International Journal of Clinical Pharmacology and Therapeutics, Vol. 52 – No. 3/2014 (227-236)
Effects of sugammadex on activated partial thromboplastin time and prothrombin time in healthy subjects Original ©2014 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965 DOI 10.5414/CP201976 e-pub: January 22, 2014
Key words hemostasis parameters – international normalized ratio – neuromuscular blockade – pharmacodynamics – pharmacokinetics
Clinical trial registration Clinical Trial Protocol 19.4.115; EudraCT Number: 2007-007772-41 Received May 29, 2013; accepted October 3, 2013 Correspondence to Pieter-Jan De Kam, PhD Clinical Pharmacology, Merck Sharp & Dohme Corp., 126 East Lincoln Ave. Rahway, NJ 07065 USA pieter-jan.de.kam@ merck.com
Pieter-Jan De Kam1, Peter Grobara2, Marita Prohn2, Floris Höppener3, Cornelis Kluft4,5, Jacobus Burggraaf4, Ronald B. Langdon2, and Pierre Peeters2,4 & Co., Inc., Whitehouse Station, NJ, USA, 2MSD BV, Oss, BV, Utrecht, 4Centre for Human Drug Research (CHDR), and 5Good Biomarker Sciences (GBS), Leiden, The Netherlands 1Merck
3Kendle International
Abstract. Objectives: To assess the impact of sugammadex on activated partial thromboplastin time (APTT) and international normalized ratio for prothrombin time (PT(INR)) in healthy subjects and characterize the concentration-dependency of sugammadex effects on APTT and prothrombin time (PT) in normal human plasma in vitro. Methods: Eight healthy subjects (18 – 45 years of age) were administered intravenous doses of 4 mg/kg sugammadex, 16 mg/kg sugammadex, or placebo in a randomized, placebo-controlled, threeperiod cross-over trial. The primary endpoint was area under the curve from 2 to 60 minutes post-dose (AUC2–60min) for APTT and PT(INR). In vitro, the effects of sugammadex on APTT and PT were assessed in pooled normal human citrate plasma. Results: In subjects dosed with 4 and 16 mg/kg sugammadex, geometric mean ratios (treated vs. placebo) for AUC2–60min were 1.085 (95% confidence interval, 0.888 – 1.325) and 1.019 (0.868 – 1.195), respectively, for APTT, and 1.047 (0.904 – 1.213) and 1.096 (0.953 – 1.261), respectively, for PT(INR). At individual timepoints, mean APTT and PT(INR) increased by up to 22% after 16 mg/kg sugammadex compared with placebo. All such increases occurred within 30 minutes post-dose. Sugammadex was generally well tolerated. In the in vitro experiments, addition of sugammadex to plasma resulted in limited, concentrationdependent increases in both APTT and PT. At 200 µg/mL (the mean maximum concentration reached therapeutically), the relative increases were 29% and 19%, respectively. Conclusions: Administration of sugammadex is associated with a dose-related, limited and transient prolongation of APTT and PT(INR) that is unlikely to be of clinical relevance.
Introduction Residual neuromuscular blockade (NMB) is a common post-operative condition that may result in delayed tracheal extubation, delayed release from the post-anesthesia care unit, unpleasant symptoms of muscle weakness, and post-operative pulmonary complications including hypoxemia and airway obstruction [1, 2, 3 ,4 ,5, 6, 7]. Sugammadex is a modified γ-cyclodextrin that binds selectively to the steroidal neuromuscular blocking agents rocuronium and vecuronium and thereby reverses NMB in surgical patients who have received these agents [8, 9, 10, 11, 12, 13, 14]. It has been widely approved for post-operative use since 2008. For routine reversal of NMB, it is administered in doses of 2 or 4 mg/kg and this generally results in recovery of the T4/T1 ratio to 0.9 in 2 – 3 minutes [15]. Sugammadex may also be administered at a higher dose (16 mg/kg) when there is a need for immediate reversal of NMB in emergency situations. During pre-clinical development, in vitro testing was performed to assess whether the presence of sugammadex in plasma might interfere with standardized clinical laboratory measurements. It was found that addition of sugammadex to plasma at a concentration of 100 µg/mL (approximately the mean maximum concentration reached in vivo after a single dose of 8 mg/kg sugammadex) resulted in small prolongations in activated partial thromboplastin time (APTT), prothrombin time (PT), and international normalized ratio for PT (PT(INR)). Compared with control plasma, the relative increases in mean APTT and PT were 18% and 13%, respectively
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De Kam, Grobara, Prohn, et al.
