Kinetic-dynamic relations and individual responses to enalapril.

Abstract

Pharmacoklnetic and phannacodynamic variability largely account for interindividual differences in the response to antihypertensive drugs including angiotensin converting enzyme inhibitors. The factors determining the response to enalapril have been investigated in a placebo-controlled study in essential hypertension. The effects of placebo, the initial dose of enalapril, and long-term (1 and 6 weeks) treatment with enalapril were studied in 13 subjects. By using an integrated kinetic-dynamic model that incorporates a parameter for saturable protein binding, individual responses for blood pressure reduction and angiotensin converting enzyme inhibition were characterized in terms of the maximum effect (E^J and the drug concentration required to produce 50% of E M (0,50). In individual subjects, plasma enalaprilat concentrations could be correlated with falls in blood pressure and changes in plasma angiotensin converting enzyme activity. For the group, E^, was -46.1 ±16.5 and -19.7 ±3.8 mm Hg for systolic and dlastolic blood pressure, respectively, and the corresponding C,50 values were 66.1 ±20.2 and 61.6 ±22.5 ng/ml. For angiotensin converting enzyme inhibition, £ " , (%) and C.50 (ng/ml) were, respectively, 102.4±5 and 19.8±13 after the first dose, 103±5 and 33.4±20J after 1 week, and 101 J±2.2 and 31 J±18.9 after 6 weeks. There was no relation between the responsiveness to enalapril ( E^ or C.50) and patient age or plasma renin activity, but there was a significant positive correlation between E^ and the pretreatment blood pressure. In individual subjects, E^ (first dose) was directly correlated with E mM1 after 1 and 6 weeks. This study, which incorporated kinetic as well as dynamic information to characterize the antihypertensive response to enalapril, has identified enalaprilat concentration-effect relations in individual hypertensive subjects. 3 Qinical studies have shown large interindividual differences in the effect of an ACE inhibitor on blood pressure and the renin-angiotensin system, particularly after the first dose, but little attempt has been made to quantify and optimize the response in individual subjects. 4 There is some evidence that reduction of blood pressure and inhibition of plasma ACE activity are dose-dependent, 5 " 7 but no consistent concentrationeffect relation has been established between plasma drug (or active metabolite) concentration and blood pressure reduction or ACE inhibition. Received May 1, 1989; accepted in revised form October 30, 1989. this is likely to reflect the wide range of intersubject variability in pharmacokinetic responses, particularly when group data are evaluated, there is preliminary evidence that concentration-effect relations for ACE inhibitors can be more readily identified when individual subjects are considered. -13This study uses integrated pharmacokineticpharmacodynamic modeling 14 to investigate and characterize the antihypertensive responses and concentration-effect relations during acute and chronic treatment with enalapril in patients with esse...

Pharmacokinetic–pharmacodynamic model for perindoprilat regional haemodynamic effects in healthy volunteers and in congestive heart failure patients

“…Plasma concentrations of the parent drug and of its metabolite Perindopril and perindoprilat plasma concentrations (ng ml x1 ) were determined from venous blood samples by radioimmunoassay as previously described [20]. Measurements were performed before and 0.5, 1, 1.5, 2, 2.5, 3,4,6,8,10,12,16,20,24,48 and 72 h after drug intake in HV. In CHF patients, the same schedule was used except that the two samples drawn at 16 and 20 h were replaced by a single one drawn at 18 h. The detection limit of the assay was 0.4 ng ml x1 for both perindopril and perindoprilat.…”

ACE (I/D) Genotype as a Predictor of the Magnitude and Duration of the Response to an ACE Inhibitor Drug (Enalaprilat) in Humans

“…7 However, the intersubject variability of plasma renin activity in salt-replete hypertensive patients is not large enough to explain the variation of drug response, 6 and with enalapril, it has been shown that pretreatment plasma renin activity accounts for Ͻ10% of the variability. 8 Differences in serum ACE activity have been thought to be less important in regulating the response to ACE inhibition, because the enzyme has not been considered to be rate-limiting for the production of angiotensin II. However, there is large interindividual but small intraindividual variation in ACE activity 9 ; recent evidence suggests that Ϸ50% of this is familial 10 and can be explained by a single major gene effect.…”

Concentration-effect analysis of antihypertensive drug responses.

“…Genetic and environmental factors do undoubtedly exert a major effect on response but pharmacokinetic factors contribute the largest identifiable component to the variability. In studies with ACE inhibitors, 17 calcium antagonists 25 -26 and ablockers, 27 -28 much of the intersubject variability in antihypertensive effect was attributable to individual differences in drug disposition and thus to plasma and tissue drug levels. In contrast, demographic and biochemical factors, such as age, sex, plasma renin activity, and plasma noradrenaline, were comparatively unimportant and did not significantly or independently influence the blood pressure responses in a group of salt-replete Caucasian patients with mildto-moderate hypertension.…”

“…To investigate adequately changes in response with time, it is necessary to undertake a comprehensive assessment not only of blood pressure but also of plasma drug levels over a dosing interval both acutely and after weeks or months of therapy. When this is undertaken, there is little evidence, at least for calcium antagonists 26 or ACE inhibitors, 17 that the response is a function of time.…”