Pharmacokinetics of recombinant human soluble thrombomodulin, thrombomodulin alfa in the rat

Abstract

1. The study aimed to investigate the pharmacokinetics of thrombomodulin alpha (TM-alpha), human-soluble thrombomodulin in rats. 2. Intravenously administered TM-alpha was eliminated in two phases (T(1/2 alpha) = 0.2-0.3 h and T(1/2 beta) = 6-8 h), and the elimination curve was linear in a dose range of 10-250 microg kg(-1). Based on the results of tissue concentration studies after reaching the steady-state, the highest concentration of TM-alpha was seen in the plasma, suggesting the low levels of transfer to tissues (< or = 22% of plasma levels). 3. In vivo metabolism of TM-alpha was also analysed using high-performance liquid chromatography. The main peak observed in the plasma was TM-alpha, and even 72 h after the last dose of repeated administrations, 80% or more was unchanged form. Approximately half of the radioactivity excreted in the urine was recovered as a peak corresponding to TM-alpha. 4. The results reveal that although plasma clearance was lower in the renally impaired rats, the decrease was not large, with a difference of only about 20%. As a result, although the cause remains unclear, it is considered unlikely that the plasma concentrations of TM-alpha will vary considerably in patients with renal impairment.

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

“…The CL of this drug was affected because of renal impairment in DIC patients, as CLcr was about 30% lower in patients with impaired renal function (<30 mL/min) than in patients with normal renal function; in a patient on dialysis treatment included in this analysis (CLcr = 10 mL/min), the decrease in CL was about 40%. The results of PPK analysis indicated an allometric effect on CL, and a large decrease in patients with major renal impairment that could not be estimated can be attributed to renal excretion rates of 54% to 74% found in phase 1 studies 15 , 16 and the presence of nonrenal clearance (in vivo degradation) found in nonclinical studies 28 . In addition, the impact of renal impairment on C max was minimal and did not exceed the C max in healthy adults, given that Vd was unaffected in renal impairment and that Vd in DIC patients, many of whom have low Hct levels, was lower than in healthy adults.…”

“…The results of PPK analysis indicated an allometric effect on CL, and a large decrease in patients with major renal impairment that could not be estimated can be attributed to renal excretion rates of 54% to 74% found in phase 1 studies 15, 16 and the presence of nonrenal clearance (in vivo degradation) found in nonclinical studies. 28 In addition, the impact of renal impairment on C max was minimal and did not exceed the C max in healthy adults, given that Vd was unaffected in renal impairment and that Vd in DIC patients, many of whom have low Hct levels, was lower than in healthy adults. Given these findings, although CL was slightly decreased in DIC patients with renal impairment, an abrupt increase in C max is unlikely to occur, and thus strict dose adjustment based on the renal function is not necessary in all cases.…”

Pharmacokinetics of Recombinant Soluble Human Thrombomodulin in Subjects with Normal and Various Impaired Renal Function

“…CLtot of Severe Impairment and ESRD Groups decreased to 27.5% and 32.4% of CLtot of Healthy Group, hence the renal clearance of thrombomodulin alfa in these renal-impaired population was thought to be very minimal. A pharmacokinetics study of thrombomodulin alfa in rats reported metabolism in liver and lung [3]. In subjects from Severe Impairment and ESRD Groups, thrombomodulin alfa was thought to be cleared by such non-renal metabolisms.…”

“…Experimental data suggest that thrombomodulin alfa has anti-inflammatory effects through activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI), and inhibition of high mobility group box 1 (HMGB1) activity directly [2]. Thrombomodulin alfa was approved for the treatment of disseminated intravascular coagulation (DIC) in Japan in 2008 [3]; and a global Phase 3 study is being conducted to confirm the efficacy and safety of thrombomodulin alfa for the treatment of severe sepsis and coagulopathy [4]. The dosing regimen for the ongoing study is 0.06 mg/kg/day up to a maximum dose of 6.0 mg/day for six days [4].…”

Population pharmacokinetics of thrombomodulin alfa in pediatric patients with hematological malignancy and disseminated intravascular coagulation

“…TM‐α contains the active, extracellular domain of thrombomodulin, which binds to thrombin to inactivate coagulation. Additionally, the thrombin/TM‐α complex activates protein C to produce activated protein C. The activated protein C inactivates factors Ⅴ and VIII in the presence of protein S, which inhibits thrombin formation . After a phase III randomized, controlled trial, TM‐α was approved and has been widely used in Japan for patients with DIC.…”