Pazopanib pharmacokinetically guided dose optimization in three cancer patients with gastrointestinal resection

Pazopanib is approved in advanced renal cell carcinoma (RCC) and soft-tissue sarcoma at a flat-fixed dose despite a large pharmacokinetics interindividual variability and a narrow therapeutic index. To our knowledge, pazopanib exposure in patients with gastrointestinal resections (GIR) has not been described. This report focuses on feasibility of pharmacokinetics-guided dose escalation in these patients and clinical implications for their management.

A retrospective data collection was performed for three patients with GIR treated with pazopanib, including pazopanib plasma concentrations (high-performance liquid chromatography with UV detection) and treatment adherence (Girerd score).

First patient (55-year-old man, RCC, gastric bypass surgery) pazopanib C_min,ss at day 39 was 4.1 mg/L. Dose escalation to 1800 mg/day fractionated allowed to reach C_min,ss of 18.5 mg/L (target threshold in RCC patients: 20.5 mg/L). Patient 2 (50-year-old woman, metastatic myxofibrosarcoma, gastric band) showed C_min,ss of 4.0 mg/L at day 13. In patient 3 (49-year-old man, gastric malignant peripheral nerve sheath tumor, gastrectomy), C_min,ss at day 13 was 2.7 mg/L. For these two patients, intake with food and dose fractioning only slightly increased pazopanib C_min,ss to 12.0 mg/L and 6.5 mg/L, respectively (therapeutic threshold in sarcoma patients: 27 mg/L). Treatment adherence was good in all patients.

Optimal pazopanib exposure cannot be achieved in patients with GIR, and thus, other therapeutic strategies should be encouraged. Pretherapeutic assessment seems crucial to evaluate factors as bariatric surgery that may impact pazopanib concentrations. Therapeutic drug monitoring could be helpful to optimize pazopanib response in these patients.