Abstract 1295: Relationship between pharmacokinetic (PK) sampling schema and reported PK variability of liposomes in patients

Abstract

Introduction: Liposomal formulations offer advantages over small molecules including increased solubility, selective targeting potential and prolonged drug exposure. Compared with conventional formulations, these agents often have greater PK and pharmacodynamic variability, which is attributed to the role of the mononuclear phagocyte system in the clearance of liposomes. Inter-patient variability in drug exposure, represented by area under the curve (AUC), of encapsulated drug can be 20- to 100-fold. However, some nanoparticle and liposomal agents report lower inter-patient PK variability. Study design and sampling schema may affect the documentation of PK variability, due to the prolonged systemic exposure of encapsulated drug. Thus, we evaluated the reported PK variability of PEGylated CKD-602 (S-CKD602) and non-liposomal CKD-602 (NL-CKD-602) using a short (0-24 h) and long (0-336 h) sampling schema. Methods: S-CKD602 and NL-CKD-602 were administered at doses ranging from 0.5 to 2.1 mg/m2 in phase I studies of patients with advanced solid tumors. Blood samples were obtained from baseline to 336 h for S-CKD602 and from baseline to 24 h for NL-CKD-602. Plasma concentration of total (lactone + hydroxy acid) encapsulated CKD-602 from S-CKD602 and total CKD-602 from NL-CKD-602 were measured by LC-MS/MS. AUC from 0 to 24 h (AUC0-24) and 0 to 336 h (AUC0-336) were calculated. The coefficient of variance % (CV%) in AUC0-24 and AUC0-336 at each dose level were calculated for S-CKD602 and NL-CKD-602. Results: Conclusion: The inter-patient variability of exposure of S-CKD602 is 2.5- to 3.4-fold greater than that of NL- CKD-602. Current PK study designs limited to 24 h underestimate the inter-patient variability of exposure of S-CKD602. PK study design of liposomal agents requires an extended PK sampling schema to accurately describe its PK disposition. A limited sampling strategy that may be applied for all nanoparticles is under development to address this issue. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1295. doi:10.1158/1538-7445.AM2011-1295

A Review of Study Designs and Outcomes of Phase I Clinical Studies of Nanoparticle Agents Compared with Small-Molecule Anticancer Agents

“…The cause of observed differences in clinical phase I studies may be due to differences in the pharmacokinetics and pharmacodynamics of nanoparticles, preclinical animal models used for toxicities of The pharmacokinetics of nanoparticles is more variable than small molecules. A meta-analysis compared differences in AUC CV% as a measure of variability between liposomal and nonliposomal anticancer agents (31). For liposomal agents, the mean AE SD of CV% of AUC was 65.6 AE 18.6.…”