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Pharmacokinetic Evaluation of N-[2-(Dimethylamino)Ethyl]Acridine-4-Carboxamide in Patients by Positron Emission Tomography

From the Cancer Research Campaign Positron Emission Tomography Oncology Group, Methodology Group, and Chemistry and Engineering Group, Division of Cancer Medicine, Imperial College School of Medicine, Medical Research Council Cyclotron Unit, Hammersmith Hospital; School of Pharmacy, University of London, London; and Department of Oncology, Addenbrookes Hospital, Cambridge, United Kingdom.

Address reprint requests to Pat M. Price, MD, Cancer Research Campaign Positron Emission Tomography Oncology Group, Division of Cancer Medicine, Imperial College School of Medicine, Medical Research Council Cyclotron Unit, Hammersmith Hospital, Du Cane Rd, London W12 0NN, United Kingdom; email: anne.mason{at}christie-tr.nwest.nhs.uk © 2001 by American Society of Clinical Oncology. 0732-183X/01/05-2

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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·min^-1·m^-2in 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 m²·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.

	INTRODUCTION

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N>-[2-(DIMETHYLAMINO)ethyl]acridine-4-carboxamide (DACA Fig 1) is a DNA-intercalating acridine derivative that stimulates DNA breakage via formation of cleavable complexes between DNA and topoisomerase I and II.^1,2 Its high activity against experimental solid tumors is thought to stem from this dual interaction with both topoisomerase I and II, as well as its ability to overcome P-glycoprotein and atypical (topoisomerase II–mediated) multidrug resistance.^2-5 DACA is a lipophilic compound with octanol:water partition coefficient of 5.⁶ This property, together with suppression of ionization of the acridine nitrogen at physiologic pH, were considered attractive for this class of compounds with regard to better distributive properties and ability to cross the blood-brain barrier to reach brain tumors. Dose-limiting neurotoxicity was observed in mice after intravenous (IV) administration of DACA,⁷ which is thought to be due to the high uptake of DACA and/or DACA metabolites into normal brain.^6,8

View larger version (8K): [in this window] [in a new window]   Fig 1. Chemical structure of DACA.

A number of important translational research questions were posed, including whether (1) the metabolic profile of the drug was altered in humans as compared with preclinical models, (2) the drug distributed well to human tumors (predictive of activity), and (3) the degree of uptake into normal tissues was high (predictive of tissue toxicity), eg, brain (predictive of neurotoxicity). To address some of these issues, we studied the tumor and normal tissue pharmacokinetics of carbon-11 radiolabeled DACA ([¹¹C]DACA) at tracer concentrations before conventional phase I trials. This constitutes the first such study aimed at providing intratumoral and normal tissue distribution data to aid drug development. In addition, to evaluate whether administration of pharmacologic doses of DACA altered tracer kinetics, we repeated [¹¹C]DACA tracer studies in patients undergoing phase I clinical trials.⁹

	PATIENTS AND METHODS

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Patient Selection
Two separate studies were performed: (1) tracer studies in patients who had never received pharmacologic doses of DACA (pre–phase I), and (2) tracer studies in patients who were being treated with DACA at one of the phase I dose levels (phase I). Patients (23 male and six female patients; age range, 27 to 87 years; median, 60 years) with histologically confirmed and incurable advanced solid tumors were recruited for this study ( Table 1). All patients had adequate hepatic function and hematopoietic reserve and a World Health Organization performance status of 0, 1, or 2. As opposed to standard phase I trials, there was no therapeutic intent with the pre–phase I clinical studies. Patients were made aware of this before consent was obtained from them. Standard phase I study subjects (n = 5) were recruited from those taking part in a dose-escalating phase I clinical trial (3-hour infusion of DACA x 3 days) at the Addenbrookes Hospital, Cambridge.⁹ All patients gave written informed consent to take part in the study. The ethics committees of Hammersmith Hospital, London, and Addenbrookes Hospital, Cambridge, granted approval for this study. Approval was also obtained from the Administration of Radioactive Substances Advisory Committee, United Kingdom, for the administration of ¹¹C-labelled DACA and ¹⁵O-labelled carbon dioxide.

