(248d) Pharmacokinetic Analysis of Motexafin Gadolinium in Mouse Tissues Using a Non-Invasive Optical Measurement System

In order to optimize the effect of the anti-cancer drug Motexafin Gadolinium (MGd), tissue-specific drug concentration information is required. Studies have considered MGd for use in combination with other chemotherapeutics and/or radiation therapy [3], where MGd facilitates the generation of reactive oxygen species which lead to apoptosis. A key consideration in radiation therapy is the elapsed time between MGd administration and tumor irradiation, since effective treatment is associated with a preferential MGd concentration gradient between tumor (high) and normal tissue (low). Current methods for measurement of in vivo drug concentration involve either destructive tissue analysis or magnetic resonance imaging, neither of which is currently applicable to a real-time clinical treatment regimen.

A novel method for in vivo drug quantitation is the optical pharmacokinetic system (OPS), a fiber-optic based spectroscopy system. The OPS measures elastic-scattering of light at an accesible tissue site, with changes in absorbance (or transmittance) due to changes in drug concentration calculated by Beer's Law [1]. Absorbtion changes are quantitated by the following metrics: (1) integrated area under the absorbtion profile between specified wavelengths (e.g., 650-810 nm); or (2) the height of peak absorbance at a specified wavelength (e.g., maximum absorbance). An algorithm was developed to compute these metrics from measured intensity spectra of a sample (medium with drug) and the respective baseline (medium with no drug). Standard curves are used to relate the metric magnitude to MGd concentration. The standard curves are constructed in vitro (in well-plates) and used to estimate MGd concentrations in vivo.

OPS measurements are compared with standard destructive tissue analysis using high preformance liquid chromotography (HPLC), the standard method of quantitating MGd concentrations in mouse tissues [2]. Mice bearing subcutanously implanted MDA-MB-231 xenografts were administered MGd, and OPS measurements were made at specific times after dosing on selected tissues pre- and post-exsanguination. Analysis of PK data shows that the OPS detects MGd in vivo with absorbtion bands separate from dominant endogenous materials (e.g., hemoglobin). Sensitivity of OPS-measured in vivo MGd concentrations to changes in standard curve experimental parameters (e.g., fluid volume depth) are investigated. Concentration vs. time profiles were generated (per tissue) via both OPS and HPLC, and were used to develop compartmental pharmacokinetic (PK) models.

A key issue is the discrepancy noted between MGd concentrations measured by OPS and HPLC for some tissues. OPS measures on in vivo tumors (measurement of the subcutaneous tumor by light penetration through the skin) do not show MGd accumulation or retention detected by HPLC. Moreover, OPS measures on in vivo tumors were similar to in vivo skin, with both measures following a similar qualitative time-course to plasma. These results question whether the light penetration depth is adequate enough to interrogate tumor tissue. We investigate the factors contributing to OPS measured MGd concentrations in tumors in vivo, including MGd contained in skin and plasma. Using the tissue-specific PK descriptions of MGd in skin and tumor tissue (with and without plasma) we estimate explicit tumor tissue MGd concentrations from in vivo OPS measures on tumors.

Bibliography

1

J. R. Mourant, T. M. Johnson, G. Los, and I. J. Bibio. Non-invasive measurement of chemotherapy drug concentrations of in vivo measurements. Phys Med Biol, 44:1397-1417, 1999.

2

R. A. Parise, D. R. Miles, and M. J. Egorin. Sensitive high-preformance liquid chromatographic assay for motexafin gadolinium and motexafin lutetium in human plasma. J Chromatogr B Biomed Sci Appl, 749(2):145-52, 2000.

3

D. I. Rosenthal, P. Nurenberg, C. R. Becerra, E. P. Frenkel, D. P. Carbone, B. L. Lum, R. Miller, J. Engel, S. Young, D. Miles, and M. F. Renschler. A phase I single-dose trial of gadolinium texaphyrin (Gd-Tex), a tumor selective radiation sensitizer detectable by magnetic resonance imaging. Clin Cancer Res, 5(4):739-45, Apr 1999.