title: Population pharmacokinetic analysis of thrombomodulin alfa to support dosing rationale in patients with renal impairment.
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.
authors.affiliation: Pharsight, a Certara Company, Montreal, QC, Canada.
authors.forename: Mohamad-Samer
authors.initials: MS
authors.lastname: Mouksassi
authors.affiliation: Pharsight, a Certara Company, Montreal, QC, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Marier
authors.affiliation: Pharsight, a Certara Company, Sunnyvale, CA, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: Bax
authors.affiliation: Asahi Kasei Pharma America Corporation, Waltham, MA, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Osawa
authors.affiliation: Asahi Kasei Pharma America Corporation, Waltham, MA, USA.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Tsuruta
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001777:Blood Coagulation / Q000187:drug effects*; D003198:Computer Simulation; D004211:Disseminated Intravascular Coagulation / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D004311:Double-Blind Method; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology*; D007674:Kidney Diseases / Q000097:blood / Q000175:diagnosis / Q000503:physiopathology*; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D018570:Risk Assessment; D018805:Sepsis / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D018180:Thrombomodulin / Q000008:administration & dosage* / Q000097:blood; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C472045:ART123; D000925:Anticoagulants; D011994:Recombinant Proteins; D018180:Thrombomodulin
keywords: pharmacokinetics; renal impairment; thrombomodulin alfa