Synthesis of [¹¹C]DACA
[¹¹C]DACA was synthesized from [¹¹C]iodomethane and N-desmethyl-DACA as previously reported.¹² Briefly, [¹¹C]iodomethane was prepared from [¹¹C]CO₂ according to the method of Luthra et al¹³ and distilled into N-desmethyl-DACA in acetone. The mixture was heated and residue extracted into chloroform. The [¹¹C]DACA produced was purified by preparative high-performance liquid chromatography and sterilized by millipore filtration. Typically, 3.2 GBq of [¹¹C]DACA with a specific activity of 41.5 GBq.µmol^-1 (corresponding to 25 µg of stable DACA or carrier) was produced by this method within 40 minutes from end of ¹¹C production.¹² All radiopharmaceuticals were quality-checked to ensure sterility and apyrogenicity and also checked for radiochemical and radionuclidic impurities. The mean radiochemical purity of [¹¹C]DACA used in this study was 96% (range, 89.7% to 97.7%).

PET Scanning Procedure
Before each scan, an arterial cannula was inserted into the radial artery under local anaesthesia for blood sampling. A venous line was also inserted into the antecubital fossa for administration of the radiotracers. PET scanning was performed on an ECAT 931-08/12 (2D) scanner (CTI/Siemens, Knoxville, TN). This scanner allows simultaneous data acquisition to form 15 transaxial planes spaced 6.75 mm apart (axial field of view = 10.8 cm). To enable correction for attenuation of photons in the body, a transmission scan was performed using ⁶⁸Ge/Ga before tracer injection. This was then followed by a blood flow scan. For this, patients inhaled 4 MBq.ml^-1 of [¹⁵O]CO₂ delivered via a light face mask at a constant flow rate of 500 mL.min^-1 for 3.5 minutes. Dynamic scanning of the radioactivity in arterial blood and tissues in the camera’s field of view including spleen, vertebra, lung, myocardium, tumor, or brain was performed for 10 minutes. The short half-life of ¹⁵O (2.04 minutes) permitted [¹¹C]DACA scans to immediately follow blood flow scans. To study the pharmacokinetics of [¹¹C]DACA, patients were administered 462 MBq (range, 175 to 667 MBq) of [¹¹C]DACA as single controlled IV injection over 30 seconds. This tracer dose corresponds to a total patient dose of 7.83 µg.m^-2 (range, 2.2 to 19.29 µg.m^-2). Dynamic PET scanning of radioactivity in arterial blood and tissues within the camera’s field of view, including liver, spleen, vertebra, lung, myocardium, tumor, or brain, was performed for at least 60 minutes. Biodistribution data were acquired as sinograms in discrete time frames ranging from 30 to 600 seconds.

Chromatographic Analysis of Plasma Samples
To obtain information on plasma metabolites, discrete arterial blood samples (5 mL) were collected into heparinized syringes before and at 2, 5, 10, 20, 40 and 60 minutes after the injection of [¹¹C]DACA. Blood was kept at 4°C and immediately centrifuged (2000 x g for 2 minutes) to obtain plasma. The radioactivity in 1 mL of plasma was measured in a well counter that had been cross-calibrated with the PET camera. Plasma samples were clarified by solid-phase extraction and analyzed by HPLC with radiochemical detection as previously described.^8,12 From the total radioactivity per milliliter of plasma and the fraction of parent [¹¹C]DACA obtained by chromatography, the radioactive concentration of [¹¹C]DACA in kilobecquerels per milliliter (kBq·mL^-1) was determined.

