Pharmacokinetic evaluation of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in patients by positron emission tomography.

PURPOSE: To evaluate tumor, normal tissue, and plasma pharmacokinetics of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA). The study aimed to determine the pharmacokinetics of carbon-11-labeled DACA ([11C]DACA) and evaluate the effect of pharmacologic doses of DACA on radiotracer kinetics. PATIENTS AND METHODS: [11C]DACA (at 1/1,000 phase I starting dose) was administered to 24 patients with advanced cancer (pre-phase I) or during a phase I trial of DACA in five patients. Positron emission tomography (PET) was performed to assess pharmacokinetics and tumor blood flow. Plasma samples were analyzed for metabolite profile of [11C]DACA. RESULTS: There was rapid systemic clearance of [11C]DACA over 60 minutes (1.57 and 1.46 L x min(-1) x m(-2) in pre-phase I and phase I studies, respectively) with the production of several radiolabeled plasma metabolites. Tumor, brain, myocardium, vertebra, spleen, liver, lung, and kidneys showed appreciable uptake of 11C radioactivity. The area under the time-versus-radioactivity curves (AUC) showed the highest variability in tumors. Of interest to potential toxicity, maximum radiotracer concentrations (Cmax) in brain and vertebra were low (0.67 and 0.54 m(2) x mL(-1), respectively) compared with other tissues. A moderate but significant correlation was observed for tumor blood flow with AUC (r = 0.76; P =.02) and standardized uptake value (SUV) at 55 minutes (r = 0.79; P =.01). A decrease in myocardial AUC ( P =.03) and splenic and myocardial SUV ( P =.01 and.004, respectively) was seen in phase I studies. Significantly higher AUC, SUV, and Cmax were observed in tumors in phase I studies. CONCLUSION: The distribution of [11C]DACA and its radiolabeled metabolites was observed in a variety of tumors and normal tissues. In the presence of unlabeled DACA, pharmacokinetics were altered in myocardium, spleen, and tumors. These data have implications for predicting activity and toxicity of DACA and support the use of PET early in drug development.

Tumor, normal tissue, and plasma pharmacokinetic studies of fluorouracil biomodulation with N-phosphonacetyl-L-aspartate, folinic acid, and interferon alfa.

PURPOSE: To evaluate the effect of N-phosphonacetyl-L-aspartate (PALA), folinic acid (FA), and interferon alfa (IFN-alpha) biomodulation on plasma fluorouracil (5FU) pharmacokinetics and tumor and liver radioactivity uptake and retention after [18F]-fluorouracil (5-[18F]-FU) administration. PATIENTS AND METHODS: Twenty-one paired pharmacokinetic studies were completed on patients with colorectal, gastric, and hepatocellular cancer, utilizing positron emission tomography (PET), which allowed the acquisition of tumor, normal tissue, and plasma pharmacokinetic data and tumor blood flow (TBF) measurements. The first PET study was completed when the patient was biomodulator-naive and was repeated on day 8 after the patient had been treated with either PALA, FA, or IFN-alpha in recognized schedules. RESULTS: TBF was an important determinant of tumor radioactivity uptake (r = .90; P < .001) and retention (r = .96; P < .001), for which radioactivity represents a composite signal of 5-[18F]-FU and [18F]-labeled metabolites and catabolites. After treatment with PALA, TBF decreased (four of four patients; P = .043), as did tumor radioactivity exposure (five of five patients; P = .0437), with no change in plasma 5FU clearance. With FA treatment, there were no differences observed in whole-body metabolism, plasma 5FU clearance, or tumor and liver pharmacokinetics. IFN-alpha had measurable effects on TBF and 5-[18F]-FU metabolism but had no apparent affect on liver blood flow. CONCLUSION: The administration of PALA and IFN-alpha produced measurable changes in plasma, tumor, and liver pharmacokinetics after 5-[18F]-FU administration. No changes were observed after FA administration. In vivo effects may negate the anticipated therapeutic advantage of 5FU biomodulation with some agents.

Sources of error in tissue and tumor measurements of 5-[18F]fluorouracil.

UNLABELLED: Central to the assessment of variability of pharmacokinetic parameters is knowledge of bias and variability of the measurement technique, preventing observed differences from being ascribed inappropriate significance. This article presents an evaluation of sources of error in the measurement of normal tissue and tumor pharmacokinetics using 18F-labeled 5-fluorouracil (FU) and PET. METHODS: A standard approach to data acquisition, processing and analysis was developed using a PET scanner, filtered backprojection reconstruction and region of interest analysis. Fourteen tracer 5-[18F]FU patient studies and a phantom study were completed, with 4 of the patient studies repeated 1 wk later. These data allowed evaluation of the overall reproducibility of the technique and the components of measurement variability due to tissue sampling. The effect of reconstruction technique and sampling region size on quantification was assessed using phantom data. RESULTS: All measured radioactivity versus time curves were tissue specific. Week-to-week variability in the area under this curve (representing combined physiological and measurement difference) was -3% to +15% for liver and -9% to -16% for spleen and kidney. Metastasis variability was greatest at -20%. Visual and computer realignment of the second paired study produced similar results. Interobserver effects were small compared to differences between studies. CONCLUSION: These results confirm the feasibility of using PET as a pharmacokinetic tool for 5-[18F]FU studies. Although overall experimental error (i.e., random variation in data acquisition, processing and analysis) was low, constraints in data interpretation emerged.

