Sandostatin® LAR® is a long-acting repeatable formulation of octreotide. Its development required extensive analytical support to ensure the quality and consistency of the formulation. Clinical PK studies have established that Sandostatin LAR produces a reliable, sustained release of octreotide [4, 5], with proven therapeutic utility in patients [3, 6, 7]. More recently, other long-acting formulations of octreotide have been introduced in selected markets.
In humans, Sandostatin LAR has a well-characterized consistent and predictable PK profile, which can be described as exhibiting three distinct phases: (1) release of surface-absorbed octreotide (burst); (2) pore diffusion, biodegradation, osmotic swelling and ionic interactions (erosion phase leading to a drug concentration plateau); and (3) fragmentation and complete biodegradation of the polymer (erosion phase leading to complete drug release) . This tripartite pattern has been regularly observed and is evident with various Sandostatin LAR doses. Octreotide concentrations exhibited an initial peak on day 1, followed by a decline over the following 3-5 days, before slowly increasing and reaching a plateau 2-3 weeks post injection before declining . The steady-state PK simulation of Sandostatin LAR 20 mg suggested a mean concentration of 1216 pg/mL (range, 1065-1585 pg/mL) with a fluctuation index of 43%. Additionally, inter-subject variability in mean Cmax was 32% for Sandostatin LAR 20 mg .
During the in vivo rabbit PK evaluations in the present study, differences in the concentration-time profile between formulations A, B and C, and Sandostatin LAR, were observed. The Sandostatin LAR concentration-time profiles in these in vivo investigations were similar to those observed in humans . During the burst phase, the three other formulations displayed AUC0-2d values ranging from 2.39-65.3 d·ng/mL, compared with 4.42 d·ng/mL for Sandostatin LAR. This variability may result from the appearance of the microparticles, and poses potential safety risks. This finding was particularly evident in formulation A, with 41% of the overall AUC achieved within the first 2 days after injection. Formulations A and B also demonstrated much lower concentrations of octreotide, while formulation C was characterized by an early and narrow erosion phase with no discernable plateau. As such, in addition to potential safety concerns related to the large burst phase, the formulations may also fail to consistently deliver therapeutic concentrations of octreotide to patients throughout the interval between injections.
It is important to note the constraints of our study that limit the interpretation of our findings. First, in vivo rabbit PK data do not always accurately reflect, and cannot replace, clinical PK studies in humans. A rabbit PK profile similar to that of Sandostatin LAR is not proof of clinical bioequivalence to Sandostatin LAR and cannot replace demonstrating human bioequivalence. This underlines the importance of performing clinical PK studies in all new depot delivery systems of octreotide. Second, clinical studies have to demonstrate equivalent safety and efficacy in specific indications; target patient populations include those with acromegaly or neuroendocrine tumors. In addition, although the in vivo study described here was designed to evaluate the formulations in an equal number of rabbits per cohort, needle clogging in formulation B caused one animal to be excluded from analysis and one animal to receive part of the intended sample amount. Furthermore, only a small quantity of formulation C was available and, therefore, this sample could be evaluated only in three rabbits. A further study with a larger sample size would strengthen the evidence presented here. Finally, disparities in study design should be taken into account: differences in serum sample time points between formulations occurred because of resource availability and the fact that the in vivo evaluations of different formulations were performed on different calendar dates. Nevertheless, it is reasonable to compare the kinetic profile of the formulations because the serum sample times covered the long in vivo release profile expected in these products.
Sandostatin LAR consists of octreotide acetate encapsulated and uniformly distributed within PLGA D-(+) glucose microspheres. Slow release of the drug occurs as the polymer biodegrades, primarily through hydrolysis. The polymer has an average molecular weight of ~52 kDa and the microparticles exhibit a mean diameter of ~50 μm .
Compared with the established characteristics of Sandostatin LAR, formulations A and C exhibited greater irregularity in microparticle shape and size. This is suggestive of inadequately encapsulated octreotide molecules and may indicate a lack of quality control in the manufacturing process. Variations in the diameter of the microspheres and the thickness of the polymer coat in formulations B and C have the potential to affect the drug-release profile , with possible failure to deliver continuous therapeutic drug concentrations, and/or can potentially cause adverse events related to excessive drug release during the initial burst phase. In addition, differences in the mannitol appearance were observed between the formulations. Since mannitol is used to improve flow and dispersability and to improve stability in drug delivery systems, it could be postulated that changes in its appearance could affect the pharmaceutical processability of PLGA-based drug delivery systems as well as the preparation of the drug for administration.
Factors such as the molecular weight and composition of the PLGA polymer also affect drug release, with low molecular weight accelerating the rate of drug release and a high lactide:glycolide ratio causing the polymer to degrade more slowly because the lactide monomer is more hydrophobic than the glycolide monomer. In previous studies of octreotide release from PLGA polymers of various molecular weights and lactide:glycolide ratios, pH and impurity content also influenced the percentage of octreotide release [10, 11]. Although the very low molecular weight in formulations A and C may be in part offset by a higher amount of lactide monomer, the differences in molecular weights and lactide:glycolide ratios between the three formulations are likely to cause different octreotide release patterns. As PLGA polymers are routinely used in sustained-release formulations and can be manufactured to a much higher purity than that present in formulation B, the polymer can be considered to be of poor quality. Variability was further evident in the porosity of microparticles in formulations A and B. Previous studies have found that biodegradation and drug release are dependent on the porosity, with variations affecting the rate of drug mobility .
The high tin concentration found in formulation B may indicate that high amounts of tin(II)-octoate were used in the polymer synthesis without proper purification, likely to be due to residual product from the catalyst used during production of the polymer. As tin(II)-octoate has been reported to be highly cytotoxic, this may affect patient safety. This impurity was not observed in Sandostatin LAR or formulation A and no arsenic content was found in any sample. Quality control to guarantee these characteristics is paramount to LAR formulations. In addition, formulations A and B had a low acid component to the octreotide salt. Theoretically, in the case of an acid-base pair, the ratio of acetate molecules to octreotide molecules should be 2:1. In these formulations, octreotide is likely to be present as a free base rather than as an acetate salt indicating that the other formulations do not share the same product characteristics as Sandostatin LAR.
In conclusion, clear differences were seen between Sandostatin LAR and formulations A, B and C, including significant differences in the PK profile, and variations in microparticle size, shape molecular weight, acid:base ratio, and impurity content. These findings suggest that other long-acting octreotide formulations may have a different drug-release pattern to that of Sandostatin LAR despite similar composition. Considering these differences, formulations A, B and C are most likely not bioequivalent to Sandostatin LAR in humans. Consequently, the safety and efficacy of these new formulations cannot be inferred from the Sandostatin LAR clinical and safety profile. Each of these other formulations should be assessed by appropriate clinical studies to determine their clinical benefit and safety profiles.