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. 1999 Oct;48(4):594–604. doi: 10.1046/j.1365-2125.1999.00050.x

Evaluation of the angiotensin challenge methodology for assessing the pharmacodynamic profile of antihypertensive drugs acting on the renin-angiotensin system

C Buchwalder-Csajka 1, T Buclin 1, H R Brunner 1, J Biollaz 1
PMCID: PMC2014379  PMID: 10583031

Abstract

Aims

The performance of the experimental paradigm of angiotensin challenges with continuous non-invasive blood pressure measurement was evaluated. Angiotensin dose–response relationships were characterized, along with the influence of clinical covariates. The stability of angiotensin-induced peaks and the variability of the angiotensin doses were assessed. Finally, the predictive value of studies based on angiotensin challenges to determine drug doses effective in therapeutics was evaluated.

Methods

The data were gathered from 13 clinical studies on nine angiotensin II receptor antagonists, one ACE inhibitor and one dual ACE-NEP inhibitor, using Finapres® for measuring the response to exogenous angiotensin challenges. Modelling of angiotensin dose–response curves and determination of the inter and intrasubject variability were performed by nonlinear regression (NONMEM). The different sources of variations in angiotensin I and II doses and angiotensin-induced peaks were evaluated by analyses of variance. The dose of ACE inhibitors and angiotensin II receptor antagonists inhibiting blood pressure increase by at least 75%, as measured by this method, was chosen for comparison with the labelled starting dose.

Results

Angiotensin challenges exhibited a clear dose–response relationship which can be characterized both by an Emax or a log linear model. The log linear model gave an average systolic/diastolic response of 24±6/20±5 mmHg for a unit dose of 1 μg of angiotensin II equivalents, and an increase of 6/6 mmHg for each doubling of the dose. The angiotensin ED50 calculated values were 0.67 μg for systolic and 0.84 μg for diastolic blood pressure. The angiotensin doses for eliciting a given response and the angiotensin induced peaks were fairly constant between period and subject, but vary significantly between studies. Based on an inhibition of blood pressure by 75%, the agreement was good between the doses of ACE inhibitors and angiotensin receptor antagonists predicted from studies using the methodology of angiotensin challenges and the doses shown to be clinically efficacious, in spite of high intersubject and intrasubject variabilities.

Conclusions

This experimental method represents a valid surrogate for the therapeutic target and a useful tool for the pharmacokinetic and pharmacodynamic profiling of drugs acting on the renin-angiotensin system.

Keywords: inhibitors, angiotensin receptor antagonists, angiotensin, non-linear mixed effect model, pharmacodynamics

Introduction

The renin-angiotensin system (RAS) is implicated in the maintenance of arterial blood pressure, body fluid volumes and electrolyte balance. Its causal role in the initiation and maintenance of essential hypertension and congestive heart failure has been extensively discussed, mostly since the discovery of specific inhibitors capable of interfering with this system [1–3]. Ever since the 1950s, investigators have been exploring ways of blocking the RAS both as a means of further defining its role in cardiovascular diseases and as a therapeutic approach in the treatment of such disorders. At present, the RAS is amenable to specific blockade at three sites: angiotensin converting enzyme (ACE), renin and angiotensin II receptors. The well established success of such interventions in managing hypertension and congestive heart failure confirms that the RAS plays a relevant role in the pathophysiology of these disease states [4, 5].

According to classical pharmacodynamics, agonist-antagonist competition can be used to quantify an antagonist’s potency by determining the response to the agonist curves in the presence of varying doses or concentrations of the antagonist. This methodology has been applied to phase I clinical trials for assessing the effect profile of ACE inhibitors and angiotensin II receptor antagonists [6]. The degree and duration of RAS blockade is clinically evaluated from the reduction in blood pressure response to repeated challenges of exogenous angiotensin I and/or II before and after administration of various doses of the drug to be tested. The predictive value of such results obtained in normotensive volunteers has only been verified in patients for the ACE inhibitors captopril and enalapril [7]. However, this information is of prime importance to support decisions about doses and intervals to be applied in therapeutic trials [8].