Analysis of PET Data
Sinograms were corrected for attenuation, detector efficiency (scatter, randoms, dead-time), and detector nonuniformity, and reconstructed into tomographic images using the standard filtered back-projection algorithm.¹⁴ PET image data were then calibrated to kBq.mL^-1. Regions of interest (ROIs) on tumor, liver, kidney, spleen, lung, myocardium, and vertebral body were manually defined on the PET images with the aid of x-ray or computed tomography films using the image-analysis software, Analyze (Mayo Clinic, Rochester, MN).¹⁵ The radioactivity per unit volume for each region of interest was derived for each time frame to obtain time-versus-radioactivity curves (TACs). From these data, blood flow per unit volume of tissue was calculated using well-established methodology.^16,17 Hepatic blood flow was not calculated, as application of the above methodology for organs with dual blood supply has not been validated in humans. For [¹¹C]DACA images, TACs were corrected for the physical decay of radioactivity and normalized to injected dose per body-surface area. The areas under the TAC (AUC) for each tissue were calculated from 0 to 60 minutes as previously described to give a measure of overall tracer exposure.¹⁷ In addition, to evaluate the retention of radiotracer (parent and metabolites) in tissues after a suitable washout period, the standardized uptake value (SUV; defined as tissue concentration at a particular time normalized to injected dose per body-surface area) was calculated at 55 minutes. Maximal tissue [¹¹C]DACA concentrations (Cmax) and time to reach Cmax (Tmax) were also calculated to give an indication of rate and level of radiotracer distribution in tissues.

Plasma Pharmacokinetics
The AUC for [¹¹C]DACA (kBq·mL^-1·sec) between 0 to 60 minutes (AUC_{0-60 minutes}) was calculated using the trapezoidal method. Systemic clearance between 0 to 60 minutes (Cl_{0-60 minutes}) was estimated from the injected dose of [¹¹C]DACA (kBq·mL^-1) and the AUC_{0-60 minutes} (dose/AUC).

Statistical Methods
Summary statistics and statistical comparisons were generated using STATA version 5.0 (Stata Corporation, College Station, TX). Tissue data (AUC, SUV, Cmax, and Tmax) were compared using the Mann-Whitney U test. Relationships between blood flow and tissue pharmacokinetic parameters were explored using Pearson’s correlation analysis. P values of .05 were considered statistically significant.

	RESULTS

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All patients (Table 1) tolerated the PET scanning protocol well. Three scans that lasted for less than 60 minutes because of technical difficulties were excluded from the analyses. PET scans to assess tissue blood blow were performed in 19 patients (14 pre–phase I; five phase I). Furthermore, because of the limited axial length (10.8 cm) over which PET data were collected for each individual study, not all tissues could be sampled for each patient.

Plasma Pharmacokinetics
We have previously reported the metabolite profile of [¹¹C]DACA in human plasma in a limited number of the patients.^8,12 [¹¹C]DACA underwent rapid and extensive metabolism, with a greater proportion of unmetabolized [¹¹C]DACA being present in phase I compared with pre–phase I samples.^8,12 Seven radioactive metabolites were observed in both pre–phase I and phase I studies.⁸ Here we have calculated the CL_{0-60 minutes} of [¹¹C]DACA for both the pre–phase I (n = 9) and phase I (n = 5) studies where 0- to 60-minutes plasma samples were available. The mean (SD) CL_{0-60 minutes} of [¹¹C]DACA was similar (P > .05) in pre–phase I (1.57 [0.65] L.min^-1.m^-2) and phase I studies (1.46 [0.03] L.min^-1.m^-2). Plasma pharmacokinetic parameters were not estimated to infinity as more than 25% extrapolation was obtained in some instances.

Tumor and Normal Tissue Biodistribution
Inspection of cumulative PET images, derived from the summing of all dynamic images (0 to 60 minutes), showed that [¹¹C]DACA was taken up by a number of tumor types ( Fig 2). Several normal tissues, including brain, heart, liver, and kidneys, also showed radiotracer uptake (Fig 2). Examination of the TACs for each tissue showed that radiotracer kinetic profiles were characteristic for each of the normal tissue, with some tissues demonstrating a rapid time to peak and slower washout, whereas other tissues demonstrated a slower time to peak ( Fig 3). For instance, Table 2 illustrates that maximal tissue concentrations were reached rapidly in lung, kidney, brain, spleen, and myocardium. In contrast, this was late in the liver in both pre–phase I and phase I studies. Tumor TACs were highly variable in contrast to normal tissue TACs. Time to reach maximal concentrations showed high variability in vertebral body and tumors. Comparison of normal tissue Cmax between pre–phase I and phase I studies demonstrated nonsignificantly lower values in the phase I group. There was, however, a significantly higher Cmax (P < .05) in tumors of the phase I group compared with the pre–phase I group ( Fig 4).

