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