Effects of Age on the Pharmacokinetics and Pharmacodynamics of Cardiovascular Drugs: Application of Concentration-Effect Modeling. 3. Trimazosin.
The effects of age on the disposition and hemodynamic responses to the selective post-synaptic alpha(1) adrenoceptor antagonist trimazosin were examined in an integrated manner using a combined pharmacokinetic--pharmacodynamic (PKPD) modeling approach. Thirty subjects were studied to represent, as far as was possible an age continuum. Single doses of trimazosin (100 mg) and placebo were administered intravenously and blood was withdrawn and heart rate and blood pressure were measured at frequent intervals up to 10 h post dose. Based on regression analysis there was a statistically significant decline in the clearance of trimazosin with increasing age. In addition, based on the ratio of the AUC values for the major metabolite and parent drug, there was evidence of a decline in the relative clearance of matabolite with increasing age. Trimazosin when compared with placebo produced significant changes in blood pressure and heart rate that were statistically greater in elderly subjects. PKPD modeling revealed that both trimazosin and its metabolite 1-hydroxy trimazosin contributed significantly to the hemodynamic profile of the drug but the blood pressure responsiveness to both parent drug and metabolite were unaffected by age. Thus the greater response in the elderly subjects could be attributed to the decline in drug clearance with age.
Meredith
P. A.
PA
University Department of Medicine and Therapeutics, Western Infirmary, Glasgow, Scotland.
Scott
P. J.W.
PJ
Kelman
A. W.
AW
Hughes
D. M.A.
DM
Reid
J. L.
JL