Prolonged Pharmacokinetic Interaction Between Capecitabine and a CYP2C9 Substrate, Celecoxib

Abstract

This study investigated the time course and magnitude of the pharmacokinetic interaction between capecitabine and the cytochrome P450 (CYP) 2C9 substrate celecoxib, with implications for coadministration of fluoropyrimidines with CYP2C9 substrates such as warfarin. Patients received celecoxib 200 mg orally twice daily continuously, with capecitabine (1000 mg/m2 orally twice daily for 14 days every 21 days) starting 7 days later. Assessment of the drug‐drug interaction (DDI) potential was performed using equivalence testing, which assumes that there is no clinically relevant DDI when the calculated 90% confidence intervals (CIs) of the drug exposure ratios fall within the range of 0.80 to 1.25. Comparison of steady‐state pharmacokinetic parameters of celecoxib between day 7 (cycle 0, celecoxib only) and day 14 (cycle 1, celecoxib + capecitabine) showed geometric mean ratios of 1.24 (90%CI, 1.04‐1.49), 1.30 (1.11‐1.53) and 1.28 (1.11‐1.47) for maximum plasma concentration, minimum plasma concentration, and area under the concentration‐time curve from time zero to 8 hours, respectively. Comparison of day 7 vs day 21 (cycle 1, after 1 week washout of capecitabine) showed a further increase in the geometric mean ratio of maximum plasma concentration (1.39; 90%CI, 1.16‐1.66), minimum plasma concentration (1.53; 1.10‐2.12) and area under the concentration‐time curve from time zero to 8 hours (1.41; 1.19‐1.68). Because the 90%CIs fell outside the prespecified equivalence margin, we conclude that coadministration results in a DDI (increased celecoxib exposure) that persists for at least 7 days after capecitabine discontinuation. Close monitoring should be undertaken when administering fluoropyrimidines with CYP2C9 substrates with narrow therapeutic indexes while also weighing the benefits and risks for individual patients.

Inhibition of imrecoxib on mRNA and protein expression of CYP2C11 enzyme in rats

“…Our previous in vivo animal studies indicate that CYP2C9 and CYP2D6 inhibitors can affect the pharmacokinetics of imrecoxib in vivo and increase the area under the curve and C max (P < 0.05) and decrease CL (P < 0.05) (He et al, 2017;He, Wang, et al, 2020). The results confirm that imrecoxib is metabolized by CYP2C9 and CYP2D6, and its metabolic characteristics are similar to those of celecoxib (Ramírez et al, 2019;Siu et al, 2018). We also find that imrecoxib has no induction or inhibitory effect on the CYP3A enzyme (Gong et al, 2014).…”

Targeting cancer-related inflammation with non-steroidal anti-inflammatory drugs: Perspectives in pharmacogenomics

“…Ibuprofen co-administered with pemetrexed suppressed the clearance of pemetrexed and increased its maximum plasma concentration ( Sweeney et al, 2006 ). Coadministration of celecoxib and capecitabine increased celecoxib exposure in patients, which suggested the importance of close monitoring of cancer patients receiving NSAIDs with a narrow therapeutic index ( Ramírez et al, 2019 ). In addition, selective COX-2 inhibitors such as celecoxib have been associated with great risk of adverse cardiovascular effects, and aspirin use was associated with a higher risk of major bleeding in individuals without cardiovascular disease ( Zheng and Roddick, 2019 ; Schjerning et al, 2020 ).…”

In vitro inhibitory effect of obtusofolin on the activity of CYP3A4, 2C9, and 2E1

“…Except CYP3A4, CYP2C9 and 2E1 also play vital roles in the pharmacokinetics of assorted drugs. The co-administration of capecitabine and celecoxib, a substrate of CYP2C9, results in a drug-drug interaction, where the maximum plasma concentration and area under the concentration-time curve of celecoxib increased [21]. The inhibition of CYP3A4, 2C9, Obtusofolin served as a non-competitive inhibitor of CYP3A4 and a competitive inhibitor of CYP2C9 and 2E1.…”