Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas

Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas

Bibliographic Details
Main Author: Arora, Priyanka
Language:English
Published: University of Cincinnati / OhioLINK 2019
Subjects:
Pharmaceuticals
Letrozole
blood brain barrier
PBPK modeling
Drug drug interactions
Temozolomide
Clinical CNS pharmacokinetics
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=ucin1552398989110981
id ndltd-OhioLink-oai-etd.ohiolink.edu-ucin1552398989110981
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Pharmaceuticals
Letrozole
blood brain barrier
PBPK modeling
Drug drug interactions
Temozolomide
Clinical CNS pharmacokinetics
spellingShingle Pharmaceuticals
Letrozole
blood brain barrier
PBPK modeling
Drug drug interactions
Temozolomide
Clinical CNS pharmacokinetics
Arora, Priyanka
Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas
author Arora, Priyanka
author_facet Arora, Priyanka
author_sort Arora, Priyanka
title Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas
title_short Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas
title_full Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas
title_fullStr Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas
title_full_unstemmed Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas
title_sort pharmacokinetic- pharmacodynamic investigations of letrozole, a potential novel agent for the treatment of high-grade gliomas
publisher University of Cincinnati / OhioLINK
publishDate 2019
url http://rave.ohiolink.edu/etdc/view?acc_num=ucin1552398989110981
work_keys_str_mv AT arorapriyanka pharmacokineticpharmacodynamicinvestigationsofletrozoleapotentialnovelagentforthetreatmentofhighgradegliomas
_version_ 1719455064951619584
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-ucin15523989891109812021-08-03T07:09:37Z Pharmacokinetic- Pharmacodynamic Investigations of Letrozole, a Potential Novel Agent for the Treatment of High-Grade Gliomas Arora, Priyanka Pharmaceuticals Letrozole blood brain barrier PBPK modeling Drug drug interactions Temozolomide Clinical CNS pharmacokinetics High-grade gliomas (HGGs) are among the most infiltrative primary malignant brain tumors with a median survival ranging from only 15 months to five years. Current standard of care includes surgical resection, followed by adjuvant radiation and chemotherapy with temozolomide. Unfortunately, the disease recurs in almost all patients with fewer therapeutic options available thereafter. Therefore, novel HGG-specific targets and, more importantly, ligands for such targets are urgently needed.Based on the discovery that estrogen synthase `aromatase’ is overexpressed in HGGs, aromatase inhibitor, letrozole, is being investigated in pre-clinical models as a novel agent against this malignancy. Employing microdialysis, in previous studies we have shown that letrozole easily crosses the blood-brain and the blood-tumor barriers. To facilitate clinical translation of these findings, here, we first conducted a comprehensive investigation of the systemic and brain pharmacokinetics of letrozole in rodents. Female and male jugular-vein cannulated (JVC) Sprague-Dawley rats were employed for this study. Both single/multiple doses of letrozole (4 mg/kg; IP) were administered and intracerebral microdialysis was performed for brain extracellular fluid (ECF) sampling. Simultaneous serial blood collection facilitated plasma pharmacokinetic determination. Essentially, marked gender-specific differences were observed in letrozole pharmacokinetics. Letrozole clearance was much slower in female rats resulting in markedly higher plasma and brain concentrations. At steady state, plasma AUC0-24 was 103.0 and 24.8 µg*h/ml and brain ECF AUC0-12 was 24.0 and 4.8 µg*h/ml in female and male rats, respectively. Given that temozolomide is the current standard of care and that letrozole will need to be clinically investigated in combination with this agent, we then discerned any potential pharmacokinetic interactions between letrozole and temozolomide in JVC rats. Microdialysis was employed to analyze unbound brain levels of temozolomide simultaneously with venous blood sampling. As such, no pharmacokinetic changes were evident when temozolomide and letrozole were administered concurrently. For instance, peak plasma and brain ECF temozolomide levels when given alone were 14.7 ± 0.7 and 4.6 ± 0.4 µg/ml, respectively, and 12.6 ± 1.4 and 3.4 ± 0.5 µg/ml, respectively, when given with letrozole.Next, we initiated a prospectively designed innovative phase 0/1 clinical trial for letrozole quantification in tumoral samples excised from recurrent HGG patients. As clinically feasible, these patients received up to four doses of letrozole (2.5, 5 or 10 mg daily) followed by pre-surgical blood collection. A tumor tissue sample was obtained intra-operatively for pharmacokinetic assessments/histopathology. Additionally, pharmacokinetic data analyses accompanied with Simcyp-based PBPK modeling of the pre-clinical and clinical data enabled quantitative estimates. Overall, our study provided first clinical evidence of brain tumor penetration of letrozole in HGG patients. Tumor tissue concentrations ranged from 0.017–0.095 µg/g in the three dose cohorts. Consistent with the published data, we observed a plasma Cmax of 0.06 µg/ml, AUC0-24 of 1.1 µg*h/ml and T1/2 of about 55 h following a 7-day lead-in period (2.5 mg/day). Furthermore, the predicted concentrations of letrozole from the PBPK models were in close agreement with the observed data. These results will guide the optimization of dosing regimen for subsequent clinical trials of letrozole for HGG treatment. 2019-06-07 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1552398989110981 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1552398989110981 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.

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