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.

The pharmacokinetics (PK) of carrier-mediated agents (CMA) is dependent upon the carrier system. As a result, CMA PK differs greatly from the PK of small molecule (SM) drugs. Advantages of CMAs over SMs include prolonged circulation time in plasma, increased delivery to tumors, increased antitumor response, and decreased toxicity. In theory, CMAs provide greater tumor drug delivery than SMs due to their prolonged plasma circulation time. We sought to create a novel PK metric to evaluate the efficiency of tumor and tissue delivery of CMAs and SMs. We conducted a study evaluating the plasma, tumor, liver, and spleen PK of CMAs and SMs in mice bearing subcutaneous flank tumors using standard PK parameters and a novel PK metric entitled relative distribution over time (RDI-OT), which measures efficiency of delivery. RDI-OT is defined as the ratio of tissue drug concentration to plasma drug concentration at each time point. The standard concentration versus time area under the curve values (AUC) of CMAs were higher in all tissues and plasma compared with SMs. However, 8 of 17 SMs had greater tumor RDI-OT AUC0–last values than their CMA comparators and all SMs had greater tumor RDI-OT AUC0–6 h values than their CMA comparators. Our results indicate that in mice bearing flank tumor xenografts, SMs distribute into tumor more efficiently than CMAs. Further research in additional tumor models that may more closely resemble tumors seen in patients is needed to determine if our results are consistent in different model systems.

The aim of this study is to report the rate and type of neurologic injury associated with flexion supracondylar fractures at a tertiary, university institution treated over a 10-year period. All supracondylar humerus fracture cases treated at our institution between January 2004 and January 2014 were retrospectively reviewed. Twenty-three flexion-type fractures were identified. Patient demographics as well as fracture classification, treatment modalities, and pre-and post-treatment neurologic status were analyzed. Twenty-three flexion-type supracondylar humerus fractures were identified and reviewed out of a total of 1000 supracondylar humerus fractures (2.3%). Details of the patients’ neurologic status upon presentation demonstrated that 17 (74%) patients were intact and six (26%) patients presented with an ulnar neuropraxia. Zero type I fractures, one type II fractures (14.3%), and five type III fractures (33.3%) demonstrated an ulnar nerve palsy. Of these, all six nerve deficits resolved following treatment. One additional patient was identified with median nerve neuropraxia following treatment with closed reduction casting, which resolved following observation. A total of 4 (17.4%) patients were treated with closed reduction casting, 15 (65.2%) with closed reduction percutaneous pinning, and four (17.4%) with open reduction internal fixation. Flexion-type supracondylar fractures of the humerus are rare yet significant injuries. The 26% of patients who developed an ulnar neuropraxia following a displaced flexion supracondylar fracture were higher than previous studies reported in the literature. This increased prevalence may be due to the high rates of type III fractures reported in the current study. Level of evidence: III, Retrospective comparative cohort analysis.

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