0360-3016/92 $5.00 + .oO Copyright (0 1992 Per&mm Press Ltd.

Inl. J. Radiarron Oncology Bml. Phys.. Vol. 24. pp. 959-963 Printed in the U.S.A. All rights reserved.

??Biology Original Contribution

PHARMACOKINETICS OF INTRATUMORAL A NEW HYPOXIC RADIOSENSITIZER KEISUKE

SASAI, M.D.,’

NOBUO BABA, M.D.,2

YUTA

SHIBAMOTO,

MASAJI TAKAHASHI, AND MITSUYUKI

M.D.,’

M.D.,3

RK-28,

TADAO MANABE,

MASAKAZU

M.D.,2

SAKAGUCHI,

PH.D.~

ABE, M.D.’

‘Department of Radiology and *First Department of Surgery, Faculty of Medicine, Kyoto University; ‘Department of Oncology, Chest Disease Research Inst. Kyoto University, Kyoto 606; and 4Pola Pharmaceutical R&D Laboratory, Yokohama 244, Japan RK-28 is one of the new hypoxic cell radiosensitizers being developed in Japan and has been tested clinically. To reduce its toxicity and increase its sensitizing activity, intratumoral injection of RK-28 was performed during intraoperative radiation therapy for pancreatic cancer. This report presents the results of pharmacokinetic studies performed in 10 of the 17 patients who were administrated intravenous or intratumoral RK-28 during intraoperative radiation therapy. No adverse effects were noted following intravenous or intratumoral injection of the drug. Pharmacokinetic studies demonstrated several metabolites of RK-28 in both serum and tumor tissues. After intratumoral injection, the tumor drug concentration ranged from 123 pg/g to 9,292 wg/g just after intraoperative radiation therapy (30-50 min after injection of the compound), while the serum concentration ranged from 4.1 to 9.8 pg/ml. The tumor drug concentration was 23.3 pg/g at 45 min after intravenous injection of RK-28. Thus, intratumoral injectionof RK-28 was superior to intravenousadministrationin this pharmacokinetic study. The combination of intraoperative radiation therapy and intratumoral injection of RK-28 appears to be a feasible treatment method.

RK-28, Hypoxic cell radiosensitizer,Intratumoral injection,Pharmacokinetics, Intraoperativeradiation therapy. INTRODUCTION

In this study, the pharmacokinetics of intratumoral RK28 during intraoperative radiation therapy (IORT) for pancreatic cancer were investigated in detail. This study was performed as a part of the Phase I and Phase II clinical trials of this sensitizer in Japan organized by Professor K. Sakamoto (the full results of the trials will be presented elsewhere).

Misonidazole was the first hypoxic cell radiosensitizer that was extensively investigated clinically. However, tolerance dose of this drug was limited because of the development of irreversible peripheral neuropathy, so that its maximum potential effect as a radiosensitizer could not be achieved (10,27). Many efforts have been made to reduce the neurotoxicity of 2-nitroimidazole sensitizers (1, 2, 6, 13, 23, 28) and several new compounds have been developed and tested clinically (6-8, 15, 20) RK-28 (Fig. 1) is one such new compound developed in Japan and it has already been tested clinically (25). This hypoxic cell sensitizer is a 2-nitroimidazole nucleoside analogue that was developed to reduce neurotoxicity. Another approach to reduce the toxicity and increase the sensitizing activity of 2-nitroimidazoles is to develop new methods of administration. Recently, several investigators have proposed intratumoral injection of these compounds and have reported that this provides a good radiosensitizing activity of several 2-nitroimidazole derivatives in both animal and clinical studies (3, 4, 5, 9, 12, 21).

Reprint requests to: Keisauke Radiology, Faculty of Medicine, Kyoto 606-O I, Japan.

METHODS

AND MATERIALS

Patients

Between April 1989 and February 199 1, 16 patients with pancreatic cancer and one patient with gallbladder cancer treated with IORT at Kyoto University Hospital were entered into this study. All patients gave signed informed consent. Table 1 shows the clinical profiles of the patients. They were aged between 4 1 and 8 1 years, with a mean of 62.7 and a median of 60 years. There were five males and 12 females. Although seven patients had no distant metastases, the other 10 had various distant metastases (liver metastases, peritoneal dissemination, or distant lymph node metastases).

