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

Research output: Contribution to journalArticlepeer-review

Authors

Colleges, School and Institutes

External organisations

  • The Institute of Cancer Research
  • University of Birmingham

Abstract

Aims
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 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 Rx identified across the four PARPi are statistically significant (χ2 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 (GI) 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 (Vd). The thrombocytopenia rate of niraparib > rucaparib > olaparib tracked with the Vd 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.

Details

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