TY - JOUR
T1 - Cost-Neutral Optimization of Pazopanib Exposure by Splitting Intake Moments
T2 - A Prospective Pharmacokinetic Study in Cancer Patients
AU - Groenland, Stefanie L
AU - van Eerden, Ruben A G
AU - Verheijen, Remy B
AU - de Vries, Niels
AU - Thijssen, Bas
AU - Rosing, Hilde
AU - Beijnen, Jos H
AU - Koolen, Stijn L W
AU - Mathijssen, Ron H J
AU - Huitema, Alwin D R
AU - Steeghs, Neeltje
N1 - Funding Information:
We thank all patients for their participation in this study. We thank Dr. Huixin Yu for performing the simulations. In addition, we thank the study team for their contribution, in particular Else Meijer and Brigitte Dufourny. This work was presented in part at the 2019 American Society of Clinical Oncology Annual Meeting, Chicago, IL, USA (J Clin Oncol. 2019;37 Suppl.:abstract 3119).
Publisher Copyright:
© 2020, Springer Nature Switzerland AG.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7
Y1 - 2020/7
N2 - 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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=85079436811&partnerID=8YFLogxK
U2 - 10.1007/s40262-020-00863-5
DO - 10.1007/s40262-020-00863-5
M3 - Article
C2 - 32020530
SN - 0312-5963
VL - 59
SP - 941
EP - 948
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 7
ER -