Sasai, M.D., Department of Kyoto University, Sakyo-ku,

Accepted

959

for publication

30 June

1992.

960

I.J. Radiation Oncology 0 Biology 0 Physics

Volume 24, Number 5, I992

Table 1. The 17 patients

Case

Age sex

Diagnosis

1 2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 17

61 F 77 F 57 F 75 F 71 F 48 M 51 M 60 M 60 F 73 F 41 F 53 F 51 M 77 F 57 M 73 F 81 F

Pancreatic Ca. Gallbladder Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca. Pancreatic Ca.

treated with IORT plus RK-28

Size of tumor (cm)

TNM T2NXMl

5X6x6

No

* T2N I MO T2NlMO T3NXMI T3NOM I T3NOM 1 TlNOMl T3NXMI TINOMO T3NOMO T3NxMI T3NlMI T3NIMI T3NXMl T2NlMO T3N I MO

Resection

3X2X2 4X4X4 3X3X3 7 X 2.5 X 1.5 5X5X5 3.5 x 3 x 3 7X5X5 2X2X2 5X3X3 12X4X4 5.5 x 5 x 3 6X6X3 7 X 6 X 6.5 5X5X4 6X6X5

Partial Noncurative Total Noncurative Partial No Total No Total Total No No No No No No

RT dose IORT

(GY) EBRT

RK-28 g/m2

Post-treatment course

30 25 30 25 30 30 30 25 30 25 25 33 20 30 30 30 30

42. I 56.1 52.1 51 51 61.2 30.8 32.4 42.5 41.5 49.3 31 0 0 47 29.6 59.5

0.4 iv 1.O iv I .O iv I.0 iv 1.2 iv I .25 iv 1.4 iv I.5 iv 1.6 iv 1.8 iv 2.0 iv 0.5 g/body it 0.5 g/body it 0.5 g/bodyit 0.5 g/body it 0.5 g/body it 0.5 g/body it

Died in the 9th mo. Died in the 8th mo. Died in the 25th mo. Died in the 5th mo. Died in the 2nd mo. Died in the 13th mo. Died in the 12th mo. Died in the 7th mo. Died in the 5th mo. 8 mo. alive, NED 8 mo. alive with ascites Died in the 3rd mo. Died in the 2nd mo. Died in the 2nd mo. Died in the 8th mo. Died in the 9th mo. Died in the 9th mo.

* Not measured. iv = intravenous: it = intratumoral.

Compound RK-28 has a sugar analogue in the side chain of the 2nitroimidazole ring (Fig. 1) and thus is a nucleoside analogue. It was developed and provided by Sakaguchi, M. The in vitro and in vivo radiosensitizing activity of this compound has already been reported (14, 25). The drug was dissolved in sterile physiological saline at a concentration of 500 mg/lO ml for intratumoral injection and at 550-2,800 mg/lOO ml for intravenous administration. The reduction potential of the compound is -0.97 V as measured by a method described previously ( 16, 18, 19). This was evaluated relative to an Ag/AgCl (saturated)/ 3.5 mol/dm3 KC1 electrode by means of cyclic voltammetry for the Ar-purged N,N-dimethylformamide solution (0.01 mol/dm3) containing 0.1 mol/dm3 tetra-N-butylammonium perchlorate as a supporting electrode. The partition coefficient in octanol/water was 0.53 measured in buffer at pH 7.4 according to the method of Fujita et al. (I 1). Treatment schema IORT and external beam radiation therapy (EBRT) were delivered as described previously (24). Most of the patients received preoperative irradiation using 10 MV xrays from a linear accelerator. It was usually delivered via three portals from the anterior, left, and right directions. After IORT, most patients also received postoperative EBRT (the total dose of EBRT was 30-6 1 Gy). IORT was performed using an electron beam generated by a betatron. Excluding the gastrointestinal tract from

* True-cut USA.

biopsy

needle,

Travenol

Laboratories,

Inc., IL,

the treatment volume, radiation was delivered to the tumor or tumor bed. The electron beam energy was lo-20 MeV, and the IORT dose was 30-33 Gy for the unresected or partially resected patients and 25 Gy for the resected patients. The details are shown in Table 1. The dose rate was about 1.5 Gy/min. Just before IORT, RK-28 was injected throughout the tumor or given by intravenous infusion over 10 min in 100 ml of saline. In the intravenous administration group, the initial dose of RK-28 was 0.4 g/m* and this was later escalated to 2 g/m2. A dose of 0.5 g of the drug was injected into the tumor randomly for all patients in the intratumoral injection group. A 22 G needle was inserted into the tumor at several positions spaced 1.5 to 2.0 cm apart over the most accesible surface of the tumor and RK-28 was injected every 0.5 to 1.0 cm along each track. Pharmacokinetic studies Just before or after irradiation and in some cases just before the end of the surgical procedure, blood and tumor samples were taken. Tumor samples were usually taken randomly using a biopsy needle* and the volume of each tumor sample was about 20-50 mg. Samples were immediately frozen and stored at -20” prior to analysis. Serum and tumor homogenates were extracted with methanol and analyzed by reverse-phase high-performance liquid chromatography (HPLC) using previously described methods (25). A solvent delivery system+ equipped with TSK-gel ODS 80TM (150 X 4.6 mm) was used. The mobile phase was 10% acetonitrile, 5 mmol/

+ JASCO Tri Rotar-VI.

-.

..

~harmacoklnetlcs

Fig. I. Structural

formula

of* intratumoral

961

RK-28 ??K. SASAI ef ul

of RK-28.

dm3 TBAP, and 15 mmol/dm3 Na2HP04 (to pH = 7.0) and the flow rate was 1.0 ml/min. The absorbance was monitored at 320 nm. RESULTS

Pharmacokinetic studies Pharmacokinetic studies were performed in 10 of the 17 patients. HPLC demonstrated several metabolites of RK-28 (Sakaguchi: unpublished data, 199 1) in both serum and tumor tissues. Table 2 shows the concentrations of RK-28 and its metabolites in each patient. Figure 2 shows serum and tumor concentrations of RK-28 in four patients after intravenous administration of the drug. Closed symbols show the serum concentrations and open ones indicate the tumor concentrations. Although the serum concentration was approximately 70 &ml at 10 min after finishing the intravenous injection of RK-28 ( I .6 g/m2),

Table 2. Total 2nitroimidazole

concentrations

Time

After

Injection

Fig. 2. The serum (closed symbols) and tumor (open symbols) concentrations of RK-28 plus its metabolites after intravenous injection at doses of 0.4-l .6 g/m2 (diamonds: 0.4 g/m2, triangles: 1 g/m*, squares: 1.25 g/m*, and circles: I .6 g/m*). Identical symbols demonstrate drug concentrations in the same patient.

in serum and tumor

tissues in 10 patients

after administration

Drug concentration Case

RK-28 g/m*

Time after injection (min)

1 2

0.4 iv 1.O iv

6

1.25 iv

9

1.6 iv

10 45

12 13

0.5 g/body it 0.5 g/body it

40 45

14 15

0.5 g/body it 0.5 g/body it

16

0.5 g/body it

50 30 90 50

50 20 40 60 80 30 60 90

Serum 1.7 (0.5) (I 1.3)* (5.0) (3.1) (2.6) (11.9) (4.8) (2.8) 69.9 (40.8) 39.3 (12.7) 9.8 4.8 5.9 6.1 7.9 4.1 6.7

(I .4) (0.3) (1.2) (1.3) (1.2) (1.0) (2.3)

3.8 (1.2) 90 6.3 (1.9) 17

0.5 g/body it

(min)

30

Note: Numbers in parentheses are concentrations of the parent compound, RK-28. * Concentrations of metabolites of RK-28 were not measured in cases 2 and 6. iv = intravenous: it = intratumoral.

of RK-28

(pg/ml, Kg/g) Tumor 1 >(l>)

