Stefanie L Groenland1, Ruben A G van Eerden2, Remy B Verheijen3, Niels de Vries3, Bas Thijssen3, Hilde Rosing3, Jos H Beijnen3,4, Stijn L W Koolen2,5, Ron H J Mathijssen2, Alwin D R Huitema3,6, Neeltje Steeghs7. 1. Division of Medical Oncology, Department of Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. s.groenland@nki.nl. 2. Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands. 3. Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands. 4. Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. 5. Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands. 6. Department of Clinical Pharmacy, University Medical Center, Utrecht University, Utrecht, The Netherlands. 7. Division of Medical Oncology, Department of Clinical Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
Abstract
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 ).
RCT Entities:
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 ).
Authors: Neeltje Steeghs; Alwin D R Huitema; Stefanie L Groenland; Remy B Verheijen; Markus Joerger; Ron H J Mathijssen; Alex Sparreboom; Jos H Beijnen; Jan H Beumer Journal: Clin Cancer Res Date: 2021-09-21 Impact factor: 12.531
Authors: Kim Westerdijk; Ingrid M E Desar; Neeltje Steeghs; Winette T A van der Graaf; Nielka P van Erp Journal: Br J Clin Pharmacol Date: 2020-01-21 Impact factor: 4.335
Authors: Anna M Mc Laughlin; Eduard Schmulenson; Olga Teplytska; Sebastian Zimmermann; Patrick Opitz; Stefanie L Groenland; Alwin D R Huitema; Neeltje Steeghs; Lothar Müller; Stefan Fuxius; Gerald Illerhaus; Markus Joerger; Frank Mayer; Uwe Fuhr; Stefan Holdenrieder; Georg Hempel; Oliver Scherf-Clavel; Ulrich Jaehde; Charlotte Kloft Journal: Cancers (Basel) Date: 2021-12-14 Impact factor: 6.639