Intrapleural administration of pemetrexed: a pharmacokinetic study in an animal model.
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.
Greillier
Laurent
L
Faculté de Médecine (Université de la Méditerranée), Assistance Publique Hôpitaux de Marseille, Service d'Oncologie Thoracique, Hôpital Sainte-Marguerite, Marseille, France.
Monjanel-Mouterde
Suzanne
S
Fraticelli
Anne
A
Devictor-Pierre
Bénédicte
B
Bouvenot
Julien
J
Coltel
Nicolas
N
Lamarche
Gérald
G
Astoul
Philippe
P
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005971:Glutamates / Q000493:pharmacokinetics* / Q000494:pharmacology; D006147:Guanine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D007262:Infusions, Intravenous; D015552:Injections, Intralesional; D016014:Linear Models; D008297:Male; D023421:Models, Animal; D000068437:Pemetrexed; D010994:Pleura / Q000187:drug effects*; D011336:Probability; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric
D000970:Antineoplastic Agents; D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine