Evaluation of the efficiency of tumor and tissue delivery of carrier-mediated agents (CMA) and small molecule (SM) agents in mice using a novel pharmacokinetic (PK) metric: relative distribution index over time (RDI-OT)

Abstract

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.

A reanalysis of nanoparticle tumor delivery using classical pharmacokinetic metrics

“…Both the pharmacology of NPs and the physiology of solid tumors are complex, and the interactions between the two are not fully understood. Recent analyses have questioned the utility of NPs for the treatment of solid tumors due to potential low tumor delivery efficiency and extent, especially the often-cited study by Wilhelm et al (19) However, the conclusions of the study by Wilhelm et al were based on a nonstandard PK metric, %ID in tumor, which was several orders of magnitude lower than other published PK metrics describing the tumor delivery efficiency of SM and NP drugs (18). To better characterize the delivery of drug-loaded NPs to solid tumors, we compiled and analyzed the source data from the published NP PK studies in mice used by the Wilhelm et al study and evaluated the relationship between established PK parameters describing the tumor disposition of NP agents and the novel %ID in tumor metric.…”

“…The RDI-OT, used to evaluate the efficiency of tumor delivery from systemic circulation, is calculated as the ratio of tumor concentration to blood concentration at the same time point (e.g., 24 hours) (18). The area under the tumor RDI-OT curve (RDI-OT AUC tumor ) from 0 to t last was calculated using the linear trapezoidal rule for each dataset.…”

“…A workshop by the Alliance for Nanotechnology in Cancer concluded that there are major gaps in the understanding of factors that affect and inhibit EPR effect and NP tumor delivery, and new fundamental preclinical and clinical studies in this area are needed to effectively advance NP drug delivery and efficacy in solid tumors (4). Recent meta-analyses, described in detail below, have reported lower than expected NP tumor delivery, highlighting the potential limitations of current EPR-based NP delivery to tumors and the need to systematically evaluate NP disposition (18,19).…”

“…Despite great promise, the impact of NPs on the treatment of solid tumors in patients, and in some cases, preclinical models, has been limited. To evaluate NP tumor delivery as compared to SM drugs, our group previously conducted a meta-analysis evaluating the plasma and tumor PK of NPs and SM anticancer agents using both standard PK parameters and a PK metric called "relative distribution index over time (RDI-OT)" that measures efficiency of tumor delivery (18). In general, standard PK parameters such as plasma and tumor C max and area under the time concentration curves (AUCs) were higher for NP agents than their respective SM drugs, as expected.…”

“…AUC tumor / AUC plasma ratio was higher for the SM drug compared to the NP formulation for 14 of 17 datasets, and similar to this traditional PK approach, every SM tumor RDI-OT AUC 0-6h value was also greater than that of its comparator NP. The lower efficiency of delivery seen with NPs compared with SMs suggests that even though NPs can deliver an overall greater total drug exposure to the tumor, there may be a limit to the extent or amount of NPs that can enter tumors (18). An important caveat to this conclusion, however, is that active, released NP drug concentrations were not evaluated, and without this key component of the PK analysis, it is impossible to infer potential advantages or disadvantages of the NP-mediated tumor delivery in comparison to SM.…”