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A population pharmacokinetic‐pharmacodynamic and logistic regression analysis of lotrafiban in patients
Author(s) -
Mould Diane,
Chapelsky Martha,
Aluri Jagadeesh,
Swagzdis James,
Samuels Robert,
Granett Jeffrey
Publication year - 2001
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2001.114925
Subject(s) - medicine , pharmacokinetics , pharmacodynamics , population , placebo , tolerability , aspirin , dosing , logistic regression , pharmacology , adverse effect , anesthesia , alternative medicine , environmental health , pathology
Objective Our objective was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of lotrafiban, an oral glycoprotein IIb/IIIa inhibitor, in patients with a recent myocardial infarction, unstable angina, transient ischemic attack, or stroke. Methods A 12‐week, double‐blind, multi‐center, placebo‐controlled, parallel‐group, phase II study of lotrafiban (the Anti‐platelet Useful Dose Study) was conducted in patients. Lotrafiban or placebo was administered as a twice daily oral dose at four dose levels (5–100 mg) for 12 weeks with daily doses of aspirin (300–325 mg). The pharmacokinetics of lotrafiban were characterized with the use of a population approach and were described by a two‐compartment model with first order absorption and first order elimination. The pharmacodynamic data, ex vivo platelet aggregation, were described with the use of a direct effect inhibitory sigmoidal model with a baseline. The relationship between the severity of bleeding episodes and predicted steady‐state lotrafiban exposure was characterized by logistic regression. Results Pharmacokinetic analysis showed that increasing age and decreasing creatinine clearance resulted in increased exposure to lotrafiban. The concentration‐effect relationship was steep, with near complete inhibition of platelet aggregation at lotrafiban concentrations in excess of 20 ng/mL. Logistic regression showed that at exposures that exceeded approximately 835 ng · h/mL, the severity of adverse bleeding events increased considerably; this suggested that dosing recommendations should be generated to minimize the likelihood of patients having an area under the plasma concentration‐time curve from 0 to 24 hours in excess of this value. Conclusions Patients whose age exceeded 65 years or whose creatinine clearance was less than 60 mL/min should be given a lower dose of lotrafiban than younger patients with good renal function. Clinical Pharmacology & Therapeutics (2001) 69 , 210–222; doi: 10.1067/mcp.2001.114925