TY - JOUR
T1 - Cost-Neutral Optimization of Pazopanib Exposure by Splitting Intake Moments
T2 - A Prospective Pharmacokinetic Study in Cancer Patients
AU - Dutch Pharmacology Oncology Group (DPOG)
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
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 ).
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 -
