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Safety, Tolerability, Pharmacokinetics, and Time Course of Pharmacologic Response of the Active Metabolite of Roxifiban, XV459, a Glycoprotein IIb/IIIa Antagonist, following Oral Administration in Healthy Volunteers
Author(s) -
Pieniaszek Henry J.,
Sy Sherwin K. B.,
Ebling William,
Fossler Michael J.,
Cain Valerie A.,
Mondick John T.,
Ma Su,
Kornhauser David M.
Publication year - 2002
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/009127002401102687
Subject(s) - pharmacokinetics , tolerability , medicine , pharmacology , placebo , oral administration , active metabolite , aspirin , dosing , metabolite , prodrug , adverse effect , antagonist , alternative medicine , receptor , pathology
Roxifiban is an ester prodrug that is hydrolyzed, after oral administration, to the active glycoprotein (GP) IIb/IIIa antagonist, XV459. The objectives of the study were to investigate the safety, tolerability, pharmacokinetics, and the time course of the pharmacologic response of XV459 in escalating doses of roxifiban and to assess the effect of age, loading dose of roxifiban, and aspirin pretreatment on XV459 pharmacokinetics, pharmacologic response, and safety profile in a five‐part double‐blind, placebo‐controlled study. Healthy male volunteers (ages 18–46 years) received 7 (0.75‐1.5 mg; n = 20) and 10 (0.75‐1.0 mg; n = 8) multiple, oral, qd doses of roxifiban or placebo (n = 5). Healthy older male and female volunteers (ages 47–75 years) received roxifiban qd doses (0.5‐0.75 mg; n = 8) or placebo (n = 3) for 7 days. Healthy male subjects (ages 18–46 years; n = 16) received a 1.5 or 1.0 mg loading dose either with or without pretreatment of 325 mg aspirin once daily for 3 days followed by single daily doses of 1.0 mg roxifiban for 6 days. Measurable plasma concentrations of XV459 appeared rapidly and were sustained throughout the dosing interval of 24 hours. The pharmacokinetics of XV459 were nonlinear. Systemic exposure of XV459 plateaued at the 1‐mg dose level; plasma concentrations approached steady state in 4 to 6 days for doses greater than 1.0 mg. The time course of pharmacologic response as measured by the inhibition of platelet aggregation in response to an ex vivo 10 μM adenosine 5′‐diphosphate (ADP) agonist correlated closely to the plasma concentration of XV459. Potent inhibition of ADP‐induced platelet aggregation (IPA) persisted over the entire dosing interval. A clear dose response was achieved with roxifiban doses of 0.5 and 1.0 mg. For doses greaterthan 1.0mg, a dose‐proportional increase in IPA was not observed. Both the pharmacokinetics and pharmacologic response of XV459 exhibited low intraindividual variability (coefficient of variation [CV] > 15%) and higher interindividual variability (CV > 30%). Pretreatment with aspirin and/or a loading dose of 1.5 mg roxifiban had no significant effect on the pharmacokinetics and pharmacologic response of XV459. A dose‐related increase in template bleeding time was observed at 1.25‐ and 1.5‐mg doses of roxifiban, as compared to placebo. However, these bleeding time increases in the 1.25‐ and 1.5‐mg dose groups were not significantly different from those at the lower dose groups. Overall, once‐daily oral administration of roxifiban was fairly well tolerated and provided sustained systemic drug exposure and pharmacologic response over the entire administration interval.