View larger version (96K): [in this window] [in a new window]   Fig 2. Typical transabdominal computed tomography scan (top left) and corresponding PET-[11C]DACA image (top right) demonstrating radiotracer uptake in kidneys, spleen, and renal tumor. Uptake of radiotracer is also seen in heart, myocardium, and mesothelioma (bottom left) and into brain and glioma (bottom right).

View larger version (24K): [in this window] [in a new window]   Fig 3. [11C]DACA TACs for brain (a), vertebral body (b), renal cortex (c), myocardium (d), liver (e), lung (f), spleen (g), and tumor (h) in the pre–phase I group. TACs were corrected for decay and normalized for the injected activity per body-surface area.

View larger version (43K): [in this window] [in a new window]   Fig 4. Tumor pharmacokinetic parameters, Cmax (a), SUV at 55 minutes (b), AUC 0-60 minutes (c), and blood flow (d), in pre–phase I and phase I studies. Abbreviations: As, astrocytoma; Lu, lung cancer; MM, malignant melanoma; Ls, leiomyosarcoma; NH, non-Hodgkin’s lymphoma; Re, renal tumor; Ma, carcinoma of the maxillary antrum; Du, duodenal tumor.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
We have applied PET methodology to study the pharmacokinetics of an investigational anticancer agent DACA, before conventional phase I clinical trials and during phase I trials. In the pre–phase I PET studies, [¹¹C]DACA could be administered at 1/1,000 the phase I starting dose (9 mg.m^-2). This study, therefore, suggests that low doses of labelled anticancer agents, which are unlikely to be toxic, can be used early to obtain important tracer pharmacokinetic information to aid drug development.

We have previously reported the metabolite profile of [¹¹C]DACA in human plasma and showed that [¹¹C]DACA was rapidly metabolized.^8,12 The high rate of metabolism and the short scanning time may explain the high clearance of [¹¹C]DACA obtained here for both pre–phase I and phase I studies. The limitation of short scanning time was the result of the short physical half-life of ¹¹C isotope (20.4 minutes) leading to decreased detection sensitivity at late time points. Another limitation of PET is its lack of in vivo chemical specificity (ie, inability to distinguish radiolabeled parent from its radiolabeled metabolites). This together with the observation of high metabolic clearance implied that tissue distribution data could not be attributed to DACA alone. We have therefore interpreted the in vivo kinetics of the radiotracer (radiolabeled parent and metabolites) from complementary knowledge obtained from rodent kill studies previously reported by our group.⁸

An important question for transfer of knowledge from preclinical to clinical trials was whether DACA was taken up into tumors and normal tissue. We have demonstrated here that [¹¹C]DACA and its metabolites distributed well into all the tumor types studied. Together with complementary rodent data, which suggest that [¹¹C]DACA is the highest contributor of tumor radioactivity at 5 minutes and decreased rapidly compared with metabolites (unpublished data), we can infer that [¹¹C]DACA is taken up into tumor. The presence of a moderate relationship between tumor blood flow and tissue pharmacokinetic parameters (AUC and SUV) underlines the importance of drug delivery in uptake and retention of the radiotracer in tumors. Overall, AUC and SUV for [¹¹C]DACA and metabolites were higher in tumors compared with brain. The pharmacokinetics of [¹¹C]DACA and metabolites in most normal tissues showed a rapid peak and slower washout. The obvious exception was liver, which showed a slower time to peak. The characteristic profile of liver pharmacokinetics, together with the longer Tmax and high SUV at 55 minutes, is indicative of high hepatic turnover and is consistent with its role as the primary tissue responsible for the metabolism of DACA.¹⁸

