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Interactions between the chemotherapeutic agent eribulin mesylate (E7389) and P-glycoprotein in CF-1 abcb1a-deficient
Jan-Shiang Taur1, Christopher S DesJardins, Edgar L Schuck
1DMPK-Andover, Biopharmaceutical Assessments, Eisai Inc., Andover, MA, USA. jesse_taur@eisai.com
Abstract:
Eribulin is a new anticancer agent currently in Phase III clinical trials for the treatment of metastatic breast cancer. In the current studies, we have investigated the effects of P-glycoprotein (P-gp) on the in vivo disposition of eribulin using CF-1 abcb1a-deficient mice, and the influence of eribulin on P-gp-mediated efflux of digoxin in Caco-2 cells. Eribulin was administered intravenously and orally in both CF-1 wild-type and CF-1 abcb1a-deficient mice. P-gp-mediated efflux of digoxin in Caco-2 cell monolayers was measured in the presence of eribulin. The plasma exposure to eribulin was higher in CF-1 abcb1a-deficient mice than that in CF-1 wild-type mice after intravenous (IV) and oral (PO) administrations. The oral bioavailability of eribulin was 62.3% in CF-1 abcb1a-deficient mice compared with 7.6% in wild-type mice. The brain penetration of eribulin in CF-1 abcb1a-deficient mice was 30-fold greater than that in wild-type mice. Eribulin decreased the efflux ratio of digoxin in a concentration-dependent manner, with the result of IC(50) greater than 10 µM. The [I]/IC(50) of eribulin was estimated to be <0.05. P-gp is likely to limit the oral absorption and brain penetration of eribulin in CF-1 wild-type mice. Eribulin inhibited the efflux of digoxin with IC(50) greater than 10 µM in Caco-2 cells. These results suggest that eribulin, given intravenously at the clinically relevant concentrations, may not alter P-gp-mediated disposition of concurrently administered drugs.
Insights
P-glycoprotein (P-gp) limits eribulin absorption and brain entry. Eribulin does not significantly affect P-gp drug transport at clinical doses, suggesting safe co-administration.
Area of Science:
- Pharmacology
- Oncology
- Drug Metabolism
Background:
- Eribulin is a novel anticancer agent in clinical trials for metastatic breast cancer.
- P-glycoprotein (P-gp) is a key efflux transporter influencing drug disposition.
- Understanding P-gp interactions is crucial for optimizing eribulin's therapeutic efficacy.
Purpose of the Study:
- To investigate the impact of P-gp on eribulin's in vivo disposition.
- To evaluate eribulin's influence on P-gp-mediated drug efflux.
Main Methods:
- Administered eribulin intravenously and orally to wild-type and P-gp-deficient mice.
- Assessed P-gp-mediated digoxin efflux in Caco-2 cells with eribulin exposure.
Main Results:
- Higher eribulin plasma exposure and oral bioavailability in P-gp-deficient mice.
- Significantly increased brain penetration of eribulin in P-gp-deficient mice.
- Eribulin showed weak inhibition of P-gp-mediated digoxin efflux (IC50 > 10 µM).
Conclusions:
- P-gp significantly restricts eribulin's oral absorption and brain penetration.
- Clinically relevant intravenous eribulin concentrations are unlikely to interfere with P-gp-mediated drug transport.
