Concentration-Effect Analysis of Antihypertensive Drug Response

Abstract

Although individualised antihypertensive therapy is widely recommended, prospective methods for optimising treatment are hampered by the paucity of basic information about dose-plasma concentration-response relationships for commonly used drugs. Concentration-effect analysis has been applied to a number of therapeutic areas. With antihypertensive drugs this approach has clearly identified direct relationships between pharmacokinetic and pharmacodynamic profiles within individual patients. Thus, either a linear or nonlinear model can be used to quantify the antihypertensive drug response in terms of parameters that incorporate pharmacokinetic and pharmacodynamic information. Furthermore, these models take account of placebo effects and time-dependent changes in blood pressure and drug concentrations during a dosage interval. Concentration-effect analysis has been used to characterise the responses to a range of calcium antagonist drugs. These studies have demonstrated that these analyses are useful for optimising dosage schedules, identifying determinants of blood pressure response, and predicting steady-state profiles of blood pressure (including peak/trough effects) after administration of a single ('test') dose. This mode of analysis warrants early inclusion in the clinical development of any new antihypertensive agent, so that the familiar difficulties in identifying the optimum dosage range are avoided.

Clarithromycin—Nifedipine Interaction as Possible Cause of Vasodilatory Shock

“…Calcium-channel blockers inhibit calcium + flux through the calcium channels of vascular smooth muscle cells, thus inducing vasodilation 9 in a dose-dependent manner. 10 Toxicity constitutes an extension of this pharmacologic effect, with extreme vasodilation due to a loss of peripheral resistance that can lead to shock and death. 4 In addition, the hypotensive effect of calcium-channel blockers shows synergy with α 1 -blockers and angiotensin-converting enzyme inhibitors 9 —the other hypotensive drugs used by our patient.…”

The Pharmacokinetics of Extended‐Release Formulations of Calcium Antagonists and of Amlodipine in Subjects with Different Gastrointestinal Transit Times

“…For antihypertensive drugs, there is now a large body of evidence that a direct relationship between pharmacokinetic and pharmacodynamic profiles exists within individual patients. 26 Therefore, based on the pharmacokinetic behavior, the predictability of the therapeutic effect is optimal for amlodipine, compared to the two compounds with formulation-based extended-release characteristics. This might in par-ticular apply to clinical situations in which the primary indication is associated with disorders or alterations of distal GI transit processes.…”

Comparative Pharmacodynamics of Olmesartan and Azelnidipine in Patients with Hypertension: a Population Pharmacokinetic/Pharmacodynamic Analysis

“…In these studies, however, the antihypertensive agents were not administered in a crossover fashion, and therefore whether the observed average trends are also reproducible in each individual patient has not yet been clearly demonstrated considering that essential hypertension is a heterogeneous disorder. The other drawback of these studies is that the pharmacokinetic (PK) variability, which is another important factor determining antihypertensive response, [16][17][18] was not adequately taken into consideration. Donnelly et al pointed out that previous studies on the heterogeneity of antihypertensive response have neglected interindividual variability in the PK and consequently conflicting and, in some cases, misleading statements have been provided.…”