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The Benefits and Risks of Using Positron Emission Tomography in Clinical Drug Development Figure 1: Mean Concentrations Across Subjects Following Injection of [18F]5-fluorouracil


0.03 0.025


0.005 0.01 0.015 0.02


0 0


500 1,000 1,500 2,000 2,500 3,000 3,500 Time (seconds)


5FU


0.03 0.025


0.005 0.01 0.015 0.02


0 0


500 1,000 1,500 2,000 2,500 3,000 3,500 Time (seconds)


5FU Metabolites Metabolites


0.03 0.025


0.005 0.01 0.015 0.02


0 0 Liver


500 1,000 1,500 2,000 2,500 3,000 3,500 Time (seconds) Metastasis


Kidney Heart


0.03 0.025


0.005 0.01 0.015 0.02


0 0 Liver


500 1,000 1,500 2,000 2,500 3,000 3,500 Time (seconds) Metastasis


Kidney Heart


Spleen


Spleen


Left column: Concentrations of parent [18F]5-fluorouracil and the radiolabelled metabolite [18F]α-fluoro-β-alanine in arterial blood plasma. Right column: Radiolabelled concentrations within selected organs. Top row: Administration of tracer doses of [18F]5-fluorouracil. Bottom row: [18F]5-fluorouracil co-administration with 375–400mg/m-2 of unlabelled 5-fluorouracil (5FU).


Such studies can also be useful outside the brain. They can be used to gain useful information on routes of metabolism and information that can assist in the optimisation of dosing schedules.


For example, studies have been conducted labelling the anticancer drug 5-fluorouracil with fluorine-18, both at tracer doses and in conjunction with therapeutic doses, and with and without the presence of proposed treatment modulators.5


For a number of organs, including the heart and spleen, the observed radioactivity versus time concentrations are consistent with both [18F]5-fluorouracil and the radiolabelled metabolite passing through these organs with little retention. Consequently, the hepatic metabolism of 5-fluorouracil with renal excretion of α-fluoro-β-alanine is clearly demonstrated.


Further studies were


conducted using the dihydropyrimidine dehydrogenase inactivator eniluracil, which inhibits the hepatic metabolism of 5-fluorouracil.6 Data from some of this work are presented in Figure 1.


For tracer doses of [18F]5-fluorouracil, rapid clearance occurs so that by 10 minutes post-injection all of the radioactivity in arterial blood plasma is due to the radiolabelled metabolite [18F]α-fluoro-β-alanine. Accumulation of radioactivity is highest in the liver, but only while measurable levels of [18F]5-fluorouracil are present in the blood plasma; thereafter, radioactivity clears from the liver. In the kidney accumulation occurs later, when only [18F]α-fluoro-β-alanine is present in the plasma, demonstrating the renal clearance of this metabolite. When [18F]5-fluorouracil is administered with 375–400mg/m-2 of 5-fluorouracil, plasma clearance is reduced, with corresponding delays in the accumulation of activity in the liver and the kidney.


DRUG DEVELOPMENT


Limitations There are a number of limitations of PET biodistribution studies. Novel radiochemistry is required, with all the implications of radiotracer development, dosimetry and toxicological assessment described above. It may also be necessary to manufacture or source GMP-grade precursors for the radiochemistry. The dose and route of administration of the PET radiotracer may differ from the intended dose and route for the drug, with the potential that the resulting concentrations differ significantly.


However, as discussed it is possible to investigate the interaction of unlabelled drug given via the desired route and at the desired dose with an intravenous trace dose of the radiolabelled drug. Although in principle other routes of administration could be considered for the PET radiotracer, the short half-life compared with the rate of absorption means that such an approach is of limited use for many drugs.


39


Percentage of labelled 5FU injected/ml


Percentage of labelled 5FU injected/ml


Percentage of labelled 5FU injected/ml


Percentage of labelled 5FU injected/ml


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