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Published on: September 17, 2019
Non-linear IV pharmacokinetics of the ATR inhibitor berzosertib (M6620) in mice
Joshua J Deppas1,2, Brian F Kiesel1,2, Jianxia Guo1
1Cancer Therapeutics Program, UPMC Hillman Cancer Center, University of Pittsburgh, Room G27e 5117 Centre Ave, Pittsburgh, PA, 15213, USA.
Background:
The Ataxia Telangiectasia and Rad3-related (ATR) protein complex is an apical initiator of DNA damage response pathways. Several ATR inhibitors (ATRi) are in clinical development including berzosertib (formerly M6620, VX-970). Although clinical studies have examined plasma pharmacokinetics (PK) in humans, little is known regarding dose/exposure relationships and tissue distribution. To understand these concepts, we extensively characterized the PK of berzosertib in mouse plasma and tissues.
Methods:
A highly sensitive LC-MS/MS method was utilized to quantitate berzosertib in plasma and tissues. Dose proportionality was assessed in female BALB/c mice following single IV doses (2, 6, 20 or 60 mg/kg). A more extensive PK study was conducted in tumor-bearing mice following a single IV dose of 20 mg/kg to evaluate distribution to tissues. PK parameters were calculated by non-compartmental analysis (NCA). A compartmental model was developed to describe the PK behavior of berzosertib. Plasma protein binding was determined in vitro.
Results:
Increased doses of berzosertib were associated with less than proportional increases in early plasma concentrations and greater than proportional increase in tissue exposure, attributable to saturation of plasma protein binding. Berzosertib extensively distributed into bone marrow, tumor, thymus, and lymph nodes, however; brain and spinal cord exposure was less than plasma.
Conclusion:
The nonlinear PK of berzosertib displayed here can be attributed to saturation of plasma protein binding and occurred at concentrations close to those observed in clinical trials. Our results will help to understand preclinical pharmacodynamic and toxicity data and to inform optimal dosing and deployment of berzosertib.
Insights
Berzosertib, an ATR inhibitor, shows nonlinear pharmacokinetics due to saturated plasma protein binding. This impacts tissue distribution and informs optimal dosing for cancer therapy.
Area of Science:
- Pharmacology and Toxicology
- Cancer Biology
- Drug Development
Background:
- The Ataxia Telangiectasia and Rad3-related (ATR) protein complex is crucial for DNA damage response.
- Berzosertib is an ATR inhibitor (ATRi) currently in clinical development.
- Understanding berzosertib's pharmacokinetics (PK), including dose-exposure and tissue distribution, is vital for its clinical application.
Purpose of the Study:
- To characterize the PK of berzosertib in mouse plasma and tissues.
- To investigate dose proportionality and tissue distribution of berzosertib.
- To elucidate the PK behavior of berzosertib for improved preclinical and clinical understanding.
Main Methods:
- Quantification of berzosertib using a sensitive LC-MS/MS method in plasma and tissues.
- Assessment of dose proportionality in mice following intravenous (IV) administration.
- Evaluation of tissue distribution in tumor-bearing mice after a single IV dose.
- Non-compartmental analysis (NCA) and compartmental modeling for PK parameter calculation.
- In vitro determination of plasma protein binding.
Main Results:
- Berzosertib exhibited nonlinear PK, with less than proportional increases in early plasma concentrations and greater than proportional increases in tissue exposure at higher doses.
- Saturation of plasma protein binding was identified as the cause of nonlinear PK.
- Extensive distribution of berzosertib was observed in bone marrow, tumor, thymus, and lymph nodes.
- Lower exposure of berzosertib was found in the brain and spinal cord compared to plasma.
Conclusions:
- The nonlinear PK of berzosertib is attributed to saturable plasma protein binding, occurring at clinically relevant concentrations.
- These findings are essential for interpreting preclinical pharmacodynamic and toxicity data.
- The study provides critical insights to inform optimal dosing strategies and therapeutic use of berzosertib.
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