Direct comparison of two pegylated liposomal doxorubicin formulations: is AUC predictive for toxicity and efficacy?
Rationally designed liposomes could improve the therapeutic indexes of chemotherapeutic drugs, which is due to alterations in the pharmacokinetics and biodistribution of encapsulated drugs. For traditional drug delivery systems, the accumulation of drugs in healthy and malignant tissues could be correlated with toxicity and efficacy. Some previous studies also indicate that the higher tumor AUC, the better therapeutic efficacy, suggestive of the possible existence of positive correlation. Are AUC values of liposomal drugs really predictive? For the purpose to address this question, we designed two pegylated liposomal doxorubicin formulations (PLD-75 and PLD-100), which had the same lipid/drug ratio and bilayer composition, but different size and internal ammonium sulfate concentration. In vitro drug retention experiments revealed that drug was released at a faster rate from PLD-75, a small size formulation. The plasma pharmacokinetics of PLD-75 was similar to that of PLD-100, regardless of whether the mice were tumor-free or not. It should be noted, though, that in tumor-bearing mice the plasma doxorubicin level in PLD-75 group was only about 59% of that in PLD-100 group at 48 h post injection. Furthermore, their biodistribution behavior in S-180 tumor-bearing KM mice was significantly different. Compared with animals receiving PLD-100, those receiving PLD-75 showed a 19.2%, 27.8%, and 23.5% decrease in liver (p<0.01), spleen (p<0.001) and lung (p<0.05) AUC, respectively. In other healthy tissues except kidney, the drug deposition also reduced by 10-15%, but the difference was not significant. The tumor AUC after administration of PLD-100 and PLD-75 were 1285.3 ugh/g and 762.0 ugh/g, respectively (p<0.001). Maximum drug levels achieved in the tumors were 33.80 microg/g (for PLD-100) and 20.85 microg/g (for PLD-75), and peak tumor concentration was achieved faster in PLD-75 group. However, enhanced drug accumulation does not mean increased antineoplastic effect, and at the same doxorubicin dose level, PLD-75 was more efficacious. As for toxicity studies, PLD-75 caused more rapid and severe body weight loss despite the fact that drug accumulation in healthy tissues was reduced. Our data indicate that liposomal systems are more complicated than conventional drug delivery systems, and it is hard to predict the toxicity and efficacy of liposomal drugs through the measure of liposomal drug accumulation.
Cui
Jingxia
J
School of Pharmacy, Hebei Medical University, No. 361 Zhongshan East Road, Shijiazhuang City, Hebei Province 050017, PR China.
Li
Chunlei
C
Guo
Wenmin
W
Li
Yanhui
Y
Wang
Caixia
C
Zhang
Li
L
Zhang
Lan
L
Hao
Yanli
Y
Wang
Yongli
Y
D000645:Ammonium Sulfate / Q000737:chemistry; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D019540:Area Under Curve; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000633:toxicity*; D004339:Drug Compounding; D007700:Kinetics; D008055:Lipids / Q000737:chemistry; D008081:Liposomes; D008297:Male; D051379:Mice; D008954:Models, Biological; D010316:Particle Size; D011092:Polyethylene Glycols / Q000737:chemistry*; D011237:Predictive Value of Tests; D012510:Sarcoma 180 / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D012995:Solubility; D013696:Temperature; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D008055:Lipids; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000645:Ammonium Sulfate