Drug-induced blood pressure increase – recommendations for assessment in clinical and non-clinical studies

ABSTRACT

Introduction: Changes in blood pressure (BP) are now proactively examined throughout the drug development process as an integral aspect of safety monitoring. This is because hypertension is a very strong risk factor for cardiovascular events and drug-induced increases in BP have attracted increased regulatory attention. However, there is currently no guidance from regulatory agencies on the minimum BP data required for submissions, and there are no specific criteria for what constitutes a safety signal for increased BP in non clinical studies.

Areas covered: Evaluation of BP increases through the drug discovery and development process.

Expert opinion: Research into the effects of drugs should begin before clinical development is initiated and continue throughout the clinical trial program. Non clinical studies should inform a benefit–risk analysis that will aid decision-making of whether to enter the drug into Phase I development. The degree of acceptable risk will vary according to the therapy area, treatment indication and intended population for the new drug, and the approach to BP assessment and risk mitigation should be tailored accordingly. However, BP monitoring should always be included in clinical trials, and data collected from multiple studies, to convincingly prove or refute a suspicion of BP effects.

KEYWORDS:

• Blood pressure
• drug development
• non-clinical development
• clinical development
• cardiovascular outcomes
• drug evaluation

Article highlights

• Drug-induced BP increases are associated with elevated CV risk and should be monitored both at the drug discovery stage and throughout development

• This CV risk can be reduced by treatment with appropriate antihypertensive medication

• The aim of any studies should be to quickly and efficiently detect and characterize any potential issues relating to a drug (including BP signals) and discontinue drug development in a timely manner if the benefit–risk profile becomes unfavourable

• The effect of a drug on BP might not be identified during non-clinical development, as it might only manifest in human studies or studies in the target patient population

• It is unlikely that a single study will be able to either prove or disprove a drug’s effect on BP, and 24-hour ABPM is recommended for studies assessing drug-induced effects on BP

• Any decisions should take into account the therapy area, target population and indication of the drug

This box summarizes key points contained in the article.

Acknowledgments

The authors would like to thank Anna Hellsten Kronander for excellent help with literature searches and David Brott, Corina Dota, Li-Ming Gan, Michael Gillen, Karin Henriksson, Boaz Hirshberg, Anthony Johnson, Alexandre Kiazand, Jiefen Munley, Shamik Parikh and Pia S Pollack, all of whom are employees of AstraZeneca/MedImmune, for reviewing the manuscript and providing useful comments and suggestions.

Declaration of interest

All authors are employees of AstraZeneca/MedImmune. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Supplemental material

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Additional information

Funding

Editorial support was provided by Alexander Jones of inScience Communications, Springer Healthcare Ltd, London, UK, and was funded by AstraZeneca.