Research Article
Meta-analysis of inter-patient pharmacokinetic variability of liposomal and non-liposomal anticancer agents

https://doi.org/10.1016/j.nano.2013.07.005Get rights and content

Abstract

A meta-analysis was conducted to evaluate the inter-patient pharmacokinetic (PK) variability of liposomal and small molecule (SM) anticancer agents. Inter-patient PK variability of 9 liposomal and SM formulations of the same drug was evaluated. PK variability was measured as coefficient of variance (CV%) of area under the plasma concentration versus time curve (AUC) and the fold-difference between AUCmax and AUCmin (AUC range). CV% of AUC and AUC ranges were 2.7-fold (P < 0.001) and 16.7-fold (P = 0.13) greater, respectively, for liposomal compared with SM drugs. There was an inverse linear relationship between the clearance (CL) of liposomal agents and PK variability with a lower CL associated with greater PK variability (R2 = 0.39). PK variability of liposomal agents was greater when evaluated from 0-336 h compared with 0-24 h. PK variability of liposomes is significantly greater than SM. The factors associated with the PK variability of liposomal agents need to be evaluated.

From the Clinical Editor

In this meta-analysis, the inter-patient pharmacokinetic variability of 9 liposomal and small molecule anti-cancer agents was studied. The authors determined that several parameters are in favor of the liposomal formulation; however, the PK variability of the formulation was higher compared with small molecule agents, the reason for which remains to be determined in future studies.

Graphical Abstract

Plasma Concentration-vs.-Time Profiles of Encapsulated S-CKD602 at 2.10 mg/m2 IV × 1 and NL-CDK602 at 0.50 mg/m2 IV × 1. This manuscript evaluates the differences in inter-patient PK variability of liposomal and non-liposomal formulations of anticancer agents, from which we have determined that PK variability of liposomal agents is significantly greater than small molecule non-liposomal agents.

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Section snippets

Systematic review and meta-analysis

To directly compare interpatient PK variability of multiple liposomal and non-liposomal anticancer agents, a systematic review and a meta-analysis were conducted utilizing PubMed (1966-2011) and manual searches of reference sections of key articles. Phase I and II studies that included PK studies were included in our analysis. The systematic review yielded 9 liposomal and non-liposomal formulations of the same anticancer agents. A complete list of evaluated agents with a brief description of

Meta-analysis of PK variability

We compared inter-patient PK variability differences of corresponding liposomal and non-liposomal anticancer agents at similar doses. Figure 1 represents the plasma concentration versus time profiles of liposomal and non-liposomal CKD-602, one of the 9 agents evaluated in the meta-analysis. Here, each agent was administered to 6 patients at the respective MTD (S-CKD602 at 2.10 mg/m2 and NL-CKD602 at 0.5 mg/m2). Visual inspection reveals a tighter grouping of profiles between patients administered

Discussion

High inter-patient PK variability observed with many anticancer agents makes it difficult to predict a patient’s response to a particular drug. Moreover, liposomes often report higher PK variability compared with small molecules and non-liposomal agents, further clouding predictions of outcomes associated with these carrier agents. We comprehensively evaluated these differences in a meta-analysis of 9 liposomal and non-liposomal anticancer agents. This is the first meta-analysis evaluating the

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