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Population pharmacokinetic analysis of thrombomodulin alfa to support dosing rationale in patients with renal impairment
Author(s) -
Mouksassi MohamadSamer,
Marier JeanFrancois,
Bax Leon,
Osawa Yutaka,
Tsuruta Kazuhisa
Publication year - 2014
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.163
Subject(s) - medicine , thrombomodulin , renal function , dosing , pharmacokinetics , sepsis , population , disseminated intravascular coagulation , hematocrit , pharmacodynamics , kidney disease , creatinine , gastroenterology , pharmacology , platelet , environmental health , thrombin
Abstract Thrombomodulin alfa is a soluble recombinant human thrombomodulin that was reported to enhance the reversal of disseminated intravascular coagulation (DIC) in subjects with sepsis or hematologic malignancy and reduce mortality in subjects with sepsis and DIC. Population pharmacokinetic (PK) analysis of thrombomodulin alfa was performed based on rich samples collected in 24 healthy subjects (0.02 and 0.06 mg/kg) and sparse samples collected in 368 subjects with sepsis and DIC (0.06 mg/kg). Sources of variability (baseline characteristics, markers of renal/liver function, hematocrit, and disease severity) were explored using non‐linear mixed effect modeling to support dosing rationale in patients with sepsis and DIC. Plasma concentrations of thrombomodulin alfa were best fitted with a one‐compartment model. Body weight and creatinine clearance were important covariates describing the PK of thrombomodulin alfa. Typical CL values in patients with normal renal function, or mild, moderate and severe renal impairment were 0.158, 0.145, 0.128, and 0.105 L/h, respectively. Based on simulations, a 0.06 mg/kg dosing of thrombomodulin alfa is expected to result in drug exposure within the therapeutic range of the product (300–5,400 ng/mL), with minimum risks of bleeding in patient with normal and impaired renal functions.