Intrapleural Administration of Lipoplatin in an Animal Model

G Model LUNG-3634; No. of Pages 6 ARTICLE IN PRESS

Lung Cancer xxx (2010) xxx–xxx

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Lung Cancer

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Intrapleural administration of lipoplatin in an animal model

Marios E. Froudarakis a,b,∗, Laurent Greillier b, Suzanne Monjanel-Mouterde c,d, Anastassios Koutsopoulos e, Benedicte Devictor-Pierre a,b,c,d,e, Romain Guilhaumou a,b,c,d,e, Georgia Karpathiou e, Sotirios Botaitis a, Philippe Astoul b a Department of Pneumonology, Medical School Democritus University of Thrace, Greece b Faculté de Médecine, Université de la Méditerranée, Assistance Publique Hôpitaux de Marseille, Service d’Oncologie Thoracique, Hôpital Sainte-Marguerite, Marseille, France c Assistance Publique Hôpitaux de Marseille, Laboratoire de Pharmacocinétique et de Toxicologie, Hôpital de la Timone Adultes, Marseille, France d Faculté de Pharmacie, Université de la Méditerranée, Laboratoire de Pharmacodynamie, Marseille, France e Department of Pathology, Medical School Democritus University of Thrace, Greece article info abstract

Article history: Background: Lipoplatin is a new liposomal cisplatin already tested in solid tumors with encouraging Received 7 March 2010 results. Little is known about the activity of lipoplatin administered intrapleurally (IP). Received in revised form 5 July 2010 Aim: The aim of this study was to assess in an animal model the pharmacokinetics, and potentially induced Accepted 26 July 2010 histopathological lesions of lung and kidney after IP vs. IV injection of lipoplatin. Methods: 15 male Wistar rats were assigned to an IV group at dose 10 mg/kg of lipoplatin (group 1) and to Keywords: IP groups at 10 (group 2) or 20 mg/kg (group 3) equal to 60 and 120 mg/m2 in humans respectively. After Lipoplatin lipoplatin administration, serial plasma samples were analyzed by atomic absorption spectrometry for Animal Pleura the maximum plasma concentration (Cmax), the area under the plasma concentration–time curve (AUC), Thoracoscopy and the total body clearance (CL). Pleura, lungs and kidneys of the rats were histologically examined for Pharmacokinetics possible lesions. Histology Results: The Cmax was significantly higher in groups 1 vs. 2 (p = 0.02) and vs. 3 (p=0.01). The AUC of groups Intrapleural treatment 3 vs. 1 was significantly higher (p = 0.028) but the AUC of groups 2 vs. 1 was significantly lower (p = 0.02). Lung cancer CL in IP rats did not differ considerably compared to the IV. Inflammatory changes were noted in the Mesothelioma pleura of IP rats and mild kidneys lesions in IV group. Conclusion: Compared to the IV route, IP20 administration of lipoplatin yielded higher AUC, equal CL, but

a signiﬁcantly lower Cmax.AsCmax is a determinant of lipoplatin toxicity, IP administration might offer a more effective therapeutic index while improving tolerability. We noted ﬁbrotic changes in the pleura of IP rats, and mild kidneys changes in IV rats, as expected. © 2010 Published by Elsevier Ireland Ltd.

1. Introduction development of tumor cells resistance to platinum compounds [4]. In addition, the efficacy of platinum-based regimens is often lim- Survival of patients with malignant pleural effusion is consid- ited by significant renal and hematological toxicity that often lead ered generally poor. Lung cancer is the leading cause of pleural to chemotherapy interruption [5]. disease [1]. Patients with non-small cell lung cancer (NSCLC) and Malignant pleural mesothelioma (MPM) is a neoplasm with malignant pleural effusion have a median survival of about 9 increasing incidence and poor prognosis. In the United States months and therefore pleural localization is considered an M1a dis- it occurs in about 2500 individuals every year, while 72,000 ease in the new staging system proposed by the IASLC [2]. Cisplatin cases are expected to occur in the next 20 years [6]. Patients (CDDP) containing chemotherapy generally offers superior survival with MPM have a median survival ranging from 6 to 12 months benefit compared with non-CDDP containing combinations of older [7]. Recent trials showed that cisplatin is active in combina- or newer generation agents in advanced NSCLC [3]. A major cause tion with newer antimetabolites in patients with advanced MPM of tumor relapse in patients with NSCLC under chemotherapy is the with improved survival [8]. However, myelosuppression and nephrotoxicity were also major factors of treatment discontin- uation and therefore tumor relapse. Toxic effects were due to

∗ both cisplatin [5] and pemetrexed [9,10] administered intra- Corresponding author at: Faculté de Médecine, Université de la Méditerranée, venously. Assistance Publique Hôpitaux de Marseille, Service d’Oncologie Thoracique, Hôpital TM Sainte-Marguerite, 270, Bd de Ste-Marguerite, 13274 Marseille, Cedex 09, France. Lipoplatin (Lipoplatin Regulon Inc. Mountain View, CA) is E-mail address: [email protected] (M.E. Froudarakis). a novel liposomal formulation of cisplatin developed in order to

Please cite this article in press as: Froudarakis ME, et al. Intrapleural administration of lipoplatin in an animal model. Lung Cancer (2010), doi:10.1016/j.lungcan.2010.07.010 G Model LUNG-3634; No. of Pages 6 ARTICLE IN PRESS 2 M.E. Froudarakis et al. / Lung Cancer xxx (2010) xxx–xxx reduce the systemic toxicity of cisplatin, while simultaneously 2.3. Experimental procedures improving the efficacy of the drug on tumor cells [11]. Lipoplatin is able to deliver the drug in a nanoparticle form that evades immune All rats were anesthetized with a first intraperitoneal injection surveillance, and extravasates preferentially through the leaky vas- of ketamine (75 mg/kg) and acepromazine (2.5 mg/kg). Additional culature characteristic of tumor cells with intense neoangiogenesis. intraperitoneal injections were performed to maintain or rein- It consists of liposome particles of an average size of 110 nm with duce general anesthesia throughout the entire procedure. The rats a lipid-to-cisplatin ratio of 10.24 mg lipid/mg cisplatin. The fuso- breathed spontaneously and their body temperature was main- genic anionic lipid dipalmitoyl phosphatidyl glycerol (DPPG) on its tained using blankets and heating lamps. In group 1, injection of surface is supposed to promote fusion between the lipid bilayer of lipoplatin was performed via the jugular veins. In groups 2 and the liposome and of the cell membrane. In addition, the nanoparti- 3, rats were placed in a right lateral decubitus position. A 3-mm cle nature of the drug results in higher uptake interpreted to arise pleural needle (Thorapix®, Thiebaud, Margencel, France) was intro- from a more avid phagocytosis of lipoplatin particles by tumor duced in the left pleural cavity and a pneumothorax was induced. cells compared to normal cells [12]. Preclinical studies on lipoplatin A 2-mm rigid telescope (Richard Wolf Company, Knittlingen, Ger- showed a low toxicity profile, an ability to concentrate in tumors many) was put inside the pleural needle to confirm the existence and to escape immune cells and macrophages, a slow clearance of pneumothorax. The intrapleural injection of lipoplatin was per- rate from the kidneys, long circulation properties in body fluids, formed with a Veress® needle (Purple Surgical, Shenley, United a half-life of 36 h in the blood, and promising therapeutic efficacy Kingdom), which was itself introduced inside the pleural needle. [11]. Phase I studies of lipoplatin alone [13] or in combination with After intrapleural injection of lipoplatin, gentle suction was applied antimetabolites [14] showed efficacy in patients with solid tumors to reexpand the lung. Before injection of lipoplatin, 0.5 ml of blood and an excellent toxicity profile. This compound has also shown was collected from one of the jugular veins (contralateral to the activity and low toxicity in association with gemcitabine in pleural lipoplatin injection site for group 1) into EDTA tubes. Additional and peritoneal mesothelioma [15]. 