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 120 mg/m(2) 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.
Subject(s)
Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacokinetics , Cisplatin/administration & dosage , Cisplatin/pharmacokinetics , Animals , Antineoplastic Agents/adverse effects , Area Under Curve , Cisplatin/adverse effects , Disease Models, Animal , Injections , Kidney/drug effects , Kidney/pathology , Lung/drug effects , Lung/pathology , Male , Random Allocation , Rats , Rats, WistarABSTRACT
BACKGROUND: Pemetrexed is a key drug for the treatment of malignant pleural mesothelioma. The intrapleural administration of pemetrexed might increase its efficacy and decrease its toxicity in comparison with intravenous administration. The aim of this study was to assess in an animal model the pharmacokinetics of pemetrexed administered intrapleurally compared with intravenously. METHODS: Thirty Wistar rats were randomly assigned to four groups defined by route (intravenous or intrapleural) and dose (10 or 100 mg/kg) of pemetrexed. After pemetrexed administration, serial plasma pemetrexed concentrations were analyzed by high performance liquid chromatography to determine the maximum plasma concentration (C(max)), the area under the plasma concentration-time curve (AUC), and the total body clearance (CL). RESULTS: The C(max) was significantly lower after intrapleural versus intravenous administration of 10 mg/kg pemetrexed (14.36 microg/ml versus 29.83 microg/ml; p = 0.008) or 100 mg/kg pemetrexed (70.64 microg/ml versus 218.64 microg/ml; p = 0.001). At either dose, the AUC and the CL did not significantly differ according to the route of administration. CONCLUSIONS: While intravenous and intrapleural administration of pemetrexed yielded similar AUC and CL, the intrapleural route yielded a significantly lower C(max). As Cmax is a determinant of pemetrexed toxicity, intrapleural administration might offer a means of widening the effective therapeutic index of the drug by improving tolerability. Future studies are needed to confirm this hypothesis in malignant pleural mesothelioma patients.