(unpublished data). In light of this preliminary in vitro finding, there has been a need for further research to determine whether sugammadex also has effects on APTT and PT when administered in vivo. The present report includes results from a clinical study and subsequent in vitro investigation. The primary objective of the clinical study was to assess whether increases in APTT and PT(INR) previously observed in vitro translate to the in vivo setting when administered to healthy subjects in single intravenous doses of either 4 mg/kg (the highest dose recommended for routine reversal of NMB) or 16 mg/kg (the highest recommended clinical dose for immediate reversal of NMB in emergency situations). Additional goals included measurement of the duration of any observed effects of sugammadex on coagulation parameters, characterization of the pharmacokinetic (PK) profile of sugammadex, exploratory evaluation of potential PK/pharmacodynamic (PK/PD) relationships, and assessment of safety and tolerability. The primary objective of the in vitro investigation was to characterize the concentration dependency of sugammadex effects on APTT and PT.
Methods Design and subjects A randomized, placebo-controlled, threeperiod cross-over clinical trial was performed in 8 healthy subjects at the Kendle Clinical Pharmacology Unit in Utrecht, The Netherlands between February 12, 2008 and March 31, 2008. This study was conducted in accordance with principles of Good Clinical Practice following a protocol that was reviewed and approved in advance by the Medisch Ethische Toetsingscomissie, Stichting Therapeutische Evaluatie Geneesmiddelen, Louis Armstrongweg 78, 1311 RL Almere, The Netherlands. All subjects provided written informed consent prior to participating. Eligible subjects were either male or female, 18 – 45 years of age, and had a body mass index between 18 and 30 kg/m2. Their health was confirmed by medical history, physical examination, electrocardiogram, and biochemistry, hematology and urinaly-
sis testing performed within 2 weeks prior to the first dose. They had normal values for APTT, PT, and international normalized ratio for PT (PT(INR)), normal blood pressure (
Effects of sugammadex on activated partial thromboplastin time and prothrombin time in healthy subjects Original ©2014 Dustri-Verlag Dr. K. Feistle ISSN 0946-1965 DOI 10.5414/CP201976 e-pub: January 22, 2014
Key words hemostasis parameters – international normalized ratio – neuromuscular blockade – pharmacodynamics – pharmacokinetics
Clinical trial registration Clinical Trial Protocol 19.4.115; EudraCT Number: 2007-007772-41 Received May 29, 2013; accepted October 3, 2013 Correspondence to Pieter-Jan De Kam, PhD Clinical Pharmacology, Merck Sharp & Dohme Corp., 126 East Lincoln Ave. Rahway, NJ 07065 USA pieter-jan.de.kam@ merck.com
Pieter-Jan De Kam1, Peter Grobara2, Marita Prohn2, Floris Höppener3, Cornelis Kluft4,5, Jacobus Burggraaf4, Ronald B. Langdon2, and Pierre Peeters2,4 & Co., Inc., Whitehouse Station, NJ, USA, 2MSD BV, Oss, BV, Utrecht, 4Centre for Human Drug Research (CHDR), and 5Good Biomarker Sciences (GBS), Leiden, The Netherlands 1Merck
3Kendle International
Abstract. Objectives: To assess the impact of sugammadex on activated partial thromboplastin time (APTT) and international normalized ratio for prothrombin time (PT(INR)) in healthy subjects and characterize the concentration-dependency of sugammadex effects on APTT and prothrombin time (PT) in normal human plasma in vitro. Methods: Eight healthy subjects (18 – 45 years of age) were administered intravenous doses of 4 mg/kg sugammadex, 16 mg/kg sugammadex, or placebo in a randomized, placebo-controlled, threeperiod cross-over trial. The primary endpoint was area under the curve from 2 to 60 minutes post-dose (AUC2–60min) for APTT and PT(INR). In vitro, the effects of sugammadex on APTT and PT were assessed in pooled normal human citrate plasma. Results: In subjects dosed with 4 and 16 mg/kg sugammadex, geometric mean ratios (treated vs. placebo) for AUC2–60min were 1.085 (95% confidence interval, 0.888 – 1.325) and 1.019 (0.868 – 1.195), respectively, for APTT, and 1.047 (0.904 – 1.213) and 1.096 (0.953 – 1.261), respectively, for PT(INR). At individual timepoints, mean APTT and PT(INR) increased by up to 22% after 16 mg/kg sugammadex compared with placebo. All such increases occurred within 30 minutes post-dose. Sugammadex was generally well tolerated. In the in vitro experiments, addition of sugammadex to plasma resulted in limited, concentrationdependent increases in both APTT and PT. At 200 µg/mL (the mean maximum concentration reached therapeutically), the relative increases were 29% and 19%, respectively. Conclusions: Administration of sugammadex is associated with a dose-related, limited and transient prolongation of APTT and PT(INR) that is unlikely to be of clinical relevance.
Introduction Residual neuromuscular blockade (NMB) is a common post-operative condition that may result in delayed tracheal extubation, delayed release from the post-anesthesia care unit, unpleasant symptoms of muscle weakness, and post-operative pulmonary complications including hypoxemia and airway obstruction [1, 2, 3 ,4 ,5, 6, 7]. Sugammadex is a modified γ-cyclodextrin that binds selectively to the steroidal neuromuscular blocking agents rocuronium and vecuronium and thereby reverses NMB in surgical patients who have received these agents [8, 9, 10, 11, 12, 13, 14]. It has been widely approved for post-operative use since 2008. For routine reversal of NMB, it is administered in doses of 2 or 4 mg/kg and this generally results in recovery of the T4/T1 ratio to 0.9 in 2 – 3 minutes [15]. Sugammadex may also be administered at a higher dose (16 mg/kg) when there is a need for immediate reversal of NMB in emergency situations. During pre-clinical development, in vitro testing was performed to assess whether the presence of sugammadex in plasma might interfere with standardized clinical laboratory measurements. It was found that addition of sugammadex to plasma at a concentration of 100 µg/mL (approximately the mean maximum concentration reached in vivo after a single dose of 8 mg/kg sugammadex) resulted in small prolongations in activated partial thromboplastin time (APTT), prothrombin time (PT), and international normalized ratio for PT (PT(INR)). Compared with control plasma, the relative increases in mean APTT and PT were 18% and 13%, respectively
228
De Kam, Grobara, Prohn, et al.
(unpublished data). In light of this preliminary in vitro finding, there has been a need for further research to determine whether sugammadex also has effects on APTT and PT when administered in vivo. The present report includes results from a clinical study and subsequent in vitro investigation. The primary objective of the clinical study was to assess whether increases in APTT and PT(INR) previously observed in vitro translate to the in vivo setting when administered to healthy subjects in single intravenous doses of either 4 mg/kg (the highest dose recommended for routine reversal of NMB) or 16 mg/kg (the highest recommended clinical dose for immediate reversal of NMB in emergency situations). Additional goals included measurement of the duration of any observed effects of sugammadex on coagulation parameters, characterization of the pharmacokinetic (PK) profile of sugammadex, exploratory evaluation of potential PK/pharmacodynamic (PK/PD) relationships, and assessment of safety and tolerability. The primary objective of the in vitro investigation was to characterize the concentration dependency of sugammadex effects on APTT and PT.
Methods Design and subjects A randomized, placebo-controlled, threeperiod cross-over clinical trial was performed in 8 healthy subjects at the Kendle Clinical Pharmacology Unit in Utrecht, The Netherlands between February 12, 2008 and March 31, 2008. This study was conducted in accordance with principles of Good Clinical Practice following a protocol that was reviewed and approved in advance by the Medisch Ethische Toetsingscomissie, Stichting Therapeutische Evaluatie Geneesmiddelen, Louis Armstrongweg 78, 1311 RL Almere, The Netherlands. All subjects provided written informed consent prior to participating. Eligible subjects were either male or female, 18 – 45 years of age, and had a body mass index between 18 and 30 kg/m2. Their health was confirmed by medical history, physical examination, electrocardiogram, and biochemistry, hematology and urinaly-
sis testing performed within 2 weeks prior to the first dose. They had normal values for APTT, PT, and international normalized ratio for PT (PT(INR)), normal blood pressure (
