BACKGROUND: Data on exposure-response or exposure-toxicity relationships of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are limited and inconclusive. We aimed to investigate whether there is an association between palbociclib exposure and progression-free survival (PFS), adverse events (AEs) and dose reductions. MATERIALS AND METHODS: Data were retrieved from the prospective, multicentre SONIA trial in which patients with advanced estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer were randomised to receive CDK4/6i treatment in first versus second line. Blood for pharmacokinetics (PK) was taken at day 15 of cycles 1 and 2 during CDK4/6i treatment. Individual trough concentrations and plasma area under the curves of palbociclib were constructed using a population PK model. Associations with palbociclib exposure were tested using Cox regression for PFS and chi-square tests for AEs or dose reductions. RESULTS: PK data were available for 344 patients. No association between palbociclib exposure and PFS was found. Although patients with higher palbociclib exposure had more dose reductions during their entire CDK4/6i treatment course, this was not reflected by a higher incidence of grade 3-4 AEs in the first 3 months. CONCLUSION: The absence of an association between palbociclib exposure and PFS and the presence of the association between palbociclib exposure and dose reductions suggest that dose reductions may safely be carried out in case of palbociclib-related toxicity.