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

Record Type:	Electronic resources : Monograph/item
Title/Author:	Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor :/
Reminder of title:	Phase I Clinical Studies and Non-Clinical Mechanistic Assessment.
Author:	Moorthy, Ganesh P.
Description:	1 online resource (182 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 78-08, Section: B.
Contained By:	Dissertations Abstracts International78-08B.
Subject:	Pharmaceutical sciences. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10308519click for full text (PQDT)
ISBN:	9781369556391

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

Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor :Phase I Clinical Studies and Non-Clinical Mechanistic Assessment. - 1 online resource (182 pages)

Source: Dissertations Abstracts International, Volume: 78-08, Section: B.

Thesis (Ph.D.)--University of Cincinnati, 2015.

Includes bibliographical references

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 are in the levels where target inhibition was noted in vitro. However, the clinical outcome in the combination was not promising due to overlapping toxicities leading to early termination of the trial.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2023

Mode of access: World Wide Web

ISBN: 9781369556391Subjects--Topical Terms:

3173021
Pharmaceutical sciences.
Subjects--Index Terms:

BEZ235Index Terms--Genre/Form:

542853
Electronic books.

Clinical Pharmacokinetics of the Novel Combination of BEZ235, PI3K/mTOR Inhibitor, and Everolimus, mTOR Inhibitor : = Phase I Clinical Studies and Non-Clinical Mechanistic Assessment.
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520 $a 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 are in the levels where target inhibition was noted in vitro. However, the clinical outcome in the combination was not promising due to overlapping toxicities leading to early termination of the trial.
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