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Pre-clinical and Clinical Pharmacokinetic/Pharmacodynamic Evaluations of Cyclin-dependent Kinase Inhibitors as Chemotherapeutic Agents

Zhao, Yuan
http://rave.ohiolink.edu/etdc/view?acc_num=osu1429839484

Abstract Details

2015, Doctor of Philosophy, Ohio State University, Pharmacy.
Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the western world. CLL is incurable with current therapies, and new strategies are needed. Cyclin-dependent kinases (CDKs) play fundamental roles in cell cycle control and gene transcription and have become promising drug targets. A selective and potent CDK inhibitor (CDKI), dinaciclib, has been discovered and has shown significant clinical efficacy in relapsed and refractory CLL patients. However, the dose-limiting toxicity (DLT) of tumor lysis syndrome (TLS) has developed in CLL patients in a phase 1 study. This potentially fatal toxicity was demonstrated to correlate with the glucuronide metabolites of flavopiridol, the first generation CDKI. Glucuronidation is also a major metabolic pathway of dinaciclib in humans. In our clinical study, our objective was to investigate the correlations between dinaciclib/dinaciclib-glucuronide plasma levels and the incidence of TLS or its biochemical markers. In addition, dinaciclib is a P-glycoprotein (P-gp) substrate based on in vitro study. We aimed to evaluate the in vivo effect of P-gp on dinaciclib disposition and potential drug-drug interaction (DDI) between dinaciclib and lenalidomide via P-gp for the potential clinical interest in combing these two drugs to treat CLL patients. A sensitive liquid chromatography-tandem mass spectrometry method has been developed and validated for quantification of dinaciclib and dinaciclib-glucuronide in human plasma samples. This assay was modified for mouse plasma and applied to study the role of P-gp in the disposition of dinaciclib using p-gp knockout (KO) and wild type (WT) mice. Our results demonstrated that dinaciclib AUC decreased in P-gp KO mice relative to P-gp WT mice, and there was an apparent DDI between dinaciclib and lenalidomide. Further study revealed this interaction may have been due primarily to protein binding displacement. Population pharmacokinetic/pharmacodynamic analysis of the patient dinaciclib/ dinaciclib-glucuronide data was performed using nonlinear mixed effects modeling. A combined four-compartment model adequately described the PK properties of both parent drug and its glucuronide metabolite. Correlations were identified between dinaciclib-glucuronide maximal concentration or area under the concentration-time curve and the maximal changes in phosphate, which is a biochemical marker of TLS. However, given that only one patient experienced clinical TLS, no relationship was observed between drug/metabolite levels and TLS incidence. TG02, an oral CDKI, is under development for hematological malignancies. Drug accumulations were observed with patients who developed grade 3 fatigue, which was DLT. In addition, great population PK variability displayed within these disease cohorts. A modeling and simulation approach was used to characterize TG02 PK and design a new dose regimen. Twice weekly dosing for four weeks was proposed given the lack of observed drug accumulation based on simulated data, and this dose regimen was applied in an ongoing phase 1 clinical trial. Thus far grade 1/2 fatigue has been mainly observed, and there was only one case of grade 3 TLS which persisted less than 24 hours. The dose regimen has increased drug tolerability and enabled drug escalation up to 300 mg thus far. Collectively, these studies contribute to the development of CDKIs for the treatment of CLL.
Mitch Phleps (Advisor)
157 p.
Pharmaceuticals

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Citations

  • Zhao, Y. (2015). Pre-clinical and Clinical Pharmacokinetic/Pharmacodynamic Evaluations of Cyclin-dependent Kinase Inhibitors as Chemotherapeutic Agents [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429839484

    APA Style (7th edition)

  • Zhao, Yuan. Pre-clinical and Clinical Pharmacokinetic/Pharmacodynamic Evaluations of Cyclin-dependent Kinase Inhibitors as Chemotherapeutic Agents. 2015. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1429839484.

    MLA Style (8th edition)

  • Zhao, Yuan. "Pre-clinical and Clinical Pharmacokinetic/Pharmacodynamic Evaluations of Cyclin-dependent Kinase Inhibitors as Chemotherapeutic Agents." Doctoral dissertation, Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429839484

    Chicago Manual of Style (17th edition)

osu1429839484
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© 2015, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.