(8.3)

17.8 9.6 23.2 133.6 123.9 1352 4255 1397 135 9292 7 148 21.9 59.7 821. I 1598

(16.6) (9.6) (13.6) (126.3) (99.4) (1338) (4218) (1368) (109) (9 130) (7005) (21.9) (59.7) (795.3) (1573)

1. J. Radiation Oncology 0 Biology 0 Physics

; 1

10”

0

QI

A V

100, 0

30

Time

After

60

90

Injection

120 (min)

Fig. 3. The serum (closed symbols) and tumor (open symbols) concentrations of RK-28 and its metabolites after intratumoral injection of a doses of 0.5 g. Identical symbols demonstrate drug concentrations in the same patient.

the tumor concentration was only 23.2 pg/rn’ at 45 min after intravenous injection. After intratumoral injection, the tumor concentration of the drug ranged from 123 pg/g to 9,292 pug/gjust after IORT (30-50 min after injection). On the other hand, the serum concentration ranged from 4.1 to 9.8 pg/ml (Fig. 3). Toxicity No adverse effects were observed in either group of pa-

tients after intravenous drug.

or intratumoral

injection of the

DISCUSSION

RK-28 belongs to the group of 2-nitroimidazole nucleosides designed to be selectively excluded from neural tissue, such as RA-263 (1, 2). It has been hypothesized that nucleosides generally do not cross the blood-brain barrier effectively (1). However, the concentration of this compound in murine central nervous tissue was found to be as high as that of misonidazole (17). Our previous pharmacokinetic study on RK-28 revealed that this compound disappeared rapidly from murine sciatic nerve tis-

Volume 24, Number 5, 1992

sue and that the peripheral nerves suffered from little drug exposure (17). Therefore, it was expected that this compound would have a low peripheral neurotoxicity. Although the acute toxicity of RK-28 in mice was higher than that of misonidazole, when 60% LDso was injected every day, the total doses that could be given were higher for RK-28 than for misonidazole (25). RK-28 was also reported to be less neurotoxic than misonidazole when compared using a rotarod performance test (25). On clinical trial, the major adverse effects of RK-28 are nausea and vomiting, which occur soon after drip infusion. These are the dose limiting factors of this compound. However, this compound has shown no cumulative toxicity up to 16 g/m2 (25). RK-28 has a 1.5 to 2.5 times higher radiosensitizing activity in vitro on EMT 6 and SCC VII cells than misonidazole. In vivo, RK-28 is almost as efficient as or slightly inferior to misonidazole against SCC VII and EMT6 tumors assayed with an in vivo-in vitro assay and a growth delay time assay at the same administration dose (25). IORT is a good venue for the clinical testing of hypoxic cell radiosensitizers, because it is believed that the hypoxic cell fraction of a tumor has an important role in resistance to irradiation, especially in the case of single or hypofractions of high irradiation doses. In fact, a clinical trial of misonidazole in combination with IORT was previously performed at our hospital (26). The pharmacokinetic study presented here showed that intratumoral injection of the drug was superior to the intravenous administration, in that it produced a higher tumor concentration and a lower serum concentration. This result suggests that intratumoral RK-28 should achieve a high radiosensitizing activity with a low level of side effects. Although heterogeneity of drug distribution in the tumor after intratumoral injection was inevitable as shown in Table 2 and in Figure 3, the minimum tumor concentration of RK-28 after intratumoral injection was 123.9 pg/g just after IORT. Our previous experiments using EMT6/KU tumors in Balb/c mice showed that the radiosensitizer enhancement ratio of RK-28 was 1.4 when it was administered at a dose of 100 pg/g intraperitoneally (22, 25). Some other investigators have already reported that intratumoral administration increases the efficacy of hypoxic cell radiosensitizers (3, 4, 5, 9, 12, 21). Because many patients in this study had advanced diseases, the preliminary survival results were not very good. However, we believe that this administration method can work well in selected patients, such as those who have locally advanced disease without distant metastasis. Combined treatment with IORT and intratumoral RK28 may be a feasible new treatment method.

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