The effects of age and gender on the pharmacokinetics and pharmacodynamics in healthy subjects of the plasminogen activator, lanoteplase

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The pharmacokinetics and pharmacodynamics of the plasminogen activator lanoteplase have not been extensively characterized in specific populations and the need for dose adjustment on the basis of age and/or gender has not been established. WHAT THIS STUDY ADDS • This paper is the first report of lanoteplase administered to healthy subjects in order to address its clinical use in these important specific populations. The results support the use of the same doses of lanoteplase in males and females and young and elderly patients. AIMS To investigate the influence of age and gender on the intravenous pharmacokinetics and pharmacodynamics of the plasminogen activator, lanoteplase. METHODS Forty healthy subjects (10 each of young males, elderly males, young females and elderly females) received a single bolus 10 kU kg−1 intravenous dose of lanoteplase. Plasma from blood serially collected for 24 h post-dose was analyzed for lanoteplase (antigen), fibrinogen, plasminogen and α2-antiplasmin concentrations, plasma plasminogen activation activity (PPAA) and rapid plasminogen activator inhibitor (PAI-1). RESULTS Lanoteplase mean total systemic clearance (CLt) values ranged from 1.9 to 2.8 l h−1 and mean steady-state volume of distribution (Vss) values ranged from 12.3 to 15.6 l. Age-by-gender interactions were observed for lanoteplase CLt (P= 0.04), but no differences were observed for Vss or elimination half-life. Elderly females had a 27% lower mean CLt than young females (95% CI for the difference 0.17, 1.27 l h−1) and 32% lower CLt than elderly males (95% CI for the difference 0.15, 1.65 l h−1). PPAA AUC/dose values did not show an age-by-gender interaction. Haemostasis parameters indicated only a slight degree of systemic plasminogen activation. CONCLUSIONS Elderly females had a lower mean lanoteplase CLt than elderly males and young females. However, no difference was observed between young and elderly females for the AUC/dose of PPAA. In addition, there were no age-related or gender-related differences observed in the other pharmacodynamic parameters measured.