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

Discussion

This is the first study or review highlighting major differences between nanoparticle and small molecule phase I clinical study design and outcomes. There was a significantly greater number of dose levels, time required to complete phase I studies, patient-related resources, and costs to conduct phase I studies of nanoparticles compared with small molecules. These results indicate the inefficiency in which phase I studies of nanoparticles are designed and/or carried out relative to small molecules. 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 nanoparticles, or study design issues of nanoparticles compared with small molecules.

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 ± SD of CV% of AUC was 65.6 ± 18.6. For nonliposomal agents, the mean ± SD of CV% of AUC was 30.7 ± 16.0. The ratio of liposomal to nonliposomal CV% of AUC for each pair was 2.7 (P < 0.001; Eq 1). Similarly, the mean ± SD ratio of AUC_max to AUC_min at the MTD was 34.1 ± 41.9 for liposomes and 3.6 ± 1.8 for non-liposomal drugs. The ratio of liposomal to non-liposomal ratio of AUC_max to AUC_min for each pair was 16.7 (P < 0.13). The significantly higher and clinically relevant pharmacokinetic variability of nanoparticles compared with small molecules may be affecting the design and progression of phase I studies of nanoparticles agents. Thus, studies need to be coducted and methods developed to evaluate and predict the factors inducing the high pharmacokinetics and pharmacodynamic variability of nanoparticles (32–34).

A potential reason for the discrepancy between nanoparticles and small molecules in human phase I studies could be model selection in preclinical studies. When allometric scaling was used to compare the pharmacokinetic disposition of three different PEGylated liposomes (S-CKD602, Doxil, SPI-077) across species (mice, rats, dogs, and humans) at the MTD, the pharmacokinetic disposition in dogs was a consistent outlier from other animal models (15). In addition, when a Dedrick Time Equivalent model was used, dogs had the highest CL and thus the lowest exposure of all 3 liposomal agents at the MTD (15). This suggests that dogs clear PEGylated liposomes faster than other species which results in a lower plasma exposure but are the more sensitive to nanoparticles toxicity at this lower exposure. Thus, using dogs to determine starting dose in man results in a dose that is lower than needed and consequently creates exposures that have a low probability of achieving response and/or inducing toxicity. This results in an increase in the number of dose levels, number of patients, and ratio of MTD to starting dose for nanoparticles compared with small molecules. Physiologically based pharmacokinetic modeling and allometric scaling have been previously used for many small-molecule agents to predict human pharmacokinetics from animal data. Mahmood reported on the MTD of 25 small-molecule anticancer drugs that could be used to predict the proper starting dose in humans (35). He concluded that the approach saves time and avoids many unnecessary steps in attaining the MTD in humans. This information is in contrast to nanoparticles, which are not extensively metabolized, have greater pharmacokinetic variability compared with small molecules, and the pharmacokinetics in animal models is not directly extrapolated to humans. (15). Although animal models have successfully predicted small-molecule pharmacokinetics in humans in prior studies, the ability to predict nanoparticle pharmacokinetics in humans based on results in animal models seems to be more problematic. The inability to extrapolate nanoparticle pharmacokinetics to patients from animal models is most likely due to differences in the MPS across species. Thus, the standard models and methods used for small molecules cannot be used for nanoparticles. Future studies are needed to determine the most appropriate animal model and scaling methods for nanoparticles.

Another potential reason for an increased number of dose levels could be that nanoparticles have a lower toxicity than small molecules and therefore the dose of nanoparticles can be escalated to higher levels than small molecules. In vitro and preclinical studies have shown that the toxicity of PEGylated liposomal agents and other nontargeted nanoparticles carriers is less than the comparative small molecule (3, 36, 37). For example, the cytotoxicity of mitomycin C was drastically reduced when prepared in PEGylated liposomes (38). It also has been clinically noted that the biodistribution pattern of liposomes can lead to a relative reduction of drug concentrations in tissues that are known to be sensitive to the drug (39). The biodistribution pattern is due to the unique pharmacokinetic profile that is obtained after administration of nanoparticles, such as increased plasma exposure (AUC) and reduced CL of the inactive-encapsulated drug (3, 22). Generally, stable nanoparticles carriers have minimal drug release in the circulation which reduces toxicities in normal organs (3, 22).

Of the nanoparticles 9 agents reviewed, 4 studies stated that the starting dose was based on dogs within the clinical phase I study. One study (Abraxane) stated that dogs had a hypersensitivity reaction to the nanoparticles and the in the remaining 4 studies, no information was provided on the starting dose. There were 3 nanoparticless that did not follow the trend of greater resources and time to complete the phase I study (e.g., greater ratio of MTD to starting dose) compared with small molecule. Those were nanoparticles were liposomal vincristine, albumin-bound paclitaxel (Abraxane), and liposomal irinotecan. These agents all exhibit “nonclassical” nanoparticles properties and interesting aspects of their preclinical and clinical results provide rationale for why they can be removed from the analysis.

