Blood pressure measurements are a critical cardiovascular health parameter and are often overshadowed by assessment of ECG (electrocardiogram) changes in cardiovascular safety pharmacology evaluations. Cardiac issues that can result in drug development failure may also be due to functional problems arising from changes in blood pressure.
Attentive Science has industry recognized subject matter experts in the field of Safety Pharmacology that will provide guidance to you when you are trying to address critical questions about drug safety. Over the past three decades, the field of safety pharmacology has been dominated by cardiovascular ECG assessments. The focus on ECG changes is primarily due to its effectiveness in predicting cardiac arrhythmias and abnormalities in cardiac conduction particularly those related to the QTc interval. The QTc interval is crucial because its prolongation can lead to Torsades de Pointes (TdP), a potentially life-threatening type of arrhythmia. Regulatory guidelines, such as those from the ICH E14, emphasize ECG monitoring to identify drugs that may cause such cardiac issues early in the development process. However, it is important to remember that blood pressure changes can reflect underlying cardiovascular issues that might not be detected through ECG assessments alone.
Importance of Blood Pressure monitoring in cardiovascular safety pharmacology
Drug-Induced Hypertension: Some drugs can cause sustained increases in blood pressure, leading to long-term cardiovascular risks such as heart failure, stroke, myocardial infarction or kidney failure. Certain drugs such as stimulants and steroids can elevate blood pressure through various mechanisms, including vasoconstriction, increased cardiac output, or alterations in fluid balance.
Examples of drugs that have been withdrawn from the market due to severe hypertensive effects include;
Rofecoxib (Vioxx): An anti-inflammatory drug withdrawn due to increased risk of heart attack and stroke, partly linked to elevated blood pressure.
Fenfluramine/Phentermine (Fen-Phen): A weight loss drug withdrawn due to its association with pulmonary hypertension and heart valve issues.
Sibutramine (Meridia): A weight loss drug withdrawn because it increased the risk of heart attacks and strokes, partly by producing elevated blood pressure.
Drug-Induced Hypotension: A drop in mean arterial pressure could result from either a decrease in cardiac output and/or a decrease in vascular resistance. Drugs triggering a sustained hypotension can significantly increase the risk of adverse effects including; 1) Dizziness and Fainting – as a result of inadequate blood flow to the brain and falls, which can result in physical injuries. 2) Shock – because of insufficient blood flow to vital organs, damage to that organ may occur, 3) Organ Damage - impair the function of essential organs such as the heart, kidneys, and brain, potentially leading to permanent damage.
Examples of drugs that have been withdrawn from the market due to severe hypotensive effects include;
Cisapride (Propulsid): A drug used to treat gastrointestinal disorders, withdrawn due to its potential to cause serious cardiac arrhythmias and severe hypotension.
Drotrecogin alfa (Xigris): Used for severe sepsis, it was withdrawn due to lack of efficacy and increased risk of serious bleeding and hypotension.
Have we flogged the topic of ECG changes in Cardiovascular Safety Pharmacology to death?
Since inception and for at least 2 decades, drug development cardiovascular safety pharmacologist have focused intensely on ECG changes that occur during drug development ensuring that we can now detect proarrhythmic potentials of test articles undergoing development with a high level of sensitivity, specificity and confidence.
The Dominance of ECG in Cardiovascular Safety Pharmacology
Three decades ago, the antihistamine terfenadine (prescribed for treatment of hay fever, was withdrawn following reports that it could evoke the potentially life threatening cardiac syndrome TdP, in otherwise healthy patients (Monahan et al., 1990; June and Nasr, 1997) as a result of QTc prolongation. Drug-induced acute QTc prolongation is more prevalent among small molecules because their mechanism typically involves accessing specific molecular targets within the hERG channel (Sanguinetti and Mitcheson, 2005; Kamiya et al., 2006). In contrast, larger molecules such as proteins, peptides, or monoclonal antibodies (biologics), which are often too large to interact with ion channels directly (Vargas et al., 2008), may cause adverse hemodynamic effects by targeting more accessible sites in the vascular space. In the 19th century, advancement of synthetic chemistry allowed for the creation of many small molecule drugs leading to drugs like aspirin (1899) and penicillin (1940s) and subsequently in the 20th century, high throughput screening/combination chemistry significantly accelerated drug discovery. Furthermore historically, a larger number of small molecules have dominated the pharmaceutical industry. The dominance of small molecules and the understanding of mechanisms of TdP has resulted in the overall dominance of ECG assessments for cardiovascular safety pharmacology.
