Identification of different side effects between PARP inhibitors and their polypharmacological multi-target rationale

Daranjit Sandhu, Albert Antolin, Anthony Cox, Alan M Jones

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Abstract

Aims: The aim of this study was to determine the differences and potential mechanistic rationale for observed adverse drug reactions (ADRs) between four approved PARP inhibitors (PARPi). Methods: The Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card drug analysis profiles and NHS secondary care medicines database enabled the identification of suspected ADRs associated with the PARPi in the UK from launch to 2020. The polypharmacology of the PARPi were data-mined from several public data sources. Results: The overall ADRs per 100 000 R x identified across the four PARPi are statistically significant (χ 2 test, P <.001). Rucaparib has the greatest relative suspected ADRs, which can be explained by its least clean kinome and physicochemical properties. The suspected gastrointestinal ADRs of rucaparib and niraparib can be ascribed to their kinase polypharmacology. Suspected blood and lymphatic system ADRs of PARPi can be linked to their high volume of distribution (V d). The thrombocytopenia rate of niraparib > rucaparib > olaparib tracked with the V d trend. Hypertension is only associated with niraparib and could be explained by the therapeutically achievable inhibition of DYRK1A and/or transporters. Arrhythmia cases are potentially linked to the structural features of hERG ion-channel inhibition found in rucaparib and niraparib. Enhanced psychiatric/nervous disorders associated with niraparib can be interpreted from the diverse neurotransporter off-targets reported. Conclusions: Despite their similar mode of action, the differential polypharmacology of PARP inhibitors influences their ADR profile.

Original languageEnglish
JournalBritish Journal of Clinical Pharmacology
Early online date30 Jul 2021
DOIs
Publication statusE-pub ahead of print - 30 Jul 2021

Bibliographical note

Funding Information:
A.A.A. thanks the Wellcome Trust for funding, the ICR (London). A.M.J., A.R.C. and D.S. thank the School of Pharmacy (Birmingham) for supporting the data collection. All authors thank the MHRA Yellow Card Scheme for open‐source data availability used in this study. A.A.A. is primarily supported by a Wellcome Trust Sir Henry Wellcome Postdoctoral Fellowship (204735/Z/16/Z).

Publisher Copyright:
© 2021 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Keywords

  • clinical pharmacology
  • oncology
  • therapeutics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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