0.5 ml blood samples were harvested 15 min after chemotherapy The rationale for the use of cytotoxic agents as intracavitary administration for group 1 only. For group 1 (IV) blood samples administration is the intense and extended exposure to local tissues were also taken at 24 and 72 h. For groups 2 and 3, blood sam- with reduced systemic effects [16]. Intrapleural chemotherapy has ples were taken at 24, 48, and 72 h after injection of lipoplatin. For the potential advantage of treating the malignancy, in addition to groups 2 and 3 no blood sample was taken before 24 h to avoid providing local control of the effusion. This route of administration multiple and harmful procedures, considering that the blood lev- might consequently increase the treatment efficacy while decreas- els of lipoplatin are generally delayed, reaching a peak at least 24 h ing toxicity [17]. Several drugs have been used intrapleurally such after intrapleural injection [24]. Tubes were centrifuged at 4 ◦Cat as platinum compounds [18,19], etoposide [20], paclitaxel [21] and 3000 c/min during 5 min and the plasma was separated and stored pemetrexed [22]. We hypothesized that, compared with the intra- at −20 ◦C until determination of lipoplatin levels. venous route, intrapleural administration of lipoplatin would both increase pleural tissue exposure and decrease systemic exposure to 2.4. Pharmacokinetic analysis the drug. We tested this hypothesis in an animal model in which the pharmacokinetics of intravenous and intrapleural lipoplatin were Total plasma was analyzed for platinum concentrations. Total assessed, with lung, pleura and kidney tissues for histopathological platinum concentrations were determined in plasma using a GF- lesions. AAS (Graphite Furnace Atomic Absorption Spectrometry) assay using an Ati-Unicam model 939QZ, as previously described [14,18]. The quantification limit was 0.02 ␮g/ml and the detection limit was 2. Materials and methods 0.01 ␮g/ml. For each animal the pharmacokinetic parameters as the clearance (CL), and the half-life were estimated with APIS soft- 2.1. Animals ware version 4.17 (WGroupe, Pommiers la Placette, France) using a model-independent mode [25]. The area under the curve (AUC) Male Wistar rats (Janvier, Le Genest-Saint-Isle, France) were was determined using the trapezoidal rule from baseline to the kept in the university rodent facility. They were housed in des- last measured time point at 72 h and extrapolated to the infinity ignated rodent-storage modules in a temperature-controlled room using the estimated half-life. Maximal experimental concentra- and had free access to water and food. The present study was con- tions (Cmax) were determined in plasma samples. ducted in compliance with the recommendations of the Federation of European Laboratory Animal Science Associations. After com- 2.5. Histopathology pletion of the experiment the rats were killed by intraperitoneal injection of sodium pentobarbital (120 mg/kg). All rats were killed and lungs and kidneys were removed and fixed in 20% formalin. They were sectioned in blocks and then dehydrated in graded concentrations of alcohols, and embedded 2.2. Study design in paraffin. The lung and kidney blocks were cut into 2 ␮m sections and stained with hematoxylin–eosin reagents. The tissue sections Two different administration routes of lipoplatin (LipoplatinTM were examined by light microscopy at 400× magnification. The Regulon Inc. Mountain View, CA) were compared: the intravenous morphometric examination for both lungs and kidneys was per- (IV) route and the intrapleural (IP) route. Two different doses of formed by a single pathologist in a blinded manner. lipoplatin were studied: 10 and 20 mg/kg (approximately equiv- Lung evaluation injury was based on the following scoring sys- alent to 60 and 120 mg/m2 in humans, respectively) [23]. Rats tem [26]. Four easily identifiable pathologic processes were scored were randomly assigned to 3 groups: 5 rats received 10 mg/kg on a scale of 0–4: (a) alveolar congestion, (b) haemorrhage (c) of lipoplatin intravenously (group 1), 5 rats received 10 mg/kg of leukocyte infiltration or aggregation of neutrophils in airspace lipoplatin intrapleurally (group 2), and 5 rats received 20 mg/kg of or the vessel wall (d) thickness of the alveolar wall. A score of: lipoplatin intrapleurally (group 3). At the end of the experiment, 0 represented normal lungs; (1) mild, <25% lung involvement; lungs and kidneys were removed for histopathological examina- (2) moderate, 25–50% lung involvement; (3) severe, 50–75% lung tion. involvement; (4) very severe, >75% lung involvement. An over-

