Model-Based Analysis of Covariate Effects on Population Pharmacokinetics of Thrombomodulin Alfa in Patients With Disseminated Intravascular Coagulation and Normal Subjects

Abstract

Thrombomodulin alfa is the recombinant extracellular domain of human thrombomodulin, which shows anticoagulation activity. To elucidate the pharmacokinetics of thrombomodulin alfa in patients with disseminated intravascular coagulation (DIC), population pharmacokinetic (PPK) analysis was performed using plasma concentration data obtained in phase 1 (20 patients, 348 time points) and phase 2 (116 patients, 305 time points) clinical trials. The actual and predicted plasma concentrations of thrombomodulin alfa based on the final PPK model showed a good linear correlation (R = 0.9504), and the pharmacokinetics of thrombomodulin alfa in DIC patients were affected by body weight, age, renal dysfunction, and hematocrit value. The distribution volume and clearance (CL) were proportional to body weight and were significantly increased in patients with lower hematocrit value (male <40%, female <35%). Furthermore, CL was decreased in patients with renal dysfunction and in elderly patients. Based on these results, the standard dose of thrombomodulin alfa is adjusted according to body weight. However, further dose adjustment is not needed based on age and hematocrit value, since these factors did not cause the large changes in plasma concentration that can affect the efficacy or safety.

Thrombomodulin improves rat survival after extensive hepatectomy

“…The experiment used only male rats, as was the case in previous reports of extensive Hx [4,8,10]. Regarding gender bias, according to the population pharmacokinetics of rTM [21], there are no differences in the efficacy of rTM according to gender. Additionally, there is no report indicating a gender bias in animal experiments using rTM.…”

Recombinant human soluble thrombomodulin (thrombomodulin alfa) to treat disseminated intravascular coagulation in solid tumors: results of a one-arm prospective trial

“…A pharmacokinetic profile of TM-α after intravenous infusion with clinical dosages for 14 consecutive days (a once-daily dose of 380 U/kg) was simulated based on the estimated population pharmacokinetic parameters. Mean values of systemic clearance, volume of distribution and body weight of patients were 0.0922 L/h, 3.62 L and 53.9 kg, respectively [5], and were used to obtain the simulated pharmacokinetic profile of TM-α using a one-compartment model (WinNonlin Professional 6.2; Pharsight Corporation, Mountain View, CA, USA).…”

A Novel Strategy for Hemolytic Uremic Syndrome: Successful Treatment With Thrombomodulin α

“…14 rTM has also been shown to have a wide safety margin and a favorable antithrombotic profile. 21 No other adverse effects were observed in these patients.…”