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

Background: Non-clinical and clinical studies showed efficacy of thrombomodulin alfa for disseminated intravascular coagulation, and its potential efficacy for severe sepsis and coagulopathy. Thrombomodulin alfa is excreted primarily via the kidney and renal function is known to affect the clearance. However the dosing adjustments for patients with renal dysfunction were not warranted, except for patients on hemodialysis, who had not been studied well. This study was conducted to assess the effect of renal impairment on the exposure of thrombomodulin alfa and to support a dosing rationale in patients with renal impairment especially patients on hemodialysis. Material and methods: Forty subjects with varying renal function participated in 5 groups. Each subject received one intravenous bolus injection of 0.06 mg/kg thrombomodulin alfa. The PK parameters were analyzed by a twocompartment model. The plasma concentration following multiple doses was simulated based on the PK parameters in each subject and various renal function groups. The predicted maximum plasma concentration (Cmax) was compared with the maximum non-toxic concentration (5,400 ng/mL). Results: Following multiple dose simulations of six, once-daily intravenous bolus injections of 0.06 mg/kg thrombomodulin alfa, the predicted mean Cmax in subjects with normal renal function, and mild, moderate, or severe renal impairment and on hemodialysis was 2,030, 2,350, 2,410, 3,710, 3,180 ng/mL, respectively. The highest individual simulated Cmax was 4,730 ng/mL, hence no renal function groups or no individually simulated Cmax exceeded the maximum non-toxic concentration. Conclusion: Although renal impairment was associated with increased exposure of thrombomodulin alfa, no dose adjustment is required for patients with renal impairment including patients on hemodialysis.