SHORT COMMUNICATION 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? Rao N. V. S. Mamidi • Steve Weng • Susan Stellar • Charles Wang • Ning Yu • Tony Huang • Alfred P. Tonelli • Michael F. Kelley • Anthony Angiuoli • Man-Cheong Fung Received: 22 February 2010 / Accepted: 11 July 2010 / Published online: 27 July 2010 Ó Springer-Verlag 2010 Abstract Purpose To examine whether a conventional bioequiva- lence approach is sufficient to ensure the therapeutic equiv- alence of liposomal products, the pharmacokinetics, efficacy and toxicity of different formulation variants of the marketed Doxil Ò /Caelyx Ò product, pegylated liposomal doxorubicin (PLD), were evaluated in several preclinical models. Methods Six different variants of the marketed PLD for- mulation 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 Ò /Caelyx Ò (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 doxoru- bicin 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 mon- keys, formulation 2 gave systemic exposure of doxorubicin approximately the same as formulation 1; however, multi- focal degeneration of renal cortical tubules and hypocellu- larity 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 establish- ing therapeutic equivalence of generic PLD products. A carefully designed clinical study evaluating clinical safety, efficacy and pharmacokinetics should be consid- ered for establishing the therapeutic equivalency of gen- eric versions of Doxil Ò . R. N. V. S. Mamidi (&) Á S. Stellar Á C. Wang Á N. Yu Á A. P. Tonelli Á M. F. Kelley Preclinical Development, Johnson & Johnson Pharmaceutical Research Development LLC, 1000 US 202S, Raritan, NJ, USA e-mail: smamidi1@its.jnj.com S. Weng Á T. Huang Alza Corporation, Mountain view, CA, USA A. Angiuoli Á M.-C. Fung Oncology Development, Johnson & Johnson Pharmaceutical Research Development LLC, Raritan, NJ, USA Present Address: S. Weng Elan Corporation Inc., South San Francisco, CA, USA T. Huang Independent Formulation Consultant, Saratoga, CA, USA 123 Cancer Chemother Pharmacol (2010) 66:1173–1184 DOI 10.1007/s00280-010-1406-x