2.6. Statistical analysis

Descriptive and analytic statistics were performed using StatView software. The weight of rats was compared between the three groups by the Kruskall–Wallis test. The same test was uti- lized to compare the pharmacokinetic parameters between group 1 vs. group 2 and between group 1 vs. group 3. The differences were considered to be signiﬁcant if p-values were less than 0.05.

3. Results

3.1. Animals

The results of the present study were obtained by the analysis of 13 animals of the three distinct groups as previously described. One rat of group 1 and one of group 2 died few hours following the begin- ning of the procedure. The mean weight of the rats was 603 ± 78.1 g. No signiﬁcant difference (overall p = 0.38) was observed in the mean ± ± Fig. 2. Mean concentrations vs. time ( SD) of Wistar rats with intrapleural admin- weight between the three groups (weight of group 1 = 607.5 82 g, istration of lipoplatin at 10 mg/kg (group 2, IP10 line) and 20 mg/kg (group 3, group 2 = 557 ± 64.5 g, group 3 = 636 ± 81.4 g). IP20 line). (For interpretation of the references to color in this ﬁgure legend, the reader is referred to the web version of the article.)

3.2. Pharmacokinetics of lipoplatin

After intravenous injection of 10 mg/kg of lipoplatin (group 1), 3.3. Histopathology findings the Cmax was achieved within the first 15 min followed by rapid decline of plasma drug concentration (Fig. 1). After intrapleu- Overall, the score of lung lesions was low (Table 2). The lesions ral injection of 10 mg/kg (group 2), and of 20 mg/kg (group 3) mainly observed consisted of alveolar/vessel congestion of the left the plasma drug concentration increased moderately and then lung (Fig. 3), secondary to the lung parenchyma compression from decreased progressively (Fig. 2). Half-life of lipoplatin administered the administration of lipoplatin solution. There were no significant IV was 26 and 125 h when administered IP. The pharmacokinetic changes between groups IP 10 vs. IP 20 (Table 2), but any IP group profiles of lipoplatin in group 3 were similar to those of group 2, had low, yet significant lesions when compared to the IV group but shifted upwards (Fig. 2). (Table 2). Overall, the score of the pleura was also low (Table 2). Concerning the pharmacokinetic parameters, the total AUC We observed some inflammatory changes on the pleura, at the between groups 1 and 2 and between groups 1 and 3 were signif- side of IP administration, significantly more important when com- icantly different (Table 1). The total CL did not differ significantly pared to the IV administration group (Table 2). Conversely, mild between group 1 and groups 2 or 3 (Table 1). The Cmax was sig- kidney lesions (Fig. 4) were observed in the IV group (Table 3). nificantly higher in rats receiving lipoplatin intravenously than in Those lesions, although mild, were significantly more prominent those receiving the drug intrapleurally (Table 1). than those observed in both the IP groups (Table 3).

Table 1 Pharmacokinetics of plasma lipoplatin in rats according to the administration mode (intrapleural vs. intravenous).

Pharmacokinetic parameters Lipoplatin groups p

Group 1 (IV10) Group 2 (IP10) Group 3 (IP20) Groups 1 vs. 2 Groups 1 vs. 3

AUC (␮g h/ml) 432.2 ± 78.8 270 ± 55.7 689.2 ± 165 0.02 0.028

Cmax (␮g/ml) 30.6 ± 6.9 1.62 ± 0.32 2.87 ± 0.72 0.02 0.01 CL (L/h m2) 14.4 ± 3.2 21.4 ± 5 19.4 ± 5.3 0.053 0.08

Table 2 Lung, pleura injury according to the mode of lipoplatin administration. Compari- son between groups in the lung values: p IP10/IV10 = 0.01 − p IP10/IV10 = 0.039 – p IP10/IP20 = 0.68. Comparison between groups in the pleura values: p pleura IV/IP10 = 0.045, −p pleura IV/IP20 = 0.040 − p pleura IP10/IP20 = 0.69.

Organ IV10 IP10 IP20

Left lung 02 3 03 2 14 3 12 2 2 Mean ± SD 0.5 ± 0.57 2.75 ± 0.95 2.4 ± 0.54

Right lung 01 1 12 0 00 1 11 0 1 Mean ± SD 0.5 ± 0.57 1 ± 0.8 0.6 ± 0.54 Total mean ± SD 0.5 ± 0.53 1.87 ± 1.2 1.5 ± 1.08

Left pleura 01 1 11 2 01 1Fig. 4. Microscopic renal tissue section shows some vessel congestion and mild 01 2tubule dilatation (arrows) without other significant findings in a rat with intra- 1 venous administration of lipoplatin at a dose of 10 mg/kg (haematoxylin and eosin ± ± ± ± Mean SD 0.25 0.5 1 0 1.4 0.54 stain, magnification 200×). Right pleura 00 0 00 1 00 0 Our findings are consistent with those reported previously with 01 0an older liposomal platinum compound (L-NDDP) tested in rats 0 0 ± 0 0.25 ± 0.5 0.2 ± 0.44 in the early 1990s [28]. This study compared IV to intraperitoneal Total mean ± SD 0.12 ± 0.35 0.625 ± 0.51 0.8 ± 0.78 (IPr) administration of L-NDDP vs. cisplatin. The authors reported that the absorption from IPr administration was much slower than that of cisplatin (peak plasma levels 20–30 min vs. 12–24 h), and 4. Discussion the peritoneal fluid levels of L-NDDP were several fold higher than those of cisplatin at 6 h [28]. This lower systemic absorption rate of In our study we aimed to assess the pharmacokinetics of lipoplatin compared to cisplatin after intrapleural administration is intrapleural administration and to compare these with the pharma- probably due to its higher molecular weight suggesting that there cokinetics of intravenous administration in our preclinical study. may be a cut off to get to the lymphatics through the Wang stomas We studied lipoplatin administered IP at two different doses, and in of the parietal pleura [18,29]. both cases the Cmax was significantly higher after intravenous than The same group has tested this compound as an intrapleural intrapleural administration. The AUC was significantly higher for administration in patients with malignant pleural effusion in a IP 20, but the CL did not significantly differ according to the route phase I [24] and in malignant pleural mesothelioma in a phase II of administration. These differences in pharmacokinetics suggest study [30]. In the phase I study, they confirmed that absorption into that the intrapleural administration might improve the patient tol- the systemic circulation was slow with peak levels of total platinum erance to lipoplatin, as lipoplatin toxicity correlates mainly with reached at or after 24 h, 3–4-fold lower than those reached after iv the Cmax [13]. administration over 4 h of a 50% lower dose. The compound pro- duced a fluid loculation effect in 13 out of the 21 studied patients (62%) and up to 50% reduction in the amount of the baseline pleural fluid in 7/21 patients (33%) [24]. Surprisingly in the phase II study, toxicity was significant with 3 treatment related deaths (9%), and grade 3/4 hematological (15%) and non-hematological (15%) toxic-

Table 3 Kidney injury according to the mode of lipoplatin administration. p was signiﬁcant between IV and IP10 (0.009) and between IV and IP20 (0.041), but not between the 2 IP groups (0.33).

Organ IV10 IP10 IP20

Left kidney 000 210 201 102 0 Left mean ± SD 1.25 ± 0.7 0.25 ± 0.5 0.4 ± 0.54

Right kidney 100 201 100 110 Fig. 3. Microscopic lung tissue section shows some vessel congestion (arrows) with- 1 ± ± ± ± out other significant findings in a rat with intrapleural administration of lipoplatin Right mean SD 1.25 0.95 0.25 0.5 0.6 0.89 ± ± ± ± at a dose of 20 mg/kg (haematoxylin and eosin stain, magnification 100×). Total mean SD 1.25 0.7 0.25 0.46 0.5 0.7

Please cite this article in press as: Froudarakis ME, et al. Intrapleural administration of lipoplatin in an animal model. Lung Cancer (2010), doi:10.1016/j.lungcan.2010.07.010 G Model LUNG-3634; No. of Pages 6 ARTICLE IN PRESS M.E. Froudarakis et al. / Lung Cancer xxx (2010) xxx–xxx 5 ity (30]. It is striking that CDDP injected intrapleurally showed no Thus, intrapleural administration might offer a means of widening grade 3/4 hematological and lower grade 3/4 non-hematological the effective therapeutic index of the drug by improving patient tol- toxicity in patients with malignant pleural effusion [18] including erance to lipoplatin. This was also confirmed by the histopathologic lung carcinoma [31]. findings. However, additional experimental and clinical studies are While the rationale behind intrapleural chemotherapy is the needed to confirm this hypothesis in patients with MPM or lung direct exposure of tumor cells to higher doses of cytotoxic agents cancer with malignant pleural effusion. [17], intrapleural administration does not avoid systemic drug exposure. In our study, the AUC for IP20 was significantly higher Conflict of interest statement than for IV10 rats. This systemic delivery might allow lipoplatin to diffuse into the inner core of tumor tissue through tumor neovascu- All authors have no conflicts to disclose. larisation, confirming the antiangiogenic action of the compound [32]. If so, the intrapleural administration of lipoplatin might com- bine two modes of action: a local effect via direct exposure to the References drug and a selective systemic effect with preferential activity of the drug in areas characterized by prominent neovascularisation. [1] Froudarakis ME. 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Please cite this article in press as: Froudarakis ME, et al. Intrapleural administration of lipoplatin in an animal model. Lung Cancer (2010), doi:10.1016/j.lungcan.2010.07.010