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PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF LENALIDOMIDE AND POMALIDOMIDE

Jiang, Yao
http://rave.ohiolink.edu/etdc/view?acc_num=osu1429830196

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Pharmacy.
Lenalidomide and pomalidomide are immunomodulatory drugs and analogues of their predecessor, thalidomide. Large variability in clinical outcomes, potential drug-drug interaction (DDI) and a number of severe toxicities are the major problems being observed in lenalidomide clinical trials. Our group first identified a clinical DDI of lenalidomide with temsirolimus caused by P-glycoprotein (Pgp). To further characterize Pgp’s role in lenalidomide disposition and elimination, we studied its pharmacokinetics (PK) in FVB wild type (WT) and mdr1a/b knockout (KO) mice with dysfunctional Pgp. Although we observed 25% increase in plasma area under curve (AUC) in KO compared to WT mice, brain AUC of lenalidomide was only 12% higher in the KO vs WT group within one hour after drug administration, which was contrary to our expectation that brain penetration would drastically increase in the KO mice as commonly observed with other Pgp substrates, like digoxin. Similar trend results were found for pomalidomide in the same mice study. These results indicated other transporters, in addition to Pgp, likely inhibited brain penetration of lenalidomide or pomalidomide. Given the mouse brain data, we have focused on another efflux transporter, the breast cancer resistance protein (BCRP), which is also highly expressed in the blood-brain barrier. Our preliminary in vitro transwell permeability data showed lenalidomide or pomalidomide was effluxed at a higher rate in MDCK overexpressing human BCRP (MDCKII/BCRP) cells compared to wild-type cells (MCDKII/WT). Further evaluations were performed in the cell uptake studies of lenalidomide and pomalidomide, and the results indicated there was less lenalidomide or pomalidoimde accumulated inside of MDCKII/BCRP cells than MDCKII/WT cells. The results from both transwell permeability and cell uptake assay suggested that lenalidomide and pomalidomide are substrates of BCRP. Lenalidomide was demonstrated to up-regulate C/EBPa-P30 isoform, resulting in increased miR-181a expression, which was linked to the improved outcomes in patients with acute myeloid leukemia (AML). Cereblon, a direct target of lenalidmide, is a component of the E3 ligase complex which targets and ubiquitinates select proteins that are subsequently degraded by the proteasome. We hypothesized C/EBPa-P30 is a target of cereblon associated E3 ligase, and lenalidomide binding to cereblon decreases ubiquitination and therefore stabilizes C/EBPa-P30. Understanding how these transporters affect intercellular lenalidomide levels and their relationship with miR-181a expression may help to explain inter-patient variability in clinical outcomes. We further measured gene expression of efflux transporters (ABCB1 and ABCG2), lenalidomide direct and downstream targets (CRBN and CEBPA) as well as miR-181a in AML patients’ bone marrow and peripheral blood mononuclear cell samples. While no strong correlations were observed between lenalidomide plasma PK, baseline expressions of genes of interest and gene expression changes post treatment, we did observe an anticipated increased expression of ABCB1 in refractory compared to treatment-naive patients as well as significant up-regulation of CRBN post lenalidomide therapy. Further strategies, such as evaluating PK and pharmacodynamic correlation in simpler systems, evaluating protein expression of lenalidomide targets, exploring the role of other drug transporters and gathering polymorphism information on genes of interest, could be employed in future studies to further evaluate the hypotheses.
A Mitchell Phelps (Advisor)
Robert Lee (Committee Member)
Flavia Pichiorri (Committee Member)
158 p.
Pharmaceuticals; Pharmacy Sciences
pharmacokinetic, pharmacodynamic, lenalidomide and pomalidomide

Recommended Citations

Citations

  • Jiang, Y. (2015). PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF LENALIDOMIDE AND POMALIDOMIDE [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429830196

    APA Style (7th edition)

  • Jiang, Yao. PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF LENALIDOMIDE AND POMALIDOMIDE. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1429830196.

    MLA Style (8th edition)

  • Jiang, Yao. "PHARMACOKINETIC AND PHARMACODYNAMIC STUDIES OF LENALIDOMIDE AND POMALIDOMIDE." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429830196

    Chicago Manual of Style (17th edition)

osu1429830196
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This open access ETD is published by The Ohio State University and OhioLINK.