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Published on: December 3, 2020
Pharmacokinetic modeling of motexafin gadolinium disposition in mouse tissues using optical pharmacokinetic system
Stephen C Kanick1, Julie L Eiseman, Robert S Parker
1Department of Chemical Engineering, University of Pittsburgh School of Engineering, Pittsburgh, PA 15261, USA.
Abstract:
Clinical use of radio- or photo-sensitizing agents in anti-cancer treatments may be limited by patient specific variability in the pharmacokinetics (PK) of the sensitizing compound. Previously, our group reported motexafin gadolinium (MGd) concentrations in mouse tissues measured noninvasively by the optical pharmacokinetic system (OPS) in vivo, nondestructively by OPS in situ, and destructively by HPLC ex vivo. This study utilized those reported data to develop compartmental PK models of MGd disposition in plasma, tumor, and skin. The model predicted both the rapid initial distribution and slow elimination phases of MGd in plasma, the fast transport of MGd out of the skin (with no MGd detectable after 120 min), and MGd retention at long times in the tumor (with detectable MGd at 24 h). The same compartmental structure was used to model MGd concentrations vs. time as measured by OPS in situ and HPLC ex vivo. In vivo tumor MGd concentrations measured using OPS were estimated by a linear combination of the model predicted PK profiles in plasma and tumor tissue, which suggests that tissue-specific PK knowledge may be needed in order to interpret volume-averaged optical measurements in vivo. The PK modeling techniques presented here are extensible to other optically active compounds and, potentially, to the development of patient-specific treatment schedules.
Insights
Pharmacokinetic modeling of motexafin gadolinium (MGd) reveals distinct tissue distribution patterns. This research aids in understanding drug disposition for improved anti-cancer therapy and patient-specific treatment schedules.
Area of Science:
- Pharmacology
- Biomedical Engineering
- Oncology
Background:
- Patient-specific variability in drug pharmacokinetics (PK) can limit the clinical efficacy of anti-cancer sensitizing agents.
- Accurate measurement of drug concentrations in tissues is crucial for understanding drug disposition and optimizing treatment.
Purpose of the Study:
- To develop compartmental pharmacokinetic (PK) models for motexafin gadolinium (MGd) disposition in plasma, tumor, and skin using previously reported data.
- To evaluate the ability of PK models to predict MGd concentrations measured by optical and HPLC methods.
- To explore the utility of tissue-specific PK knowledge for interpreting in vivo optical measurements.
Main Methods:
- Utilized previously reported ex vivo HPLC and in vivo/in situ OPS data for motexafin gadolinium (MGd).
- Developed compartmental pharmacokinetic (PK) models to describe MGd disposition in plasma, tumor, and skin.
- Modeled MGd concentrations over time using a consistent compartmental structure for both optical and HPLC measurements.
Main Results:
- The PK model accurately predicted rapid plasma distribution and slow elimination phases for MGd.
- MGd was rapidly cleared from the skin within 120 minutes, but showed prolonged retention in tumors up to 24 hours.
- In vivo tumor MGd concentrations measured by OPS were estimated using a linear combination of plasma and tumor PK profiles.
Conclusions:
- Compartmental PK modeling effectively describes MGd disposition in different tissues.
- Tissue-specific PK knowledge is essential for accurate interpretation of in vivo optical measurements.
- The presented PK modeling techniques are adaptable for other optically active compounds and patient-specific treatment optimization.
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