The relationship between dose, concentration and toxicity of everolimus in the treatment of neuroendocrine tumors: A prospective observational study

Everolimus is used in the treatment of patients with advanced neuroendocrine tumors (NET) and is administered at fixed doses despite known interpatient pharmacokinetic variability. This may affect both efficacy and tolerability. We wanted to investigate the relationship between prescribed dose, blood trough concentrations (C_trough), and toxicity in NET patients receiving everolimus in routine clinical practice. In this prospective observational study NET patients were treated with everolimus, mostly as third- or fourth-line therapy. Dose was adjusted according to adverse effects and tumor response. Concentrations (C_trough) of everolimus were measured at each routine follow-up and correlated to dose and cumulative adverse event (cAE) scores. Associations were evaluated using linear and generalized linear mixed models which accounted for repeated measurements within patients and varying dose regimens over time. Thirty-six patients were included. Everolimus dose was a significant predictor of C_trough (p < .001), but considerable interindividual variability was observed. Median C_trough levels increased with dose: 3.9, 5.1, 7.4, and 16.4 ng/mL for 2.5, 5.0, 7.5, and 10.0 mg per day, respectively. Considerable overlap in blood concentration was observed across dose groups; patients receiving 2.5 mg reached levels as high as 8.6 ng/mL, while those on 5 mg exhibited a wide range from 1.1 to 21.2 ng/mL. C_trough ≥ 6.0 ng/mL was associated with increased toxicity (p = .03), whereas nominal dose was not a reliable independent predictor of adverse events. Although median blood concentrations increased with higher doses, there was considerable variation between patients, resulting in overlapping concentration ranges across all dose groups. This indicates that fixed-dose regimens may not reliably predict systemic drug exposure. Everolimus blood concentrations were superior to dose levels in predicting adverse events. Therapeutic drug monitoring and individualized dose adjustment may improve the balance between efficacy and toxicity in NET patients treated with everolimus.