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.

Studies on the metabolism of the novel antitumor agent [N-methyl-11C]N-[2-(dimethylamino)ethyl]acridine-4-carboxamide in rats and humans prior to phase I clinical trials.

This study reports on the biodistribution and metabolism of the 11C-labeled novel antitumor agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) (also known as NSC 601316) in rats (plasma and tissues) and humans (plasma). Information on plasma metabolites was uniquely obtained in humans prior to Phase I clinical trial following i.v. injection of [11C]DACA at tracer dose. DACA was labeled in the N-methyl position using no-carrier-added [11C]iodomethane. Rapid high-performance liquid chromatography methods were developed for metabolite analysis of [11C]DACA. The metabolism of [11C]DACA was investigated in patients by plasma sampling. The biodistribution and metabolism of [11C]DACA was investigated in rats by plasma sampling, sacrifice experiments with tissue analyses, and imaging using positron emission tomography scanning. Analysis of human plasma demonstrated rapid and extensive metabolism of [11C]DACA. The levels of [11C]DACA changed from 77 +/- 8% (SD) at 5 min to 25 +/- 5% at 45 min postinjection. Seven radioactive metabolites were observed in human plasma, and one was identified as [11C]DACA-N-oxide. Rapid clearance of 11C radioactivity from rat blood, plasma, and major organs was observed. The half-life of 11C radioactivity clearance in rat blood between 15 and 90 min was calculated to be 3.2 h; the levels of [11C]DACA in rat plasma decreased from 69 +/- 3% (SD) at 2 min to 29 +/- 1.5% at 25 min. The number of radioactive metabolites in rat plasma was the same as in human plasma except that the proportions differed. Again, one metabolite was identified as the [11C]DACA-N-oxide. Analysis of rat tissues showed rapid and extensive metabolism in tissues, particularly liver and kidney; however, [11C]DACA (i.e., the parent compound) was the major radioactive component in the lung, heart, and brain over 40 min. Positron emission tomography scanning using [11C]DACA in the rat showed little retention of 11C radioactivity in major organs with rapid excretion via gut and kidney. The rat data were consistent with animal (mouse and rat) preclinical data obtained with preexisting techniques with longer-lived isotopes. Labeling of potential anticancer drugs with positron-emitting radionuclides and performing in vivo preclinical evaluation at tracer doses in animals and humans prior to Phase I clinical trials provides unique information that could speed up the assessment of the drug and could potentially assist drug development programs. In this example, there was no unexpected interspecies difference in metabolism of DACA that would have alerted us to make a change in the planned Phase I study.

Carbon-11 labelling of the antitumour agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and determination of plasma metabolites in man.

The potential anti-cancer agent N-[2-(dimethylamino)ethyl] acridine-4-carboxamide, DACA has been labelled with carbon-11. N-[2-11C-methyl]DACA was produced in 73% radiochemical yield from [11C]iodomethane in 40 min from EOB. The average radiochemical yield was 3.2 GBq with specific radioactivity of 41.5 GBq mumol-1 at EOS, corresponding to 24 micrograms of stable DACA. The position of labelling was confirmed by co-labelling with [11/13C]iodomethane. PET studies in patients have been performed prior to Phase I trial of DACA and during Phase I trial of DACA. Analysis of serial plasma samples showed that the metabolism of N-[2-11C-methyl]DACA is rapid and extensive in patient plasma.

Spontaneous regression of metastatic renal cell carcinoma following palliative irradiation of the primary tumour.

A 58 years old man presented with a bulky renal primary tumour, paratracheal lymphadenopathy and multiple pulmonary metastases. Spontaneous regression of intrathoracic metastases occurred after low dose palliative irradiation of the primary tumour. Serum levels of Interleukin-2 receptor were elevated during the period of tumour regression but concentrations of other cytokines were normal. Progressive abdominal disease eventually caused death. Autopsy confirmed the presence of renal cell carcinoma with intrathoracic metastases.

New techniques in the pharmacokinetic analysis of cancer drugs. IV. Positron emission tomography.

Positron emission tomography is a powerful tool for the absolute quantification of injected positron emitting radiotracer concentration within tissues in vivo. Very detailed spatiotemporal data can be obtained without biopsy sampling. Most chemotherapeutic agents can be labelled with a positron emitter, and human tissue and tumour pharmacokinetics can be obtained non-invasively. Its main limitations are the inability to discriminate metabolites, the short half-life of the isotopes used and the specialized equipment required. Despite this, PET has the potential to make a major contribution in the study of the pharmacokinetics of anti-cancer drugs.

Cervical cancer in young women in Northern Ireland: 1970-1985.

From 1970 to 1985, 109 patients under 35 years of age developed invasive cervical cancer in Northern Ireland (NI). Information on incidence, staging, histology, primary treatment and survival was collected retrospectively and results compared with a community-based sample of all age groups from the West Midlands of England. Incidence increased in NI over the study period. Young patients presented with early stage disease, typical histology and had a stage for stage outcome similar to the all age groups. NI results do not demonstrate more aggressive disease in the under 35s.