This work aims to assess the validity of the method of angiotensin boluses with photoplethysmographic blood pressure recording used in the clinical development of cardiovascular drugs targeted on the RAS. The evaluation of the performance of this blood pressure recording method in such settings is addressed in the companion paper [9]. The objectives of this paper are:

to characterize the dose–response relationship of angiotensin intravenous bolus challenges and its determinants, and to assess its variability among a population of healthy subjects

to estimate the stability of the response to serial injections of angiotensin, and to identify factors influencing it in typical phase I trials

to report on the doses of angiotensin I (Ang I) and angiotensin II (Ang II) used for challenges through studies

to assess the relevance of trials based on this experimental paradigm for predicting the dose associated with therapeutic efficacy.

Methods

The data were gathered from 13 phase I clinical studies performed in our centre, involving nine angiotensin II receptor antagonists (losartan, tasosartan, candesartan cilexedil, TAK-536, SC-52458, L-159,282, LRB-081, UP 269–6, CS-866), one ACE inhibitor (CS-622) and one dual ACE-NEP inhibitor (MDL 100 240). Preliminary angiotensin dose-findings were performed in each of the volunteers to determine the dose of Ang I or Ang II needed to increase blood pressure approximately by 30 mmHg. The same dose was to be used throughout the trial in the subject. The blocking effect of single doses of the Ang II antagonist or the ACE inhibitor studied was then evaluated from the response to serial boluses of angiotensin.

Blood pressure was recorded continuously and non-invasively with the Finapres® device, which consists of a servo-photoplethysmomanometer enabling blood pressure to be recorded beat-to-beat at the finger by transdigital photometry [10]. The response to the angiotensin challenge was expressed by the height of the blood pressure peak induced by angiotensin.

The blocking action of an ACE inhibitor or Ang II antagonist is reflected in the decrease of the peak height observed at various times after a given dose of angiotensin I or angiotensin II respectively. The results are usually expressed as percentage of inhibition of pre-drug response.

Angiotensin dose–response relationship

Increasing angiotensin bolus doses (range: 0.49–5.4 μg as a function of the body weight) were injected into each of the 228 volunteers until a blood pressure peak of about 30 mmHg was reached. This dose-finding procedure served to determine an individual dose of angiotensin to be injected into the volunteers throughout the trial. Population pharmacodynamic parameters of the 1144 angiotensin-induced blood pressure peaks were estimated using a nonlinear regression analysis (NONMEM® version IV run with NM-TRAN version II and a user-specified PRED routine). The first-order method is used to estimate the population mean parameters, the intersubject variabilities in these parameters and the residual intrasubject variability between observed and predicted systolic (SBP) and diastolic (DBP) blood pressure values.

The pharmacostatistical model of the effect E was developed by comparing three pharmacodynamic models:

a linear model:

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an Emax model:

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a log linear model:

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with the intersubject variability specified by the following statistical model:

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The dose D is expressed in μg of Ang II equivalents; for Ang I, it is obtained by multiplying the actual dose by the molar ratio of the two peptides (Q =0.78). The parameters a and b are the population mean estimates of slope and intercept (for linear and log linear models) or of Emax and ED50 (for the Emax model), which are determined for systolic and diastolic blood pressure. The estimates aj and bj are the corresponding (hypothetical) true parameters of the jth subject and and are random variables with means zero and whose (intersubject) variances are being estimated. The influence of demographic factors, such as age, weight, height, ethnic group (all the volunteers were male), are sequentially included in order to refine the structural model. The selection between models is based upon an improvement of the objective function (OF), the latter being similar to twice the negative log likelihood of the data. A decrease in the objective function (which approximately follows the χ2 distribution) of 4 units is considered statistically significant (P<0.05).

