Paula Wells

Pharmacokinetic assessment of novel anti-cancer drugs using spectral analysis and positron emission tomography: A feasibility study

Purpose: The aim of this study was to investigate the feasibility of evaluating the pharmacokinetics of radiolabeled anti-cancer drugs using spectral analysis, a non-compartmental tracer kinetic modeling technique, and positron emission tomography (PET). Methods: Dynamic PET studies were performed on patients receiving tracer doses of 5-fluorouracil (5-[18F]-FU) and two developmental drugs – [11C]-temozolomide and [11C]-acridine carboxamide. Spectral analysis was then used to (a) determine individual and group average pharmacokinetics, (b) predict tumour handling in response to different drug administration regimens, and (c) produce functional parametric images describing regional pharmacokinetics. Results: Spectral analysis could distinguish tumour kinetics from normal tissue kinetics in an individual [11C]-temozolomide study and demonstrated a markedly greater volume of distribution (VD) in glioma than in normal brain, although there was no appreciable difference in mean residence time. Analysis of pooled acridine carboxamide data (n=22) revealed a relatively large VD (and prolonged retention) in the liver and spleen and a markedly lower VD (and initial uptake) in the brain. Continuous infusion of 5-[18F]-FU was predicted to achieve a concentration in colorectal metastases in liver approximately 10 times that achieved in plasma at 10 h after commencement of the infusion. Conclusions: We conclude that spectral analysis provides important pharmacokinetic information about radiolabeled anti-cancer drugs with relatively few model assumptions.

Measurement of renal tumour and normal tissue perfusion using positron emission tomography in a phase II clinical trial of razoxane.

Measurement of tumour and normal tissue perfusion in vivo in cancer patients will aid the clinical development of antiangiogenic and antivascular agents. We investigated the potential antiangiogenic effects of the drug razoxane by measuring the changes in parameters estimated from H215O and C15O positron emission tomography (PET) to indicate alterations in vascular physiology. The study comprised 12 patients with primary or metastatic renal tumours >3 cm in diameter enrolled in a Phase II clinical trial of oral razoxane. Perfusion, fractional volume of distribution of water (VD) and blood volume (BV) were measured in tumour and normal tissue before and 4–8 weeks after treatment with 125 mg twice-daily razoxane. Renal tumour perfusion was variable but lower than normal tissue: mean 0.87 ml min−1 ml−1 (range 0.33–1.67) compared to renal parenchyma: mean 1.65 ml min−1 ml−1 (range 1.16–2.88). In eight patients, where parallel measurements were made during the same scan session, renal tumour perfusion was significantly lower than in normal kidney (P=0.0027). There was no statistically significant relationship between pretreatment perfusion and tumour size (r=0.32, n=13). In six patients scanned before and after razoxane administration, there was no statistically significant change in tumour perfusion: mean perfusion pretreatment was 0.81 ml min−1 ml−1 (range 0.46–1.26) and perfusion post-treatment was 0.72 ml min−1 ml−1 (range 0.51–1.15, P=0.15). Tumour VD and BV did not change significantly following treatment: mean pretreatment VD=0.66 (range 0.50–0.87), post-treatment VD=0.71 (range 0.63–0.82, P=0.22); pretreatment BV=0.18 ml ml−1 (range 0.10–0.25), post-treatment BV=0.167 ml ml−1 (range 0.091–0.24, P=0.55). Tumour perfusion, VD and BV did not change significantly with tumour progression. This study has shown that H215O and C15O PET provide useful in vivo physiological measurements, that even highly angiogenic renal cancers have poor perfusion compared to surrounding normal tissue, and that PET can provide valuable information on the in vivo biology of angiogenesis in man and can assess the effects of antiangiogenic therapy.

The Use of Radiolabelled Anticancer Drugs in Phase I/II Clinical Trials and the Assessment of Therapeutic Efficacy of New Agents Using PET

PET Oncology is emerging as a new investigational area for cancer research. We present a strategy based on in vivo tracer kinetics of radiolabelled compounds which may be developed to investigate, for the first time, the in vivo molecular interactions, pathways and mechanisms of action of current novel anti-cancer strategies. We outline how PET studies can parallel Phase I & II clinical trials, and could provide new information on tumour and normal tissue pharmacokinetics and functional response. This approach promises to radically assist translation of scientific developments into clinical advances.

Tumor Proliferation: 2-[11C]-Thymidine Positron Emission Tomography

Publisher Summary [11C]-labeled-thymidine is the first radiotracer used for noninvasive imaging of tumor proliferation and one of the most appropriate pharmacodynamic tools to assess treatment response and assist early validation of novel anticancer agents, because its uptake is directly related to DNA synthesis and correlates with proliferation in human tumors. As a vital component for DNA synthesis, thymidine is essential for cell proliferation and is therefore also a key molecule for measuring tumor proliferation and an important target for cancer therapy. This methodology has been applied to the development of positron-emitting tracers that can provide a measure of cell proliferation in vivo using PET. While the identification of new therapeutic targets is important, the development of more accurate and relevant methods of measuring response to treatment is also vital, especially for the early assessment of new agents. Cancer treatment-induced changes in DNA cell proliferation are more pronounced than changes in glucose metabolism, further supporting the need for a direct marker to image and measure cell proliferation. In contrast, radiolabeled thymidine is incorporated into DNA, and its uptake is a direct measure of cell proliferation rate. Uptake of 2-[11C]-thymidine is related to DNA synthesis and, in comparison with 18F-FDG, has been shown to be a more sensitive discriminator of early clinical response in small cell lung cancer and sarcoma. But the short half-life of 11C and its rapid metabolism in vivo have inhibited its widespread clinical use.

The Potential of Tracer Kinetic Studies in Drug Development Programs: A New Investigational Area for Cancer Research

This paper covers a unique program created in the United Kingdom between the MRC Cyclotron Unit and the CRC Phase I and II drug development committee to investigate the potential of tracer kinetic studies to investigate in vivo tumor and normal tissue kinetics, molecular interactions, pathways, and mechanism of action of novel anti-cancer agents. Positron emission tomography technology offers great potential in streamlining anti-cancer drug development programs, however, significant investment in new methodology and multidisciplinary teams is necessary.