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University of Cincinnati

1. Moorthy, Ganesh. Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment.

Degree: PhD, Pharmacy: Pharmaceutical Sciences/Biopharmaceutics, 2015, University of Cincinnati

Dysregulation of PI3K/Akt/mTOR pathway has been implicated in tumorigenesis and malignancy in numerous solid tumors. Everolimus is a potent allosteric inhibitor of mTORC1, and has been approved for the treatment of number of cancers including renal and breast cancer. BEZ235, a dual PI3K/ mTOR inhibitor, in combination with everolimus has shown promising in vitro and preclinical evidence for synergistic activity against solid tumors. This led to an investigator initiated Phase 1b clinical trial to determine the safety, pharmacokinetics and pharmacodynamics of the combination of BEZ235 with everolimus in subjects with advanced solid tumors. The combination of BEZ235 and everolimus has the potential for significant pharmacokinetic drug-drug interaction (DDI), given the prominent role of cytochrome P450 3A4 (CYP3A4) in the metabolism of everolimus. Thus, the integral aspect of the dissertation was to evaluate the pharmacokinetics of the two agents, investigate DDI and to conduct correlative studies to assess the mechanism(s) that may underlie this DDI. We describe here, 1) first report of clinical pharmacokinetics of BEZ235 at doses ranging from 200 to 800 mg/day with everolimus at 2.5 mg/day, and investigation of DDI, 2) correlative studies to delineate the mechanism of this interaction, 3) mechanistic physiologically based pharmacokinetic modeling (PBPK) to understand the impact of physiological and drug specific parameters on DDI.Phase I dose escalation consisted of 28-day study treatment cycles with BEZ235 doses of 200, 400 and 800 mg/day with everolimus at 2.5 mg/day. Nineteen subjects were enrolled in the study and blood samples were collected on days 1 and 28. We delineated the pharmacokinetics of BEZ23 on day 1 and day 28, which was linear and dose proportional in the dose range tested. Everolimus pharmacokinetics was evaluated on day 1 and day 28, there was a significant increase in everolimus blood Cmax and AUC0-24 from day 1 to day 28. Everolimus clearance (CL/F) decreased from 24.76±2.91 L/h on day 1 to 13.41±2.31 L/hr on day 28. Population based and non-compartmental approaches showed that there was a 1.7 fold increase in everolimus when dosed with BEZ235. In correlative in vitro studies, BEZ235 was observed to be a time-dependent inhibitor (TDI) of CYP3A4. In primary human hepatocytes, BEZ235 had a potential to induce CYP3A4 based on mRNA levels however, there was no corresponding increase in CYP3A4 activity. A PBPK model was developed using mechanistic static and dynamic model to study the interaction. Prediction based on both the models were close to the observed interaction. PBPK simulations indicated a 5-fold reduction in gut CYP3A4 activity in presence of BEZ235, leading to a significant decrease in everolimus gut metabolism. Thus, an increase in everolimus Fg, fraction escaping gut metabolism, when co-administered with BEZ235 might play a role in the observed interaction. Overall, Phase I study provide insights into the pharmacokinetics and suggest that the systemic exposure of BEZ235 and everolimus… Advisors/Committee Members: Desai, Pankaj (Committee Chair).

Subjects/Keywords: Pharmaceuticals; pharmacokinetics; Phase I; PBPK; DDI; BEZ235; Everolimus

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APA (6th Edition):

Moorthy, G. (2015). Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment. (Doctoral Dissertation). University of Cincinnati. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439296033

Chicago Manual of Style (16th Edition):

Moorthy, Ganesh. “Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment.” 2015. Doctoral Dissertation, University of Cincinnati. Accessed April 10, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439296033.

MLA Handbook (7th Edition):

Moorthy, Ganesh. “Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment.” 2015. Web. 10 Apr 2021.

