(M1030-04-20) A Physiologically Based Pharmacokinetic Model of ¹⁸F-FMAU to Accompany Positron Emission Tomography in Humans

Purpose: Glioblastoma (GBM) is a highly aggressive cancer type that originates in brain astrocytes. Patients with GBM have a 5-year survival rate of 6.9%, which is complicated by tumor pseudo-progression. This phenomenon is characterized by cancer treatment causing increased contrast enhancement, mimicking tumor progression, even in the absence of true growth. Current tools to differentiate pseudo-progression from true tumor growth have proven inconclusive, leading to consequences such as premature treatment discontinuation and excessive chemotherapy. The molecular imaging tool 2’-Deoxy-2’-[¹⁸F]fluoro-5-methyl-1-β-D-arabinofuranosyl uracil (¹⁸F-FMAU) has shown promise in collecting Positron Emission Tomography (PET) Imaging data, which may better determine tumor progression. Despite its use in short-term imaging studies, there are no human pharmacokinetic (PK) studies that can help to plan, model, and evaluate the results of PET imaging.

Methods: Ten consented patient volunteers with primary or secondary recurrent glioblastoma were recruited to analyze the potential of ¹⁸F-FMAU in tumor progression using dynamic PET captured over one hour. Past this one-hour scan, it was not possible to obtain samples to clarify the clearance of ¹⁸F-FMAU; therefore, GastroPlus software was used to perform Physiologically Based Pharmacokinetic (PBPK) modeling of ¹⁸F-FMAU plasma concentrations across 24-hours. This approach allows simulation of human and animal pharmacokinetics, even in the absence of experimental data. A literature search yielded few relevant studies of ¹⁸F-FMAU administration in any species. One exception was for an ¹⁸F-FMAU stereoisomer called clevudine (L-FMAU), which was performed in rats. GastroPlus tools currently considers stereoisomers equivalent. Thus, a PBPK model of clevudine was developed using rat data and assumptions from the literature. This model was next converted to human physiology, unique to each patient. Individual PK profiles were generated, factoring in each patient’s age, weight, BMI, and ethnicity. The final predictions were then validated to pass through concentrations observed in plasma by PET imaging in the carotid artery.

Results: A strong correlation was found between all 10 patients simulated using GastroPlus plasma concentrations and the results of the one-hour PET imaging study. Scans of the carotid artery depicted high contrast enhancement that decayed to a plateau over about ten minutes, which was mirrored in GastroPlus predictions of a ‘distribution’ phase. For the remainder of the scan, an ‘elimination’ phase was observed where ¹⁸F-FMAU plasma levels remained constant. Only after the scan was complete did the PBPK model show decreasing levels indicative of clearance. Even in the absence of plasma-based ¹⁸F-FMAU PK in humans, this approach allows estimation of an average volume at steady state (V_ss) and clearance (CL) to be 85 L and 5.8 L/hour. Moreover, this modeling suggests ¹⁸F-FMAU is cleared through a ‘bi-exponential’ decay model. The average linear regression r² value of 0.793 between observed and GastroPlus predicted ¹⁸F-FMAU concentrations suggests the modeling mostly predicts the levels observed during the imaging studies.

Conclusion: These findings support the hypothesis that ¹⁸F-FMAU follows two-compartment pharmacokinetics, which may help interpret data from a one-hour PET scan. This approach predicts plasma concentrations of ¹⁸F-FMAU in any patient, with a variety of demographics. This study also establishes that the 1-hour imaging period normally reserved for imaging represents the distribution phase of ¹⁸F-FMAU; furthermore, the radiotracer’s PK elimination phase extends well beyond the imaging period. By helping to differentiate the distribution vs. elimination phases, this may affect the modeling and interpretation of dynamic PET data.

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Acknowledgements: I would like to express my deep gratitude to Dr. Andrew MacKay for his guidance, and for the Gavin Herbert Professorship, to Dr. Hossein Jadvar and the USC Ming Hsieh Institute for funding this study, to Dr. Michael Bolger for his time, dedication, and commitment to the project, and to Colleen Eng.


18F-FMAU Plasma Concentration (ug/mL) vs Time (min) Plot between Observed plasma concentration in the carotid and GastroPlus predicted plasma concentration in the carotid.


PBPK Model developed by GastroPlus for a patient receiving an 18F-FMAU IV Bolus dose of 1.13 ug in 0.72 mL.


Table showing the estimation of Pharmacokinetic fit parameters based on GastroPlus predicted
18F-FMAU plasma concentrations.