Intrapleural administration of lipoplatin in an animal model

Froudarakis, Marios E.; Greillier, Laurent; Monjanel-Mouterde, Suzanne; Koutsopoulos, Anastassios; Devictor-Pierre, Benedicte; Guilhaumou, Romain; Karpathiou, Georgia; Botaitis, Sotirios; Astoul, Philippe

doi:10.1016/j.lungcan.2010.07.010

« Previous Next »Lung Cancer
Volume 72, Issue 1 , Pages 78-83, April 2011

Intrapleural administration of lipoplatin in an animal model

Marios E. Froudarakis
- Department of Pneumonology, Medical School Democritus University of Thrace, Greece
- Faculté de Médecine, Université de la Méditerranée, Assistance Publique Hôpitaux de Marseille, Service d’Oncologie Thoracique, Hôpital Sainte-Marguerite, Marseille, France
- Corresponding author at: Faculté de Médecine, Université de la Méditerranée, Assistance Publique Hôpitaux de Marseille, Service d’Oncologie Thoracique, Hôpital Sainte-Marguerite, 270, Bd de Ste-Marguerite, 13274 Marseille, Cedex 09, France.
Laurent Greillier
- Faculté de Médecine, Université de la Méditerranée, Assistance Publique Hôpitaux de Marseille, Service d’Oncologie Thoracique, Hôpital Sainte-Marguerite, Marseille, France
Suzanne Monjanel-Mouterde
- Assistance Publique Hôpitaux de Marseille, Laboratoire de Pharmacocinétique et de Toxicologie, Hôpital de la Timone Adultes, Marseille, France
- Faculté de Pharmacie, Université de la Méditerranée, Laboratoire de Pharmacodynamie, Marseille, France
Anastassios Koutsopoulos
- Department of Pathology, Medical School Democritus University of Thrace, Greece
Benedicte Devictor-Pierre
- Department of Pneumonology, Medical School Democritus University of Thrace, Greece
- Faculté de Médecine, Université de la Méditerranée, Assistance Publique Hôpitaux de Marseille, Service d’Oncologie Thoracique, Hôpital Sainte-Marguerite, Marseille, France
- Assistance Publique Hôpitaux de Marseille, Laboratoire de Pharmacocinétique et de Toxicologie, Hôpital de la Timone Adultes, Marseille, France
- Faculté de Pharmacie, Université de la Méditerranée, Laboratoire de Pharmacodynamie, Marseille, France
- Department of Pathology, Medical School Democritus University of Thrace, Greece
Romain Guilhaumou
- Department of Pneumonology, Medical School Democritus University of Thrace, Greece
- Faculté de Médecine, Université de la Méditerranée, Assistance Publique Hôpitaux de Marseille, Service d’Oncologie Thoracique, Hôpital Sainte-Marguerite, Marseille, France
- Assistance Publique Hôpitaux de Marseille, Laboratoire de Pharmacocinétique et de Toxicologie, Hôpital de la Timone Adultes, Marseille, France
- Faculté de Pharmacie, Université de la Méditerranée, Laboratoire de Pharmacodynamie, Marseille, France
- Department of Pathology, Medical School Democritus University of Thrace, Greece
Georgia Karpathiou
- Department of Pathology, Medical School Democritus University of Thrace, Greece
Sotirios Botaitis
- Department of Pneumonology, Medical School Democritus University of Thrace, Greece
Philippe Astoul
- Faculté de Médecine, Université de la Méditerranée, Assistance Publique Hôpitaux de Marseille, Service d’Oncologie Thoracique, Hôpital Sainte-Marguerite, Marseille, France

Received 7 March 2010; received in revised form 5 July 2010; accepted 26 July 2010. published online 23 August 2010.

Abstract

Background

Lipoplatin is a new liposomal cisplatin already tested in solid tumors with encouraging results. Little is known about the activity of lipoplatin administered intrapleurally (IP).

Aim

The aim of this study was to assess in an animal model the pharmacokinetics, and potentially induced 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 10mg/kg of lipoplatin (group 1) and to IP groups at 10 (group 2) or 20mg/kg (group 3) equal to 60 and 120mg/m² in humans respectively. After lipoplatin administration, serial plasma samples were analyzed by atomic absorption spectrometry for the maximum plasma concentration (C_max), the area under the plasma concentration–time curve (AUC), and the total body clearance (CL). Pleura, lungs and kidneys of the rats were histologically examined for possible lesions.

Results

The C_max was significantly higher in groups 1 vs. 2 (p=0.02) and vs. 3 (p=0.01). The AUC of groups 3 vs. 1 was significantly higher (p=0.028) but the AUC of groups 2 vs. 1 was significantly lower (p=0.02). CL in IP rats did not differ considerably compared to the IV. Inflammatory changes were noted in the 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 C_max. As C_max 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.

Keywords: Lipoplatin, Animal, Pleura, Thoracoscopy, Pharmacokinetics, Histology, Intrapleural treatment, Lung cancer, Mesothelioma