Vancouver:

Moorthy G. Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment. [Internet] [Doctoral dissertation]. University of Cincinnati; 2015. [cited 2021 Apr 10]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439296033.

Council of Science Editors:

Moorthy G. Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor: Phase I Clinical Studies and Non-clinical Mechanistic Assessment. [Doctoral Dissertation]. University of Cincinnati; 2015. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1439296033


Swedish University of Agricultural Sciences

2. Sun, Ren. Studies of enzymes in mitochondrial DNA precursor synthesis.

Degree: 2013, Swedish University of Agricultural Sciences

As important enzymes in mitochondrial nucleotide salvage pathway, thymidine kinase 2 (TK2) and deoxyguanosine kinase (dGK) are expressed constitutively in almost all cells. These two enzymes catalyze the initial rate-limiting phosphorylation of pyrimidine and purine deoxynucleosides, respectively, providing DNA precursors for mitochondrial DNA (mtDNA) replication. Inherited genetic defects in TK2 have been associated with infantile myopathic form of mtDNA depletion syndrome (MDS). In study I, two mutations, R225W and a novel T230A, in TK2 are identified as a new genetic cause of adult-onset autosomal recessive progressive external ophthalmoplegia (arPEO) and the kinetic and structural effects of the two mutations on enzyme function have been characterized. Nucleoside analogs are widely used in anti-viral and anti-cancer chemotherapy, but they can cause severe side-effect such as mtDNA depletion. In study II, the potential mechanism underlying pyrimidine nucleoside analogs-associated mitochondrial toxicities was investigated, and showed that thymidine analogs had opposite effects on dThd and dCyd phosphorylation and thus can inhibit dThd salvage, leading to imbalanced dTTP and dCTP pools. It was found that the mechanism is most likely due to that TK2 normally exists in an inactive form with bound dTTP. The redox regulation of TK2 and dGK was studied in study III and IV. The activity of both enzymes was sensitive to the cellular redox status. Under oxidative stress, both TK2 and dGK can be reversibly S-glutathionylated by GSSG. The modification of the conserved Cys189 in TK2 was responsible for a partial inactivation and selective degradation of TK2 in mitochondria, most likely via the AAA⁺ Lon protease. The oxidative effect of nucleoside analogs was also evaluated. Treatment with 3’-azido- 2’,3’-dideoxythymidine (AZT) and 2’,3’-dideoxyinosine (ddI) led to degradation of mitochondrial TK2 and dGK, whereas uridine and guanosine supplementations to AZT respective ddI treatments prevented both proteins from degradation.

Subjects/Keywords: enzymes; thymidine; kinases; mitochondria; dna; Thymidine kinase 2; Deoxyguanosine kinase; Mitochondrial DNA; Progressive external ophthalmoplegia; Nucleoside analogs; AZT (3’-azido-2’,3’- dideoxythymidine); ddI (2’,3’-dideoxyinosine); S-glutathionylation

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APA (6th Edition):

Sun, R. (2013). Studies of enzymes in mitochondrial DNA precursor synthesis. (Doctoral Dissertation). Swedish University of Agricultural Sciences. Retrieved from http://pub.epsilon.slu.se/10780/

Chicago Manual of Style (16th Edition):

Sun, Ren. “Studies of enzymes in mitochondrial DNA precursor synthesis.” 2013. Doctoral Dissertation, Swedish University of Agricultural Sciences. Accessed April 10, 2021. http://pub.epsilon.slu.se/10780/.

MLA Handbook (7th Edition):

Sun, Ren. “Studies of enzymes in mitochondrial DNA precursor synthesis.” 2013. Web. 10 Apr 2021.

Vancouver:

Sun R. Studies of enzymes in mitochondrial DNA precursor synthesis. [Internet] [Doctoral dissertation]. Swedish University of Agricultural Sciences; 2013. [cited 2021 Apr 10]. Available from: http://pub.epsilon.slu.se/10780/.