Stability of the angiotensin-induced response

The angiotensin-induced systolic and diastolic blood pressure peak after placebo was used to evaluate the stability of the response to a given angiotensin dose (range: 0.49–5.4 μg). A total of 1592 angiotensin challenges performed during 167 placebo periods in 101 volunteers were included in the analysis. The interstudy, intersubject, interperiod and interchallenge variabilities were determined by hierarchical analysis of variance (anova). The independent variables included in the anova model were: study, subject (nested within study), period (nested within study) and challenge (nested within period). The dependent variables were the diastolic and systolic angiotensin peaks after placebo administration. The time fluctuation of blood pressure during 24 or 36 h was further assessed by polynomial regression of the residuals of an anova model including the factors study, subject and period and their appropriate interaction.

Angiotensin doses used for challenges

A total of 81 angiotensin I (range: 0.75–5.4 μg) and 154 angiotensin II (range: 0.63–4.41 μg) doses were used for the challenges in the 13 clinical trials. The effect of the study, the angiotensin type (I or II) and various demographic factors (body weight, height, age, race) were evaluated using a general linear model (analysis of variance combined with linear regression when appropriate).

The influence of the angiotensin type on the doses, the response and the time to peak blood pressure was also evaluated in a single study [11], where the same subjects were administered both angiotensin I and angiotensin II (anova). The inter vs intra-subject variabilities in the doses were also compared among 27 subjects having participated in two or three studies, with an anova testing for the subject effect.

Prediction of the clinical antihypertensive dose from studies based on angiotensin challenges

The predictive value of the method of angiotensin challenges for determining the therapeutic dose of various drugs acting on the RAS was assessed by reviewing published articles having applied this method in phase I studies. Thirteen phase I studies concerning five ACE inhibitors (captopril, enalapril, lisinopril, cilazapril and ramipril) and five angiotensin II receptor antagonists (losartan, candesartan, valsartan, irbesartan and tasosartan) were retrieved by a Medline search and reference cross-checking. For this part, both invasive arterial blood pressure determination and noninvasive Finapres® measures were considered. The comparison criterion chosen was the dose inhibiting by 75% the blood pressure response to exogenous angiotensin at maximum effect. This 75% inhibitory dose (ID75) is thought to represent the minimal dose required for clinical efficacy. The starting doses, or range of doses, used in treating hypertensive patients are those provided by the manufacturers’ product label and approved by registration authorities, or from phase III clinical trials. The doses derived from phase I studies are plotted against the therapeutic antihypertensive doses for each drug and the predictive performance assessed qualitatively by examining their concordance.

Results

Angiotensin dose–response relationship

Injection of exogenous angiotensin in increasing doses produced stepwise transient increases in blood pressure. For each challenge test, the peak response was plotted against the dose, resulting in a dose–response curve whose average population parameters were assessed by three different models using nonlinear mixed effect modelling. The results of the population estimates are depicted in Table 1.

Table 1.

Mean population parameters and variability (±s.d.) of the angiotensin dose–response relationship using three different models:.

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The linear model extrapolated an intercept, corresponding to an angiotensin dose equal to zero, of 13.3 mmHg for diastolic and 17.0 mmHg for systolic; such a high zero-dose effect was considered inadequate. Both the Emax model and the log linear model fitted adequately the data, with a slightly better characterization of the dose–response relationship by the Emax model (improvement of the objective function by 9 units). The Emax and ED50 mean estimates are, respectively, 36.4±4.8 mmHg and 0.8±0.5 μg for the diastolic and 40.3±5.9 mmHg and 0.7±0.6 μg for the systolic blood pressure. The restricted range of angiotensin doses injected conceivably covered only the inferior ascending part of the dose–response curve, therefore not allowing adequate characterization of the upper plateau. For this reason, the log-linear model was thought to give more adequate estimates. The mean slope and intercept characterizing the log linear model adaptation for diastolic blood pressure were 8.5±2.3 mmHg, and 19.6±4.5 mmHg and 9.1±3.7 mmHg and 23.8±6.0 mmHg for systolic blood pressure, respectively

