title: A PK-PD model-based assessment of sugammadex effects on coagulation parameters.
abstract: Exposure-response analyses of sugammadex on activated partial thromboplastin time (APTT) and prothrombin time international normalized ratio (PT(INR)) were performed using data from two clinical trials in which subjects were co-treated with anti-coagulants, providing a framework to predict these responses in surgical patients on thromboprophylactic doses of low molecular weight or unfractionated heparin. Sugammadex-mediated increases in APTT and PT(INR) were described with a direct effect model, and this relationship was similar in the presence or absence of anti-coagulant therapy in either healthy volunteers or surgical patients. In surgical patients on thromboprophylactic therapy, model-based predictions showed 13.1% and 22.3% increases in respectively APTT and PT(INR) within 30min after administration of 16mg/kg sugammadex. These increases remain below thresholds seen following treatment with standard anti-coagulant therapy and were predicted to be short-lived paralleling the rapid decline in sugammadex plasma concentrations.
authors.affiliation: Quantitative Pharmacology & Pharmacometrics, MSD Oss B.V., Oss, The Netherlands. Electronic address: R.Bosch@lapp.nl.
authors.forename: Rolien
authors.initials: R
authors.lastname: Bosch
authors.affiliation: Quantitative Pharmacology & Pharmacometrics, MSD Oss B.V., Oss, The Netherlands.
authors.forename: Marie-José
authors.initials: MJ
authors.lastname: van Lierop
authors.affiliation: Clinical Research, Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Pieter-Jan
authors.initials: PJ
authors.lastname: de Kam
authors.affiliation: CHDR (Centre for Human Drug Research), Leiden, The Netherlands.
authors.forename: Annelieke C
authors.initials: AC
authors.lastname: Kruithof
authors.affiliation: CHDR (Centre for Human Drug Research), Leiden, The Netherlands.
authors.forename: Jacobus
authors.initials: J
authors.lastname: Burggraaf
authors.affiliation: Quantitative Pharmacology & Pharmacometrics, MSD Oss B.V., Oss, The Netherlands.
authors.forename: Rik
authors.initials: R
authors.lastname: de Greef
authors.affiliation: Clinical Research, Merck & Co., Inc., Kenilworth, NJ, United States. Electronic address: sandra.visser@merck.com.
authors.forename: Sandra A G
authors.initials: SA
authors.lastname: Visser
authors.affiliation: Scientific Affairs, Merck & Co., Inc., Kenilworth, NJ, United States.
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.affiliation: Quantitative Pharmacology & Pharmacometrics, MSD Oss B.V., Oss, The Netherlands.
authors.forename: Huub-Jan
authors.initials: HJ
authors.lastname: Kleijn
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology* / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006493:Heparin / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D000077122:Sugammadex; D013927:Thrombosis / Q000517:prevention & control; D055815:Young Adult; D047408:gamma-Cyclodextrins / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D047408:gamma-Cyclodextrins; D000077122:Sugammadex; D006493:Heparin
keywords: APTT; PK–PD model; PT(INR); Pharmacodynamics; Pharmacokinetics; Sugammadex