Council of Science Editors:

Sun R. Studies of enzymes in mitochondrial DNA precursor synthesis. [Doctoral Dissertation]. Swedish University of Agricultural Sciences; 2013. Available from: http://pub.epsilon.slu.se/10780/


University of Otago

3. Lee, Au-Chen. Dipolar Bose-Einstein Condensate with a Vortex .

Degree: University of Otago

We theoretically consider the properties of a dipolar Bose-Einstein condensate with a vortex. Our theory includes the influence of the leading order quantum fluctuation corrections which allows the condensate to stabilize into a droplet state in the regime of dominant dipole interactions. We develop numerical techniques to accurately and efficiently calculate the stationary vortex states and the quasi-particle excitations. These methods are carefully benchmarked where possible. We make a brief study of self-bound vortex droplets, considering their basic properties, and presenting a phase diagram for where they exist. We also compare our calculations to results which appeared from another group during our research. We show that their results suffer from serious numerical issues and are unreliable. We focus on studying the properties of a vortex line in an elongated dipolar Bose-Einstein condensate confined by a prolate trap. Increasing the strength of the dipole-dipole interactions relative to the short ranged contact interactions we find that the system crosses over to a self-bound vortex droplet stabilized from collapse by quantum fluctuations. We calculate the quasiparticle excitation spectrum of the vortex state, which is important in characterizing the vortex response, and assessing its stability. When the DDIs are sufficiently strong we find that the vortex is dynamically unstable to quadrupolar modes. Advisors/Committee Members: Blakie, Blair (advisor).

Subjects/Keywords: Bose-einstein condensates; BEC; nonlinear; condensate; Gross-Pitaevskii; nonlinear Schrödinger equation; vortices; Collective excitations; vortex self-bound droplets; dipolar BEC; dipolar quantum; quantum fluctuations; Bogoliubov-de Gennes; instability; quadrupolar modes; dynamical stability; dipole interaction; density approximation; dipolar Bose-Einstein condensate; quasi-particle excitations; vortex; Hankel Transformation; Bessel function; cosine transformation; Cylindrical; BdG; Bogoliubov-de Gennes Equation; numerical calculations; DDI; dipole-dipole interactions; phonon dispersion; dynamical instability; eigenvalue problem; eigenvector; imaginary time evolution; laplacian operator; GPE; Gross–Pitaevskii equation; zero-norm; Kohn modes; Bessel grid; DDIs; numerical techniques; dipolar; dipolar BECs; LHY term; local density treatment; vortex stationary states; Kelvin wave (helical) excitations; stabilized from collapse; quasi-particle; leading order quantum fluctuation correction; lanthanides dysprosium; dysprosium; Dy; s-wave interaction; many-body physics

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APA (6th Edition):

Lee, A. (n.d.). Dipolar Bose-Einstein Condensate with a Vortex . (Masters Thesis). University of Otago. Retrieved from http://hdl.handle.net/10523/9254

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Chicago Manual of Style (16th Edition):

Lee, Au-Chen. “Dipolar Bose-Einstein Condensate with a Vortex .” Masters Thesis, University of Otago. Accessed April 10, 2021. http://hdl.handle.net/10523/9254.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

MLA Handbook (7th Edition):

Lee, Au-Chen. “Dipolar Bose-Einstein Condensate with a Vortex .” Web. 10 Apr 2021.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Vancouver:

Lee A. Dipolar Bose-Einstein Condensate with a Vortex . [Internet] [Masters thesis]. University of Otago; [cited 2021 Apr 10]. Available from: http://hdl.handle.net/10523/9254.

Note: this citation may be lacking information needed for this citation format:
No year of publication.

Council of Science Editors:

Lee A. Dipolar Bose-Einstein Condensate with a Vortex . [Masters Thesis]. University of Otago; Available from: http://hdl.handle.net/10523/9254

Note: this citation may be lacking information needed for this citation format:
No year of publication.

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