When introducing the angiotensin type (Ang I or AngII) as a covariate, a clear effect on the dose–response curves was observed, with a statistically significant decrease in the objective function (P<0.001). This influence was thought to be related to the differences in molecular weight (MW) of the two peptides. After correcting the doses by the factor ratio of the molar weight of the two peptides (Q=0.78), the final mean estimates of the Emax model were: Emax =36.7± 4.8 mmHg and 40.9±6.6 mmHg for diastolic and systolic blood pressure, respectively, and ED50 =0.8±0.3 μg for diastolic and 0.65±0.4 μg for systolic blood pressure. When this covariate was taken into account the mean population parameters of the log linear model for slope and intercept were 8.5±2.4 mmHg and 20.2±4.5 mmHg for diastolic and 9.1±4.0 mmHg 24.5±6.0 mmHg for systolic blood pressure. The blood pressure response to a unitary dose of 1 μg Ang II is thus 20.2±4.5 mmHg for systolic and 24.5±6.0 mmHg for diastolic blood pressure. The increase in diastolic and systolic blood pressure after a doubling of the dose is ln(2)×8.5±2.4 mmHg and ln(2)×9.1±4.0 mmHg, respectively. The individual dose–response curves and the average curves of the log-linear model and the Emax model for diastolic blood pressure after injection of both angiotensin I and II are presented in Figure 1.

Figure 1.

Figure 1

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Individual peak diastolic blood pressure responses to angiotensin challenges in 185 healthy subjects, with the average population dose–response curves (log linear and Emax models) after angiotensin I (Ang I) and angiotensin II (Ang II) injection.

It is worth mentioning that an attempt to derive the value of Q from the experimental data led to a value very close to the theoretical figure of 0.78. This is consistent with the complete transformation of injected angiotensin I into angiotensin II under physiological conditions. The demographic factors did not influence the dose–response relationship over the range of data analysed.

Stability of the angiotensin-induced response

The average blood pressure response to angiotensin I or II after placebo administration, without regard to the doses injected, was significantly different from one study to another (P =0.0001 for SBP and DBP). However, these inter-study differences are small, probably reflecting slight differences in procedures and blood pressure readings. The mean systolic blood pressure response was 29±5 mmHg (study averages ranging from 24.4 to 35.5 mmHg) and the mean diastolic blood pressure 25±4 mmHg (study averages ranging from 20.5 to 30.8 mmHg). Neither the intersubject variability (P =0.3) nor the interperiod variability (P =0.9) were statistically greater than interchallenge variations. The fluctuations of blood pressure values following repeated injections of angiotensin over 24 or 36 h were best described by a third polynomial curve (P =0.04 vs constant trend) but were small, suggesting limited diurnal variations (maximal deviation=±5.8 mmHg for SBP and ±3.9 for DBP).

Angiotensin doses used for challenges

The individual angiotensin doses, without regard to angiotensin type (I or II), differed significantly between studies (P<0.001); the mean dose was 2.1±0.8 μg with a coefficient of variation of 37%. A smaller but still significant difference in doses was revealed with regard to angiotensin I and II, consistent with the difference in molecular weight (P =0.03). The correction for body weight (dose/body weight) did not reduce the variability (CV=36%) and other covariates showed no influence of the angiotensin dose over the range of data studied. The comparison of angiotensin I and angiotensin II dose injected to the same set of subjects in one study (MDL 100 240) [11] demonstrated a significant difference (P =0.004). The mean angiotensin I dose was 1.63±0.32 μg and the mean angiotensin II dose was 1.15±0.41 μg. The analysis of the time to reach peak effect revealed a non significant difference after injection of either angiotensin I or II for systolic (P =0.2), diastolic (P =0.9), mean blood pressure (P =0.8) and heart rate (P =0.4). Angiotensin I seems therefore almost instantaneously cleaved into angiotensin II.

The analysis of angiotensin doses in 27 subjects who were included in two or three separate studies revealed that the intra-subject variation (27%) is significantly smaller than the inter-subject variation (P =0.001), suggesting the existence of individual factors affecting the response and therefore the choice of the dose.