A study conducted by Zhigaltsev and colleagues, compared drug loading and retention among liposome-encapsulated vinca alkaloids: vincristine, vinblastine, and vinorelbine (40). While vincristine had the greatest percentage of drug retention after a single dose of the 3 tested vinca alkaloids, it had only approximately 56% or 78% drug retention after 24 hours for the 0.1 w/wt and 0.3 wt/wt drug-to-lipid ratio formulations, respectively. This finding is in contrast to preclinical and clinical in vivo data of other liposomal anticancer agents which have a much greaterpercentage of (i.e., 90%–95%) drug retention during the first 24 hours and beyond (22, 41). One of the most compelling examples of low vincristine retention in liposomes comes from a study conducted by Sapra and colleagues, whose objective was to find an effective strategy for treating B-cell malignancies in a murine model of human B-cell lymphoma (42). Long-circulating sterically stabilized immunoliposome formulations of vincristine and doxorubicin were given to these mice. The liposomal vincristine formulation had a much faster drug release rate from the liposomes than liposomal doxorubicin. In addition, after normalization of drug load to lipid amount, the drug to lipid ratio was several fold higher for liposomal doxorubicin than for liposomal vincristine over a 48-hour period (42). Thus, the liposomal vincristine included in this review seems to have rapid CL and release of drug from the carrier and thus does not exhibit classic nanoparticle properties of prolonged circulation of encapsulated drug that is cleared by the MPS. Instead, the vincristine is rapidly released from the liposome and cleared via hepatic metabolism and thus acts more like a small-molecule agent than the other nanoparticles included in this review.

The pharmacokinetics and pharmacodynamics of IHL-305 were also different than other nanoparticless. IHL-305 is a PEGylated liposome formulation of CPT-11. CPT-11 is a prodrug that must be converted to the active moiety SN-38 by carboxylesterase enzymes in vivo (43). The complexity of CPT-11 metabolism goes further, to include active lactone and inactive carboxylate forms of both the CPT-11 and SN-38, which exist at an equilibrium dependent upon pH and binding proteins (44). The complexity of metabolism increases with the involvement of genetic polymorphisms in uridine diphosphate glucuronosyltransferases (UGT) isoform 1A1, (UGT1A1), which is responsible for glucuronidation of SN-38 (45). Therefore, it is unclear whether differences in phase I outcomes are observed due to IHL-305 formulation, or due to the dosing of a prodrug that is dependent upon many factors for metabolism.

The phase I starting dose of albumin-bound paclitaxel was not based on the dog toxicology studies because dogs had a hypersensitivity reaction to human albumin which lead to an early termination of toxicologic studies in dogs (46). Therefore, the starting dose of albumin-bound paclitaxel was based on toxicology studies in nonhuman primates. Dogs seem to be inherently sensitive to the toxicologic effects of nanoparticles, as evidenced through toxicology studies as well as allometric scaling (15). The starting dose of albumin-bound paclitaxel based on toxicity studies in nonhuman primates was most likely higher than would have been determined on the basis of toxicology studies in dogs. Thus, the number of dose levels from the higher starting dose to the MTD of albumin-bound paclitaxel was less than other nanoparticles in the review. This highlights the potential benefits of conducting toxicologic and pharmacologic studies of nanoparticles in nonhuman primates instead of dogs as the nonrodent species of choice.

There are major differences between the design and performance of phase I studies of nanoparticles compared with small molecules. There is a significant difference in the number of dose levels and ratio of MTD to starting dose as well as increased number of patients enrolled and overall costs associated with studies of nanoparticles versus small molecules. These findings indicate that patients are being treated at doses that are very low and unlikely to produce toxicity and/or response. This undoubtedly leads to an inefficient use of patient resources, time, and funding. The potential primary cause of these issues in phase I studies of nanoparticles is that the low starting dose results from the use of an inappropriate toxicology model, which seems to be dogs or the ability to escalate the dose of nanoparticles higher. An alternative nonrodent model such as nonhuman primates may be more suitable.

There is preliminary evidence that suggests that factors associated with the MPS may contribute to nanoparticles pharmacokinetic and pharmacodynamic variability. Thus, there is a compelling need to identify the factors associated with MPS function to improve the preclinical and clinical studies of nanoparticles. It will be essential to further test whether the pharmacokinetics of nanoparticles can be scaled across species using various measurements and surrogates of the MPS, such as monocyte and macrophage activity or function, genetics, complement, or cytokines. In addition, the most appropriate animal models for GLP toxicology studies must be identified. Identification of the correct animal model may drastically decrease the number of dose levels, patients, and costs associated with phase I clinical studies. In addition, there must be exploration into new study designs for phase I studies of nanoparticles, as the unique pharmacology of nanoparticles agents may not be amenable to trial designs established for small molecules.