title: Pharmacokinetics, efficacy and toxicity of different pegylated liposomal doxorubicin formulations in preclinical models: is a conventional bioequivalence approach sufficient to ensure therapeutic equivalence of pegylated liposomal doxorubicin products?
abstract: OBJECTIVE
  To examine whether a conventional bioequivalence approach is sufficient to ensure the therapeutic equivalence of liposomal products, the pharmacokinetics, efficacy and toxicity of different formulation variants of the marketed Doxil(/Caelyx product, pegylated liposomal doxorubicin (PLD), were evaluated in several preclinical models.
  
  
  METHODS
  Six different variants of the marketed PLD formulation were prepared by incorporating minor changes in the composition and liposome size of the original formulation. The pharmacokinetics of 5 formulations were evaluated in albino mice following i.v. administration at 6 mg/kg. Selected variants along with Doxil/Caelyx (formulation 1, Doxil-control) were tested for antitumor activity in the MDA-MB-231 xenograft mouse model following 3 repeated administrations at 2 mg/kg or 3 mg/kg (once weekly for 3 weeks) and/or toxicity in Cynomolgus monkeys following 6 repeated administrations at 2.5 or 4.0 mg/kg. Formulations 1-4 were tested for antitumor activity and formulations 1, 2, 6 and 7 were evaluated in a monkey toxicity study. The toxicokinetics of total doxorubicin was determined after the first and last dose in the monkey toxicity study.
  
  
  RESULTS
  In the albino mouse, formulations 2 and 3 had plasma pharmacokinetic profiles similar to Doxil-control (formulation 1). Although these three formulations had similar pharmacokinetic profiles, formulation 2 showed significantly (P < 0.05) longer survival time and better efficacy (reduced tumor volume) over other formulations tested for antitumor activity at the 3 mg/kg dose. In monkeys, formulation 2 gave systemic exposure of doxorubicin approximately the same as formulation 1; however, multi-focal degeneration of renal cortical tubules and hypocellularity of the bone marrow were observed with formulation 2 but not with formulation 1 (Doxil-control). Formulations 6 and 7 gave lower exposure to doxorubicin compared to Doxil-control, but were associated with higher severity and frequency of toxic effects (hematological effects, elevated liver enzymes). It was concluded that plasma pharmacokinetics and systemic exposure of doxorubicin did not correlate well with the antitumor activity and toxicity profiles for PLD products. Hence, a conventional bioequivalence approach is not appropriate for establishing therapeutic equivalence of generic PLD products. A carefully designed clinical study evaluating clinical safety, efficacy and pharmacokinetics should be considered for establishing the therapeutic equivalency of generic versions of Doxil.
authors.affiliation: Preclinical Development, Johnson & Johnson Pharmaceutical Research Development LLC, 1000 US 202S, Raritan, NJ, USA. smamidi1@its.jnj.com
authors.forename: Rao N V S
authors.initials: RN
authors.lastname: Mamidi
authors.forename: Steve
authors.initials: S
authors.lastname: Weng
authors.forename: Susan
authors.initials: S
authors.lastname: Stellar
authors.forename: Charles
authors.initials: C
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Yu
authors.forename: Tony
authors.initials: T
authors.lastname: Huang
authors.forename: Alfred P
authors.initials: AP
authors.lastname: Tonelli
authors.forename: Michael F
authors.initials: MF
authors.lastname: Kelley
authors.forename: Anthony
authors.initials: A
authors.lastname: Angiuoli
authors.forename: Man-Cheong
authors.initials: MC
authors.lastname: Fung
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy*; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D004334:Drug Administration Schedule; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D008252:Macaca fascicularis; D051379:Mice; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D016019:Survival Analysis; D013810:Therapeutic Equivalency; D014183:Transplantation, Heterologous; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin