A population pharmacokinetic-pharmacodynamic and logistic regression analysis of lotrafiban in patients.
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.
Mould
D
D
Center for Drug Development Science, Department of Pharmacology, Georgetown University Medical Center, Washington DC 20007, USA.
Chapelsky
M
M
Aluri
J
J
Swagzdis
J
J
Samuels
R
R
Granett
J
J
D000328:Adult; D000367:Age Factors; D000368:Aged; D001569:Benzodiazepines; D003404:Creatinine / Q000378:metabolism; D003710:Demography; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006331:Heart Diseases / Q000378:metabolism*; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D010880:Piperidines; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D012737:Sex Factors
D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D001569:Benzodiazepines; D003404:Creatinine; C412702:lotrafiban