Crossover Dose Escalation Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of R1663, an Oral Factor Xa Inhibitor, in Healthy Male Volunteers

Abstract

This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti-factor Xa activity) and plasma concentrations of R1663 were dose-dependent and showed low to moderate (<40%) intersubject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time to maximum concentration of R1663): clotting times were prolonged up to 2.5-fold, whereas endogenous thrombin potential (ETP) and peak height were decreased by 48% and 85% from their baseline values, respectively. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations, with IC50 values of 182 and 2680 ng/mL for peak height and ETP, respectively. Oral doses of R1663 up to 480 mg were well tolerated, with predictable pharmacodynamics and pharmacokinetics. R1663 prolonged clotting times (PT, aPTT) and inhibited thrombin generation without increasing bleeding time.

Pharmacokinetics and Pharmacodynamics of Emicizumab in Persons with Hemophilia A with Factor VIII Inhibitors: HAVEN 1 Study

“…This was, however, associated with relatively large variability, possibly due in part to the concomitant use of BPAs for the treatment of breakthrough bleeding; such variability also aligns with data reported for TG values in both PwHA and healthy people. [30][31][32] These TG peak height results confirmed the procoagulant effect of emicizumab and demonstrated the ability of TG assays to provide an indication of emicizumab procoagulant activity. Although availability of TG assays is limited to specialized laboratories, this usage was evidenced by a recently published case in which TG was used to guide the management of breakthrough bleeds with BPAs in a participant receiving emicizumab.…”

Bayesian adaptive designs in single ascending dose trials in healthy volunteers

“…Other designs where each volunteer receives more than one dose level (e.g. three dose levels with a sufficient wash out between each dose level) are used in SAD trials and are called dose escalation with crossover designs or leap frog designs . The performance of the Bayesian adaptive approach with crossover designs is of great interest and further research work should be conducted to explore an area where improvements are also possible.…”

Safety, pharmacokinetics and pharmacodynamics of multiple ascending doses of R1663, an oral factor Xa inhibitor, in healthy young subjects coupled with exploration of influence of gender and age

“…Adverse events were graded on a three-point scale according to their severity (mild, moderate and severe). Bleeding time assessments were determined using a modified Ivy bleeding time test (16,17) before the first dose on day 1 and at 3 h (around t max ) and 8 h after the last dose on day 7.…”

“…It has demonstrated antithrombotic activity in rabbit thrombosis models, with significant dose-dependent inhibition of FXa activity and prolongation of clotting times (prothrombin time [PT] and activated partial thromboplastin time [aPTT]), without significantly affecting bleeding time (Himber J, Burcklen L, Mary JL, unpublished data, 2006). Previous clinical data showed that renal elimination of the unchanged drug was minimal (16). In fact, R1663 was mainly eliminated by metabolism, either hydrolysed by ubiquitous amidases or dealkylated by CYP3A4, and converted into two main metabolites, both devoid of pharmacological activity (Mary JL, unpublished data, 2006).…”

“…In fact, R1663 was mainly eliminated by metabolism, either hydrolysed by ubiquitous amidases or dealkylated by CYP3A4, and converted into two main metabolites, both devoid of pharmacological activity (Mary JL, unpublished data, 2006). In a single ascending dose study, R1663 has been shown to be safe and well tolerated up to 480 mg in healthy male volunteers, with predictable pharmacody-namics and pharmacokinetics, where it caused concentration-dependent prolongation of clotting times and inhibition of thrombin generation without increasing bleeding time (16).…”