Prediction of the clinical antihypertensive dose from studies based on angiotensin challenges

The published reports about angiotensin II receptor antagonists and ACE inhibitors, to which the method of angiotensin challenges was applied, are reviewed and presented in Table 2. Both angiotensin bolus injection or continuous infusions of increasing doses of angiotensin were used to assess their pharmacodynamic profile. For ACE inhibitors, most studies relied upon invasive arterial blood pressure measurements, and data on blood pressure inhibition at 24 h were usually not available, since blood pressure was monitored only over 4 h after drug administration.

Table 2.

Maximal inhibition of blood pressure response to exogenous challenges of angiotensin I or II by ACE inhibitors and angiotensin II receptor antagonists in healthy subjects. Summary of the studies reviewed.

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All the ACE inhibitors showed a clear dose-dependent blockade of blood pressure response to exogenous angiotensin I [2, 10–19]. Maximal or close to maximal inhibition was reached for all inhibitors at the highest tested dose levels, except for CGS 13928C and ramipril which induced maximal blockade at intermediate doses (5 mg for ramipril and 0.5 mg for CGS 13928C). Inhibitors strongly differed with regard to their potency (equivalent doses 5 mg to 500 mg). The onset of action was rapid for most substances, with time to maximal effect (tmaxE) varying from 0.2 to 1.5 h. However, enalapril, lisinopril, cilazapril, and CGS 13928C had a slower onset of action (3–4 h).

Similar results were obtained with continuous infusions of increasing angiotensin I doses [12, 20]. Cilazapril (4 mg), captopril (25 mg), and enalapril (10 mg) demonstrated a shift to the right of the dose–response curves with an apparent elimination half-life of about 4 h for cilazapril and 2 h for captopril. A time-dependent reduction of the drug effect was seen, and more than 24 h after drug administration the baseline responsiveness to angiotensin I had fully recovered [13].

Angiotensin receptor antagonists demonstrated a dose-dependent blockade of the blood pressure response to exogenous angiotensin II, reaching close to maximal effect at the high doses [21–31]. Time to maximal effect varied between antagonists, ranging from 1 to 8 h and some inhibition was still visible at 24 h. The maximal inhibitory effect of valsartan and losartan was reached with a dose of 80 mg and for losartan, the intensity and duration remain unchanged from 80 to 120 mg [27, 30, 31]. Candesartan cilexetil efficacy is entirely due to its active metabolite CV-11794 and is dose-dependent over the range of 1–8 mg and its clinical antihypertensive dose is stated to be around 4 mg day−1 [26]. There exists a clear dose-effect relationship up to the 200 mg dose of tasosartan, up to 150 mg for SC-52458 and up to 5 mg for TAK-536. Higher doses of these drugs do not increase further their blocking effect [22, 23, 32].

The doses of the ACE inhibitors and the angiotensin II receptor antagonists inhibiting blood pressure response to angiotensin by 75% compared with the doses used in therapeutics are presented in Table 3 and the corresponding graph is depicted on Figure 2. The concordance of doses is good, except for captopril, whose therapeutic antihypertensive dose is labelled as 25–50 mg, which is much higher than the dose inhibiting blood pressure response to angiotensin I by 75%. This is probably related to its shorter duration of action leading to the use of higher doses to prolong its effect.

Table 3.

Prediction of the therapeutic antihypertensive doses of ACE inhibitors and angiotensin II receptor antagonists with exogenous challenges of angiotensin in healthy subjects.

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Figure 2.

Figure 2

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Effective therapeutic dose prediction of angiotensin receptor antagonists and ACE inhibitors by phase I studies using exogenous angiotensin challenges. ▴ enalapril, ▪ captopril, ▾ lisinopril, ♦ cilazapril, • ramipril, □ losartan, ▿ valsartan, ▵ candesartan cilexetil, ◊ irbesartan, ○ tasosartan. ID75: dose inducing a 75% inhibition of the blood pressure response to angiotensin challenges. Each point represents one study. The delimited horizontal and vertical lines represent the range of dosing intervals associated with 75% inhibition and used in therapeutics, respectively.

