Abstract 5047: Celecoxib fixed dose combination - therapeutic drug monitoring
Authors: Lee Cynthia , Lee Dongwon , Khateri Sam , Wang Wen , Trieu Vuong 
Published: July 2017

Background: The anticancer properties of Celecoxib (CEL) have been demonstrated in different cancer indications, including colorectal, breast and non-small cell lung cancers. However, its use is associated with dose related cardiovascular adverse events including edema and hypertension. We have shown that combination of CEL and OLM (Olmesartan) would negate drug induced edema caused by CEL. To further improve on the safety of this combination, we are now exploring therapeutic drug monitoring (TDM) guided dosing on CEL. This study demonstrated that TDM via lateral flow platform would be able to quantify plasma drug concentration and guide the optimal dosing for CEL.

Methods: Pharmacokinetic (PK) data (Cmax and AUC) to oral formulations of CEL as single dose to healthy adults were collected from published clinical trials. PK data were analyzed against dose and demographic factors to evaluate the variability. To develop the lateral flow methods for quantification, mAbs against CEL were generated by synthesizing BSA-CEL immunogen and hybridoma technology. The best clones demonstrating a dose response to CEL were selected and tested. The assay requires the configuration of immobilizing BSA-CEL onto the membrane followed by flowing the colloidal-gold labeled mAb against CEL through in presence of test analyte. This resulted in a competitive assay where the signal decreased as the concentration of CEL in blood increased.

Results: For CEL, the AUC and Cmax across multiple doses were significantly overlapped. With 200 mg CEL, we used meta-analysis to show that older subjects have a significantly higher AUC than young subjects (p&lt;0.001). These results indicated that different individuals may have very different drug exposure with same dose of CEL, depending on their age and other factors, resulting in over exposure and toxicity. Using a cutoff of 6,741 ng*hr/mL, we were able to separate out almost all of the elderly subjects from the young subjects. Therefore, to avoid toxicity, we will use TDM guided dosing to maintain AUC at the target AUC of 6,741 ng*hr/mL. To make possible TDM guided dosing, we developed a quantitative point of care lateral flow assay for CEL. mAb against CEL were selected based on good sensitivity and binding ability to CEL. Coupled with the lateral flow reader by Qiagen, the assay exhibited a dynamic range of 7.5ng/ml to 30mg/ml of CEL, from a drop of blood with read time of less than 20 min.

Conclusion: A quantitative lateral flow platform coupled to a reader was developed to easily detect the CEL concentrations in finger-prick blood samples, allowing for in-home personal PK testing. The individual PK profiles built from the concentration data will be used to guide the optimal dosing of CEL, to maximize treatment efficacy and minimize toxicity. This should allow for higher dosing of CEL without hitting the toxic exposure limit. This additional enhancement on top of combination with OLM in the fixed dose combination should insure the safety of our patients on these drugs.

Citation Format: Cynthia Lee, Dongwon Lee, Sam Khateri, Wen Wang, Vuong Trieu. Celecoxib fixed dose combination - therapeutic drug monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5047. doi:10.1158/1538-7445.AM2017-5047