameters were absolute lymphocyte counts and lymphocyte subsets (CD4 and CD8 T and B cells). CS‐0777 resulted in a pronounced, dose‐dependent decrease in absolute lymphocyte counts (mean percent decrease from baseline at 24 hours postdose: 7%, 26%, 52%, 79%, and 85%, for placebo and 0.1, 0.3, 1.0, and 2.5 mg, respectively). Dose‐related decreases of similar magnitude were observed for T and B cell subsets. Mean total white blood cell and neutrophil counts remained within normal ranges for all dose levels. CS‐0777 was well tolerated, and there were no serious or severe adverse events. Mild, asymptomatic bradycardia and transaminase elevations (<3‐fold upper limit of normal), similar to findings for other S1P receptor modulators, were observed at the highest dose level (2.5 mg). Therefore, CS‐0777 shows potent activity in humans and may hold potential for treatment of autoimmune conditions such as multiple sclerosis.

Nonvitamin K antagonist oral anticoagulant activity: challenges in measurement and reversal

BackgroundFour nonvitamin K antagonist oral anticoagulants (NOACs) are approved for the prevention of stroke in patients with nonvalvular atrial fibrillation and for the treatment of venous thromboembolism. These include the direct thrombin inhibitor dabigatran and the direct factor Xa inhibitors rivaroxaban, apixaban, and edoxaban. Bleeding is a complication for all anticoagulants and concerns regarding bleeding risk and the suitability of effective reversal strategies may be a barrier to their prescription. Despite the reduced risk of bleeding compared with vitamin K antagonists, questions persist regarding the management of bleeding related to NOAC use.Main textTo date, although a number of assays are responsive to NOACs, no single routine laboratory test has been identified to accurately measure the clinical anticoagulation state of patients on NOACs or established as a reliable predictor of bleeding risk. In addition, the establishment of a reliable human bleeding model to test novel inhibitors of the coagulation cascade has proved challenging. Although routine monitoring of anticoagulant levels is not necessary in patients taking NOACs, anticoagulant reversal and a means of measuring reversal may be required for patients who present with bleeding or require urgent surgery. Prothrombin complex concentrates are pooled plasma products containing varying amounts of inactive vitamin K-dependent clotting factors in addition to vitamin K-dependent proteins and can replenish factors in the intrinsic and extrinsic coagulation cascade, reversing an anticoagulant effect. Only one agent, idarucizumab, has been approved for rapid reversal of dabigatran-induced anticoagulation and one more agent, andexanet alfa, has been submitted for approval to reverse the anticoagulatory effects of direct and indirect factor Xa inhibitors.ConclusionsThis review discusses the laboratory tests available for assessing anticoagulation, human models of bleeding, and the use of current strategies—including prothrombin complex concentrates for reversal of anticoagulation by NOACs—to manage bleeding in patients.

Use of an Exposure‐Response Model to Aid Early Drug Development of an Oral Sphingosine 1‐Phosphate Receptor Modulator

Pharmacokinetic (PK) and exposure‐response modeling of a selective sphingosine 1‐phosphate receptor‐1 modulator (CS‐0777) was conducted in an iterative process to guide early clinical development decisions. A model based on preclinical data from monkeys was extrapolated to humans to support a single ascending dose (SAD) study. The model was updated after each cohort, providing guidance on both maximal inhibition and time to recovery for lymphocyte counts. A 2‐compartment PK model with first‐order absorption and elimination was found to describe the monkey and human datasets. The relationship between lymphocyte counts and active metabolite (M‐1) concentrations was modeled via an indirect response model, whereby M‐1 inhibited the reentry of lymphocytes to the circulation. The indirect‐response model based on SAD data had an Imax of approximately 85% and an IC50 of 0.24 ng/mL. Additionally, based on SAD data, similar models were developed for lymphocyte subsets, including CD4 cells. Subsequently, simulations were utilized to design a multiple ascending dose study with adaptive dosing regimens that would meet targeted pharmacodynamic (PD) response thresholds (eg, minimum 40% reduction in lymphocytes) while maintaining CD4 counts above a reasonable safety threshold. In conclusion, model‐based development and use of adaptive designs for dose optimization can reduce the time and number of subjects needed in early clinical development.

Metabolism and disposition of [14C]tivantinib after oral administration to humans, dogs and rats

Abstract 1. The biotransformation and disposition of tivantinib in humans, dogs and rats was examined after a single oral administration of [14C]tivantinib. Tivantinib constituted no more than one-third of the plasma radioactivity in all species, demonstrating significant contribution of the metabolites to plasma radioactivity. The major circulating metabolites in all species were M4 and M5, hydroxylated metabolites at the benzyl position of the tricyclic ring, accounting for 19.3 and 12.2% of the AUC of the total radioactivity, respectively, in humans. 2. The majority of radioactivity was excreted to the feces via bile. Tivantinib was detected at trace levels in urine, feces and bile, demonstrating extensive metabolism prior to biliary excretion and nearly complete tivantinib absorption under fed conditions. 3. Seven metabolic pathways were identified for tivantinib and included six oxidations (M4, M5, M7, M8, M9 and M11) and one glucuronidation (M23). The major metabolic and excretory pathways were found to be common among all species. Species differences in the metabolic pathways included lactam metabolite (M8) formation in humans and dehydrogenated metabolite (M11) formation in animals. 4. None of the metabolites identified in this work are believed to significantly impact the efficacy or toxicity of tivantinib in humans.