Background and Objective: Pazopanib is an oral tyrosine kinase inhibitor used in the treatment of renal cell carcinoma and soft-tissue sarcoma. At the approved dose of 800 mg once daily (QD), 16–20% of patients are being underdosed and at risk of decreased efficacy. This study aimed to show whether splitting intake moments, as a cost-neutral alternative to a dose increase, leads to an increased exposure. Methods: We performed a cross-over trial comparing the pharmacokinetics of pazopanib 800 mg QD with pazopanib 400 mg twice daily. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. Results: Nine evaluable patients were included. At the 800 mg QD dosing schedule, median minimum plasma concentration (Cmin), area under the concentration–time curve from 0 to 24 h (AUC0–24h), and maximum plasma concentration (Cmax) were 23.2 mg/L (interquartile range 18.5–27.6), 773 mg h/L (557–1009), and 40.6 mg/L (36.4–56.4) compared with 41.6 mg/L (30.5–55.8, p = 0.004), 942 mg h/L (885–1419, p = 0.027), and 50.2 mg/L (46.8–72.5, p = 0.074) at 400 mg twice daily. One patient experienced a grade 3 event (i.e., diarrhea). Conclusions: This study demonstrates that splitting intake moments of pazopanib leads to a 79% increase in Cmin, with acceptable tolerability. Therefore, this new dosing schedule offers a cost-neutral opportunity to optimize treatment in patients with low exposure. Clinical Trial Registration: NL6137 (http://www.trialregister.nl).

Additional Metadata
Persistent URL dx.doi.org/10.1007/s40262-020-00863-5, hdl.handle.net/1765/124905
Series VSNU Open Access deal
Journal Clinical Pharmacokinetics
Note corresponding author at NKI
Citation
Groenland, S.L. (Stefanie L.), van Eerden, R.A.G. (Ruben A. G.), Verheijen, R.B, de Vries, N. (Niels), Thijssen, B, Rosing, H, … Steeghs, N. (2020). Cost-Neutral Optimization of Pazopanib Exposure by Splitting Intake Moments: A Prospective Pharmacokinetic Study in Cancer Patients. Clinical Pharmacokinetics. doi:10.1007/s40262-020-00863-5