Discussion

The experimental paradigm of angiotensin challenges with continuous noninvasive blood pressure measurement has been applied repeatably to the evaluation of the drugs presented here. This method appears to have sufficient internal and external validity to be applied to the development of drugs in this area of cardiovascular therapy.

The blood pressure effect of angiotensin challenges exhibits a clear dose–response relationship. Over the range of doses analysed in this study, the stepwise increase in blood pressure with increasing angiotensin doses can be characterized both by an Emax model or a log-linear model. A correction factor was introduced to account for the difference in molecular weight between angiotensin I and II. A fairly large intersubject and intrasubject variability for diastolic and systolic blood pressure was present, which may reflect the influence from both technical and physiological sources. Neither body weight, nor other demographic factors included in the model showed any influence on the dose–response relationship. This is possibly due to the small range of these variables in the population studied. The adaptation of the angiotensin dose for body weight may not be necessary during the preliminary dose-finding procedures.

The angiotensin-induced peaks recorded during the placebo periods were stable, revealing no significant interperiod and intersubject variability, except for a significant between-study variability. Both variabilities may reflect influnces from several sources, such as differences in study methodology, physiological factors (genetics, body composition, environmental influences, sensitivity to angiotensin) or technical factors (purity of angiotensin, actual vs nominal dose, standardization of the batches, loss of drug during the sterile filtration).

The statistical analysis of angiotensin doses demonstrated that their variability was high between the studies. The few subjects who participated in several studies at intervals exceeding 1 year appeared to need fairly reproducible angiotensin doses to elicit a given response and suggesting that the sensitivity to angiotensin presents some individual component. No demographic covariates showed any statistical influence on the doses.

Inhibition of the pressor response to exogenous angiotensin represents a useful approach for the evaluation of the blockade of the renin-angiotensin system and has often been preferred in phase I studies, coupled with hormonal measurements. The characterization of angiotensin II receptor antagonists and ACE inhibitors with the method presented here provides useful information on the magnitude of the blockade, the minimal dose needed for full efficacy, and the onset and duration of inhibition. There seems to be good agreement between the doses eliciting a 75% blockade of the effect of angiotensin I or II in healthy volunteers and the doses retained for therapeutic use. The choice may be further affected by the duration of blockade, as exemplified in the case of captopril (this drug is efficient at much lower doses than those labelled, as indicated by the use of minute test doses at treatment). The method of angiotensin challenges can also provide peak/trough estimates of RAS blockade. The clear dose–response relationship of angiotensin challenges justifies such an approach to characterize the efficacy of angiotensin II receptor antagonists and ACE inhibitors in healthy subjects.

In conclusion, the external validation of the experimental paradigm of angiotensin challenges, evaluated by comparison of the doses of ACE inhibitors and angiotensin II receptor antagonists used clinically, demonstrates that it has a good predictive value. The use of this paradigm has numerous advantages: it permits the quantitative evaluation of a surrogate measure related to the clinical efficacy. A well-validated surrogate is of considerable investigative value, since it can substantially shorten clinical development time or help to reach a critical decision point in exploratory development [33]. Moreover, it is applicable in phase I studies, to provide meaningful and relevant information early in clinical development. It further enables the determination of the ‘therapeutic response surface’ invoked by Sheiner [34], which conceptualizes the relationships between the patient factors, the drug exposure and the response to the drug (efficacy and toxicity) and aims at evaluating at best the expected effect of the drug. The knowledge of the ‘response surface’ is still uncertain for ACE inhibitors and for angiotensin receptor antagonists [35–38]. Further efforts have thus to be devoted to develop true pharmacokinetic-pharmacodynamic modelling for these cardiovascular agents. The definition of the correct concentration-effect relationship is very important in understanding the pharmacological and toxicological end-points and for rational drug use.

Acknowledgments

This work was supported in part by the Swiss National Fund for Scientific Research (grant N°3200–043264.95/1).

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