In keeping with the high partition coefficient of DACA and the fact that it is not a substrate for P-glycoprotein, brain uptake was observed. In rodents, lethal neurotoxicity was seen with high IV infusions of DACA but was absent with intraperitoneal administration.¹⁹ This was attributed to high DACA Cmax observed with IV administration and not to drug exposure (AUC).¹⁹ The uptake of radiotracer in human brain was lower than most of the other tissues studied. This may explain the low incidence of neurologic side effects in phase I studies of DACA.^9,10 Another common dose-limiting toxicity with anticancer drugs commonly associated with Cmax is myelosuppression. This study has demonstrated that the Cmax observed in vertebral body was less than for other tissues analyzed, suggesting that myelotoxicity is unlikely to be dose-limiting. On the other hand, we observed an unusually high uptake of radiotracer in the myocardium. Even though it is the absolute amount of drug that would be related to toxicity, this observation would alert us to possible cardiovascular side effects. One would need to establish a possible relationship between tissue concentration and toxicity. Dose-limiting pain in the infusion arm and one instance of myocardial ischemia observed in the phase I trial could be a manifestation of the cardiovascular toxicity of DACA, although the mechanism for these effects is unclear.^9,10

Having recognized the implicit assumption for comparing tracer tissue kinetics with kinetics of pharmacologic doses (ie, existence of linear kinetics over a large range) we also studied the tissue kinetics of [¹¹C]DACA during phase I trials of the compound. Comparison of pre–phase I and phase I tissue pharmacokinetic parameters demonstrated an overall decrease in Cmax, AUC, and SUV for all normal tissues analyzed. Of these, the decrease was statistically significant for spleen (SUV) and myocardium (AUC and SUV) only. It is possible that such decreases would have reached significant levels in other tissues if the study was larger or higher phase I doses were also studied. This nonlinearity in splenic and myocardial pharmacokinetics with increasing dose could be due to saturable process in drug uptake, tissue binding, or metabolism. The mechanism responsible for this observation is unknown. In contrast to that seen in normal tissues, tumor pharmacokinetic parameters (Cmax, AUC, SUV) increased significantly; this could be due in part to the decrease in exposure to normal tissues. This finding has to be interpreted with caution, as only three tumors, all with the same histology (mesothelioma), were sampled in the phase I group in comparison with the pre–phase I group (11 tumors; Fig 4).

In summary, we have for the first time studied the tumor and normal tissue pharmacokinetics of an anticancer agent before conventional phase I trials. The key findings to emerge from these studies included (1) the observation that several tumor types showed radiotracer uptake, (2) the lower than expected brain uptake compared with other tissues studied, (3) low vertebral body uptake, and (4) high myocardial uptake. In addition, the plasma metabolite profile and the characteristic liver profile suggested that DACA was extensively metabolized in humans. Important information could be gained even for [¹¹C]DACA, which is highly metabolized. For drugs that are less rapidly metabolized, it may be possible to gain further information including prediction of drug activity for guiding drug development. Toward this goal, a program to evaluate metabolically stable analogs of DACA has been initiated at our center.

	ACKNOWLEDGMENTS

 
Supported by educational grants from Cancer Research Campaign (grant no. SP2 193/0101) and Medical Research Council, United Kingdom. A.S. and R.J.H. were partly supported by educational grants

from Xenova, Slough, Berkshire, and Schering-Plough, Welwyn Garden City, Hertfordshire, United Kingdom, respectively.

We thank Prof N.R. Newell (Newcastle, United Kingdom) for initial help in setting up this study and Prof W.A. Denny (Auckland, New Zealand) who supplied the original DACA. This study could not have been accomplished without the expert assistance of blood lab, radiochemistry, radiography and QC staffs at the Medical Research Council Cyclotron Unit, Hammersmith Hospital, London, United Kingdom.

	REFERENCES

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Submitted July 11, 2000; accepted October 27, 2000.

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