Abstract 731P
Background
For pazopanib (PZ), a target trough concentration (Cmin) of PZ above 20.5 mg/L has been associated with improved clinical efficacy. Absorption of PZ is pH-dependent and concomitant therapy with proton pump inhibitors (PPIs) reduces its exposure by ∼40%. However, since PPIs do not elevate intragastric pH over the full 24-hour range, staggered dosing of the PPI one hour after intake of PZ is proposed as strategy to overcome this interaction. To evaluate the effect of this strategy clinically, we investigated the influence of staggered dosing of PPIs on PZ exposure.
Methods
From patients treated with PZ 800 mg OD (taken fasted) between March 2013 and March 2020, the first measured PZ Cmin levels at steady state were collected. The concomitant use of PPIs was extracted from the electronic medical records. All patients were instructed to take the PPI one hour after intake of PZ. Geometric mean (GM) PZ Cmin levels were compared between the groups of patients who were treated with and without a PPI. Additionally, the effect of the type of PPIs on PZ exposure was explored.
Results
Of the 132 patients treated with PZ, 50 patients were treated with PPI. The GM PZ Cmin was 24.1 mg/L (95% CI 21.3-27.3) in the patients who were treated with PPI compared to 28.2 mg/L (95% CI 25.9-30.5)(p= .033) in those without PPI. In patients treated with PPI, 32% had a Cmin below the target threshold compared to 21% of the patients without PPI. Sub-analysis showed that the reduced PZ exposure was mainly observed in patients who were co-treated with omeprazole (n=26) (GM Cmin 22.8 mg/L (95% CI 18.8-27.6) (p=.038), while minimal reduction in PZ exposure was observed in those treated with pantoprazole (n=19) (GM Cmin 26.6 mg/L (95% CI 22.0-32.2) compared to patients without PPI.
Conclusions
Despite staggered dosing of PZ and PPIs, concomitant treatment still resulted in reduced PZ exposure. Therefore, we conclude that the staggered dosing of PPIs did not mitigate the effect PPIs have on PZ exposure. Within the PPI group, a more pronounced decrease in PZ exposure was observed for omeprazole compared to pantoprazole. Hence, for patients unable to stop PPIs during PZ treatment, pantoprazole might be preferred over omeprazole. Furthermore, PZ Cmin should be monitored to prevent subtherapeutic exposure.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Radboudumc.
Funding
Has not received any funding.
Disclosure
F. jansman: Advisory/Consultancy, Advisory board: Amgen; Advisory/Consultancy, Advisory board: Servier. D. Burger: Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Janssen; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Merck; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): ViiV Heatlhcare; Honoraria (institution), Advisory/Consultancy, Research grant/Funding (institution): Bristol-Myers Squibb; Honoraria (institution), Advisory/Consultancy: Gilead; Honoraria (institution): AbbVie. C. Van Herpen: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Merck Sharp and Dohme; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Sanofi; Research grant/Funding (self): Novartis. N. Van Erp: Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Janssen-Cilag; Research grant/Funding (institution): Gilead; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Roche; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Ipsen; Research grant/Funding (institution): Sanofi. All other authors have declared no conflicts of interest.