title: Development of docetaxel-loaded intravenous formulation, Nanoxel-PM™ using polymer-based delivery system.
abstract: Nanoxel-PM™, docetaxel-loaded methoxy-poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PDLLA) micellar formulation was prepared in an effort to develop alternative, less toxic and efficacious Tween 80-free docetaxel formulation, and its pharmacokinetics, efficacy, and toxicity were evaluated in comparison with Taxotere® in preclinical studies. The mean diameter of the Nanoxel-PM™ was 10-50 nm and the polydispersity of samples exhibited a narrow size distribution and monodisperse unimodal pattern. Pharmacokinetic study in mice, rats and beagle dogs revealed that Nanoxel-PM™ exhibited similar pharmacokinetic profiles (C(max), AUC, t(1/2), CL, V(ss)) to Taxotere, and the relative mean AUC(t) and C(max) of Nanoxel-PM™ to Taxotere® were within 80-120%. Furthermore, excretion study in rats demonstrated that there was no statistically significant difference in the amount excreted in feces or urine as an unmetabolized docetaxel between Nanoxel-PM™ and Taxotere®. Its pharmacokinetic bioequivalence resulted in comparable anti-tumor efficacy to Taxotere® in human lung cancer xenografts H-460 in nude mice as well as in lung, ovary and breast cancer cell lines. Several animal toxicity studies on Nanoxel-PM™ compared with Taxotere® were carried out. In single dose rat and dog model and repeated dose mouse model, both Nanoxel-PM™ and Taxotere® exhibited similar toxic effects on hematology and body weight gain. On the other hand, vehicle related hypersensitivity reactions and fluid retentions were not observed when Nanoxel-PM™ was administered, unlike Taxotere®, in the beagle dog study. Based on these results, it is expected that Nanoxel-PM™ can reduce side effects of hypersensitivity reactions and fluid retention while retaining antitumor efficacy in cancer patients. Currently, Nanoxel-PM™ is under evaluation for bioequivalence with Taxotere® in a multi-center, open-label, randomized, crossover study.
authors.affiliation: Samyang Pharmaceutical R&D Center, Daejeon 305-717, Republic of Korea.
authors.forename: Sa-Won
authors.initials: SW
authors.lastname: Lee
authors.forename: Min-Hyuk
authors.initials: MH
authors.lastname: Yun
authors.forename: Seung Wei
authors.initials: SW
authors.lastname: Jeong
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: In
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Min-Hyo
authors.initials: MH
authors.lastname: Seo
authors.forename: Chaul-Min
authors.initials: CM
authors.lastname: Pai
authors.forename: Sun-Ok
authors.initials: SO
authors.lastname: Kim
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D007275:Injections, Intravenous; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D008823:Micelles; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D043823:Taxoids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D018675:Toxicity Tests; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D008823:Micelles; D011091:Polyesters; D043823:Taxoids; C561465:methoxy poly(ethylene glycol)-block-poly(lactic acid); D000077143:Docetaxel; D011092:Polyethylene Glycols