Pharmacokinetic and Pharmacodynamic Analysis of GCC-4401C, a Novel Direct Factor Xa Inhibitor, in Healthy Volunteers

Aims: GCC-4401C, an orally active direct factor Xa inhibitor which is similar to rivaroxaban, is currently under development for venous thromboembolic disease. The purpose of the present population analyses was to characterize the pharmacokinctics (PK)/pharmacodynamics (PD) of GCC-4401C and predict the proper dosage regimens in patients with venous thromboembolism, especially compared with rivaroxaban.

Methods: PK/PD data used in this analysis were from 94 healthy male subjects in two phase 1 studies, where 88 subjects received single or single (day 1) and multiple oral doses (day 3 through day 9) of placebo or GCC-4401C in fasting status in the range of 2.5 and 80 mg, and 6 received single and multiple oral dose of rivaroxaban, 20 mg in fed status. Most of the subjects were Caucasian (n=41) and African American (n=40). Plasma concentrations of GCC-4401C were measured using validated HPLC/MS-MS, and various PD endpoints were measured through the multiple assays such as PT, aPTT, coagulation factor X (CFX) assay, coagulation factor X chromogenic activity assay (FXCAA), ecarin-stimulated thrombin activity (ESTA), LMWH/anti-factor Xa (AFX) assay, and anti-thrombin III (AT III) activity assay. GCC-4401C (plasma and urine) and rivaroxaban (plasma) PK and PD were analyzed by nonlinear mixed effect modeling using NONMEM (version 7.2). Monte-Carlo simulations for plasma concentration and PD markers over time after various dosing regimens of GCC-4401C and rivaroxaban were performed based on the PK/PD models constructed in this study, and the respective median and 95% prediction intervals were visualized to compare the PK and PD characteristics between the two drugs.

Results: Plasma GCC-4401C concentrations over time were best described by a two compartment linear model. The plasma and urine PK modeling analysis results suggested that most GCC-4401C was eliminated by non-renal routes. All of the PD markers were described well with sigmoid, simple (inhibitory) Emax, or linear models, except for ESTA. For rivaroxaban, a two-compartment, linear model best described the plasma concentration over time for drug administration. Rough comparisons based on the simulation plots suggest that 20 and 40 mg of GCC-4401C are comparable to 10 and 20 mg of rivaroxaban in CFX assay, respectively. In other PD markers, the simulation showed that 10 mg of GCC-4401C under fasting status was comparable to 20 mg of rivaroxaban under fed status in AFX and 30-40 mg of rivaroxaban in FACAA and PT, whereas 20 mg of GCC-4401C was comparable to approximately 40 mg of rivaroxaban in AFX and PT, and 80 mg of rivaroxaban in FXCAA.

1. Cohen, A.T. et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality. Thrombosis and haemostasis 98, 756-764 (2007).
2. Naess, I.A., Christiansen, S.C., Romundstad, P., Cannegieter, S.C., Rosendaal, F.R. & Hammerstrom, J. Incidence and mortality of venous thrombosis: a population-based study. Journal of thrombosis and haemostasis 5, 692-699 (2007).
3. Heit, J.A., Silverstein, M.D., Mohr, D.N., Petterson, T.M., O’Fallon, W.M. & Melton, L.J. 3rd. Predictors of survival after deep vein thrombosis and pulmonary embolism: a population-based, cohort study. Archives of internal medicine 159, 445-453 (1999).
4. Andresen, M.S. et al. Mortality and recurrence after treatment of VTE: long term follow-up of patients with good life-expectancy. Thrombosis research 127. 540-546 (2011).
5. Heit, J.A., Mohr, D.N., Silverstein, M.D., Petterson, T.M., O’Fallon, W.M. & Melton, L.J. 3rd. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Archives of internal medicine 160. 761-8 (2000).