Drug Safety Assessment Based on Target Affinity, Drug Exposure and Plasma Protein Binding: Drug-Induced Cardiotoxicity from a Translational Pharmacology Perspective

Catozzi, Simona; Sips, Fianne; Totis, Niccolò; Bisotti, Marc-Antonio; Stathopoulos, Sofia; Torchia, Mario; Emili, Luca; Carbone, Vincenzo; Baker, Candice; Mahoney, J. Matthew; Röshammar, Daniel

doi:10.3390/ijms27104563

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Open AccessArticle

Drug Safety Assessment Based on Target Affinity, Drug Exposure and Plasma Protein Binding: Drug-Induced Cardiotoxicity from a Translational Pharmacology Perspective

by

Simona Catozzi

¹

,

Fianne Sips

²,

Niccolò Totis

¹,

Marc-Antonio Bisotti

¹,

Sofia Stathopoulos

¹,

Mario Torchia

¹,

Luca Emili

¹,

Vincenzo Carbone

¹

,

Candice Baker

³,

J. Matthew Mahoney

³ and

Daniel Röshammar

^1,* on behalf of the Cardioverse Project

¹

InSilicoTrials Technologies S.p.A., 34123 Trieste, Italy

²

InSilicoTrials Technologies B.V., 1017 BR Amsterdam, The Netherlands

³

The Jackson Laboratory, Bar Harbor, ME 04609, USA

^*

Author to whom correspondence should be addressed.

Int. J. Mol. Sci. 2026, 27(10), 4563; https://doi.org/10.3390/ijms27104563

Submission received: 18 March 2026 / Revised: 11 May 2026 / Accepted: 13 May 2026 / Published: 19 May 2026

(This article belongs to the Special Issue Understanding Cardiotoxicity: From Mechanisms to Therapeutic Implications)

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Abstract

Cardiac safety assessment is an integral part of drug discovery and development. Drug candidates that adversely affect cardiac or hemodynamic function should be discontinued early unless a favorable benefit-risk ratio for patients can be justified. In this hypothesis-generating work, we aimed to develop a conceptual framework for informing early safety risk assessment based on in vitro drug affinities to pharmacological targets. For illustration, we used the drug-induced cardiotoxicity rank (DICTrank) data comprising 1318 drugs with cardiac safety concerns according to FDA labeling. The data was enriched with information on affinity to the most plausible mechanistic targets, clinical drug exposure, and human plasma protein binding. We descriptively identified 18 target classes potentially associated with elevated cardiovascular risk: potassium channels (accounting alone for 20% of the ‘most concern’ safety group); adrenergic, dopamine, serotonin, androgen, sex hormone, and opioid receptors; cyclooxygenase; sodium and calcium channels; muscarinic and glucocorticoid receptors; phosphodiesterase; topoisomerase; angiotensin-converting enzyme; angiotensin II type 1 receptor; monoamine transporters, and acetylcholinesterase. Overall, 80% of the ‘most concern’ drugs compared with only 12% of the ‘no concern’ drugs were associated with these targets in this exploratory descriptive analysis. Concentration–response analyses revealed differences in target potency and free drug exposure that appeared associated with variability in the severity of cardiotoxicity among drugs acting on the same target. This framework demonstrates how in vitro data can be used to benchmark new compounds early in development, enabling the timely discontinuation of candidates associated with substantial risk.

Keywords: DICTrank; cardiovascular safety; target affinity; drug exposure; plasma protein binding; drug discovery and development

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MDPI and ACS Style

Catozzi, S.; Sips, F.; Totis, N.; Bisotti, M.-A.; Stathopoulos, S.; Torchia, M.; Emili, L.; Carbone, V.; Baker, C.; Mahoney, J.M.; et al. Drug Safety Assessment Based on Target Affinity, Drug Exposure and Plasma Protein Binding: Drug-Induced Cardiotoxicity from a Translational Pharmacology Perspective. Int. J. Mol. Sci. 2026, 27, 4563. https://doi.org/10.3390/ijms27104563

AMA Style

Catozzi S, Sips F, Totis N, Bisotti M-A, Stathopoulos S, Torchia M, Emili L, Carbone V, Baker C, Mahoney JM, et al. Drug Safety Assessment Based on Target Affinity, Drug Exposure and Plasma Protein Binding: Drug-Induced Cardiotoxicity from a Translational Pharmacology Perspective. International Journal of Molecular Sciences. 2026; 27(10):4563. https://doi.org/10.3390/ijms27104563

Chicago/Turabian Style

Catozzi, Simona, Fianne Sips, Niccolò Totis, Marc-Antonio Bisotti, Sofia Stathopoulos, Mario Torchia, Luca Emili, Vincenzo Carbone, Candice Baker, J. Matthew Mahoney, and et al. 2026. "Drug Safety Assessment Based on Target Affinity, Drug Exposure and Plasma Protein Binding: Drug-Induced Cardiotoxicity from a Translational Pharmacology Perspective" International Journal of Molecular Sciences 27, no. 10: 4563. https://doi.org/10.3390/ijms27104563

APA Style

Catozzi, S., Sips, F., Totis, N., Bisotti, M.-A., Stathopoulos, S., Torchia, M., Emili, L., Carbone, V., Baker, C., Mahoney, J. M., & Röshammar, D., on behalf of the Cardioverse Project. (2026). Drug Safety Assessment Based on Target Affinity, Drug Exposure and Plasma Protein Binding: Drug-Induced Cardiotoxicity from a Translational Pharmacology Perspective. International Journal of Molecular Sciences, 27(10), 4563. https://doi.org/10.3390/ijms27104563

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Drug Safety Assessment Based on Target Affinity, Drug Exposure and Plasma Protein Binding: Drug-Induced Cardiotoxicity from a Translational Pharmacology Perspective

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