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?

PURPOSE: 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.

PhRMA survey on the conduct of first-in-human clinical trials under exploratory investigational new drug applications.

The FDA guidance on exploratory IND studies is intended to enable sponsors to move ahead more efficiently with the development of promising candidates. A survey of PhRMA member companies was conducted in 2007 to obtain a cross-sectional industry perspective on the current and future utility of exploratory IND studies. About 56% of survey responders (9 companies of 16 survey responders) conducted or were planning to conduct clinical studies under exploratory INDs. The majority of microdosing studies are performed to characterize human pharmacokinetics or to examine target organ pharmacokinetics using PET imaging techniques. On the other hand, the majority of pharmacological end point studies conducted under exploratory IND are performed to determine whether the compound modulated its pharmacological target or to evaluate the degree of saturation of a target receptor. The present survey suggests that although the merits of exploratory INDs are still being debated, the diversity in the applications cited, the potential for early clinical guidance in decision making and the increasing pressure on containing drug development costs, suggest that the exploratory IND/CTA will be a valuable option with evolving and possibly more specific applications for the future.