The importance of detecting the liability for QTc prolongation is covered by both nonclinical and clinical regulatory guidelines (International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use [ICH] (S7B) and (E14) respectively (Anon., 2005a,b, 2015).
Stay Attentive to Blood Pressure
Blood pressure is a critical parameter in evaluating the overall cardiovascular safety profile of a test article. Paying close attention to changes in blood pressure during cardiovascular safety pharmacology studies ensures robust safety data, thereby enhancing patient health and safety.
Blood Pressure Assessments during cardiovascular safety pharmacology
The ICH S7A guidance document highlights the assessment of the effects of test article on arterial blood pressure (BP) as a key endpoint, typically within the scope of in-vivo cardiovascular safety pharmacology evaluations. However, a cross-company data analysis published a decade ago showed that the predictive value of heart rate and Diastolic Blood Pressure (DBP) was poor for translating nonclinical data to phase I outcomes (Ewart et al., 2014). Clinical data indicates that even a slight elevation in arterial BP (~2–3 mmHg) is strongly associated with adverse cardiovascular morbidity and mortality outcomes in patients (Lewington, Clarke, Qizilbash, Peto, & Collins, 2002; MacMahon et al., 1990). Persistent increases in blood pressure can lead to cardiovascular risks, raising clinical concerns about even small, chronic BP elevations. The importance of this issue has prompted the release of several guidelines including a revised draft FDA guidance document titled ‘Assessment of Pressor Effects of Drugs’ (U.S. Food and Drug Administration/Center for Drug Evaluation and Research, 2022). This guidance details the aspects of clinical BP measurement and recommends using Ambulatory Blood Pressure Measurement (ABPM) instead of routine BP measurement for drugs intended for chronic use in the target patient population. This guidance now suggests that a drug-induced increase in blood pressure is likely to have similar deleterious effects, no matter the mechanism of the increase.
Recommendations for industry best practice for blood pressure assessments as part of cardiovascular safety pharmacology
While nearly every drug development program includes assessments of a test article’s effects on blood pressure, there is room for improvement in the consistency and adequacy of these methods. Enhancing these assessments will ensure that even small increases in blood pressure changes during cardiovascular safety pharmacology, which could be relevant to the risks, are reliably detected, thereby improving the overall safety profile of new drugs.
Blood pressure (Changes in systolic, diastolic, pulse pressure, and diurnal variation) and ECG assessments need to be given equal priority during cardiovascular safety pharmacology assessments. Sponsors should include a thorough blood pressure assessment for any drug intended for chronic use as the risk related to blood pressure is a continuous function, and a sustained increase in blood pressure correlates with long-term increases in the risk of cardiovascular events. The nonclinical study designs should include pharmacokinetic samples at appropriate time points in an effort to demonstrate pharmacokinetic exposure and to explore any dose response relationships.
It is important to note that some researchers have shown that SBP is a more effective predictor of cardiovascular risk than DBP (Strandberg and Pitkala, 2003). However, considering our knowledge of cardiovascular hemodynamics, this predictive effect for nonclinical evaluations remains to be confirmed. We currently await the full publication from Health and Environmental Sciences Institute (HESI) on the consortium’s efforts and evaluation of drug induced Blood Pressure changes.
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Incorporating comprehensive blood pressure assessments alongside ECG monitoring offers a more complete evaluation of a test article's impact on cardiovascular safety, thereby helping to identify potential adverse effects earlier in the development process and ultimately leading to safer therapeutic options for patients. Contact Us. The Attentive commitment to staying at the forefront ensures our clients receive the highest standard of safety pharmacology services.