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

Abstract

Purpose A meta-analysis was conducted to evaluate the inter-patient pharmacokinetic (PK) variability of liposomal and small molecule (SM) anticancer agents. Methods Inter-patient PK variability of 9 liposomal and SM formulations of the same drug were 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). Results 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. Conclusion PK variability of liposomes is significantly greater than SM. The factors associated with the PK variability of liposomal agents needs to be evaluated.

When Is It Important to Measure Unbound Drug in Evaluating Nanomedicine Pharmacokinetics?

“…The MPS also appears to be responsible for saturable clearance of some formulations (e.g., liposomes) at higher doses, and for a higher intersubject variability in the extent of drug exposure as compared with that seen with conventional formulations (Song et al, 2012). This variability can influence the clinical response (safety and effectiveness) (Schell et al, 2014).…”

Roles of chemokines CCL2 and CCL5 in the pharmacokinetics of PEGylated liposomal doxorubicin in vivo and in patients with recurrent epithelial ovarian cancer

“…A meta-analysis was performed to assess the inter-patient variability in the PK of liposomal anticancer agents compared to small molecule (SM) formulations of the same drug 7 . The PK variability of liposomal drugs measured as coefficient variance (CV%) of area-under-the concentration versus time curve (AUC) was significantly greater compared with SM.…”

“…This finding indicates that slower CL of liposomal drugs may be attributable to more heterogeneous NP recognition and CL pathways (i.e., mononuclear phagocyte system (MPS)) resulting in the greater extent of PK variability 7,8 . The PK variability of NP agents including A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 6 liposomal drugs is of high clinical relevance because it implies that individual patient response to a particular NP drug is hard to predict.…”

Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling

“…In a PK study using Kunming mice, danorubicin liposomes had a 13-fold higher AUC0-48h compared with free drug (Ying et al, 2011). Drug in liposomes often show greater PK variability than free drug, which is exacerbated when the clearance rate of the liposomes is low (Schell et al, 2013). This could potentially prevent the use of liposomes to deliver drugs with a small therapeutic window.…”