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Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men

1994; Wiley; Volume: 56; Issue: 4 Linguagem: Inglês

10.1038/clpt.1994.152

1532-6535

Jeffrey S. Barrett, Gail Murphy, Kathelijne Peerlinck, Inge De Lepeleire, Robert J. Gould, Deborah Panebianco, Elizabeth Hand, Hans Deckmyn, Jos Vermylen, Jef Arnout,

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Clinical Pharmacology & TherapeuticsVolume 56, Issue 4 p. 377-388 Pharmacokinetics and Drug Disposition Pharmacokinetics and pharmacodynamics of MK-383, a selective non-peptide platelet glycoprotein-IIb/IIIa receptor antagonist, in healthy men Jeffrey S Barrett PhD, Corresponding Author Jeffrey S Barrett PhD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenJeffrey S Barrett, PhD, Somerset Pharmaceuticals, Department of Pharmacokinetics and Biopharmaceutics, 777 South Harbour Island Blvd., Suite 880, Tampa, FL 33602.Search for more papers by this authorGail Murphy MD, Gail Murphy MD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorKathelijne Peerlinck MD, Kathelijne Peerlinck MD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorInge De Lepeleire PharmD, Inge De Lepeleire PharmD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorRobert J Gould PhD, Robert J Gould PhD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorDeborah Panebianco MS, Deborah Panebianco MS Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorElizabeth Hand BS, Elizabeth Hand BS Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorHans Deckmyn PhD, Hans Deckmyn PhD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorJos Vermylen MD, PhD, Jos Vermylen MD, PhD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorJef Arnout DSc, Jef Arnout DSc Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this author Jeffrey S Barrett PhD, Corresponding Author Jeffrey S Barrett PhD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenJeffrey S Barrett, PhD, Somerset Pharmaceuticals, Department of Pharmacokinetics and Biopharmaceutics, 777 South Harbour Island Blvd., Suite 880, Tampa, FL 33602.Search for more papers by this authorGail Murphy MD, Gail Murphy MD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorKathelijne Peerlinck MD, Kathelijne Peerlinck MD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorInge De Lepeleire PharmD, Inge De Lepeleire PharmD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorRobert J Gould PhD, Robert J Gould PhD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorDeborah Panebianco MS, Deborah Panebianco MS Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorElizabeth Hand BS, Elizabeth Hand BS Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorHans Deckmyn PhD, Hans Deckmyn PhD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorJos Vermylen MD, PhD, Jos Vermylen MD, PhD Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this authorJef Arnout DSc, Jef Arnout DSc Merck Research Laboratories, West Point; Merck Research Laboratories, Brussels Center for Molecular and Vascular Biology, LeuvenSearch for more papers by this author First published: October 1994 https://doi.org/10.1038/clpt.1994.152Citations: 15AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract MK-383 (L-tyrosine, N-n-butylsulfonyl)-O-[4-butyl(4-piperidinyl)], monohydrochloride monohydrate) is a potent and specific platelet fibrinogen receptor antagonist that may be useful in preventing processes that lead to occlusive thrombus formation in the lumen of the blood vessel. Two placebo-controlled phase I trials were completed in 56 healthy volunteers to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of MK-383 administered as 1- and 4-hour infusions in the presence and absence of aspirin. When administered to healthy male subjects by constant infusions up to 0.4 µg/kg/min over 1 hour or up to 0.2 µg/min over 4 hours, it provided a well-tolerated reversible means of inhibiting platelet function. At infusion rates of 0.25 and 0.15 µg/kg/min for 1 and 4 hours, respectively, MK-383 extended baseline bleeding time by 2.0- to 2.5-fold and inhibited adenosine diphosphate (ADP)-induced platelet aggregation by at least 80%. The pharmacokinetics of MK-383 include a mean plasma clearance of 329 ml/min, steady-state volume of distribution of 76 L, and half-life of 1.6 hours. The percentage of dose excreted in the urine was 37%. Correlations between MK-383 plasma concentration (C) and inhibition of platelet aggregation were examined by fitting with a sigmoid maximum-effect model. The plasma concentration yielding 50% inhibition (C50) for MK-383 in healthy volunteers is approximately 13 ng/ml, with a Hill coefficient >5. Based on a naive pooled analysis, an exponential empirical model best describes the MK-383 C–extension of template bleeding time (BTE) relationship. The model indicates that the MK-383 plasma concentration necessary to double BTE is approximately 30 ng/ml (i.e., 2.5-fold greater than the C50 for ADP-induced inhibition of platelet aggregation). The pharmacokinetics of MK-383 was unaffected by pretreatment with 325 mg aspirin 1 day before and 1 hour before infusion. Conversely, aspirin pretreatment reduced C50 and increased bleeding time extension, suggesting that aspirin may have an additive effect with respect to inhibition of platelet function. Based on the putative role of the fibrinogen receptor in thrombotic processes and an acceptable human pharmacokinetic-pharmacodynamic profile, MK-383 should be evaluated in patients with unstable angina. Clinical Pharmacology and Therapeutics (1994) 56, 377–388; doi:10.1038/clpt.1994.152 Citing Literature Volume56, Issue4October 1994Pages 377-388 RelatedInformation