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

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 (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 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.

Keywords: clinical pharmacology; oncology; therapeutics.