A subcutaneous depot formulation of octreotide has a rapid onset, greater bioavailability, and a similar duration of effect compared with intramuscular octreotide long-acting repeatable (LAR). The pharmacokinetics and pharmacodynamics of subcutaneous octreotide were compared with those of octreotide LAR in a randomized phase I study, the results of which were presented by John Roberts, PhD, at the 2014 Neuroendocrine Tumor Symposium.
Octreotide is a somatostatin analogue that is widely used for the long-term treatment of severe diarrhea and flushing associated with advanced neuroendocrine tumors. Octreotide AR is a long-acting formulation administered monthly, but it requires a multistep reconstitution process and intragluteal injection.
According to Roberts, a clinical oncology pharmacist at Novartis, which manufactures octreotide, the subcutaneous formulation offers several advantages over LAR that enhance convenience. It is a ready-to-use formulation that allows self- or partner administration using prefilled syringes. The subcutaneous injection uses a thinner needle (thin-walled 22-gauge x 16 mm) and the volume to inject is significantly smaller compared with octreotide LAR (0.5-1.0 mL vs 2.0-2.5 mL).
“We believe that [the subcutaneous depot formulation] is going to provide the opportunity for individualized dosing and interval and offer enhanced convenience when administered through the prefilled syringe,” Roberts said.
In the phase I trial, liquid content of octreotide was injected at a 45-degree angle into subcutaneous tissue. “It forms a gel-like liquid crystal depot in situ, which rapidly encapsulates the octreotide,” said Roberts. Once it forms, the depot begins to biodegrade, resulting in continuous release of octreotide into the circulation. The study compared three octreotide test formulations with intramuscular octreotide LAR, evaluating the pharmacokinetic/pharmacokinetic (PK/PD) profiles and the safety and tolerability of each.
One hundred twenty-two healthy adults entered a screening phase in which they received a single 200-µg dose of subcutaneous octreotide (immediate release). Individuals were then randomized 1 week later to one of four arms (three injections of subcutaneous octreotide at 10, 20, or 30 mg/month, or octreotide LAR at 30 mg/month). Blood samples for octreotide and insulin-like growth factor-1 (IGF-1) analyses were collected pre- and post-injection, and at prespecified time points during the study.
“Octreotide subcutaneous demonstrated a robust PK/PD response across doses,” said Roberts. “We think it gets to a steady state faster than the octreotide LAR. What you see is an early peak at about 24 hours in terms of octreotide concentration,” he said. “We’re seeing about an 18-hour half life. The max effect translates to a 5-day peak.” The subcutaneous depot formulation had a sustained release of 2 to 4 weeks.
Octreotide concentrations for the subcutaneous depot (30 mg) formulation “equaled or exceeded those for octreotide LAR over the dosing interval on a dose-matched basis,” he said. Bioavailability was about five-fold higher with the subcutaneous depot formulation with similar Ctrough
, “which is what’s driving the pharmacologic threshold toward the end of the dosing intervals. That’s the key overall—the later Ctrough
that we’re trying to optimize in terms of later trial design,” said Roberts.
Octreotide subcutaneous depot at 30 mg also demonstrated a more rapid and greater suppression of IGF-1 after the first injection compared with octreotide LAR. IGF-1 suppression was similar after the second and third injections.
Adverse events were more frequent overall with the subcutaneous depot formulation compared with octreotide LAR. The rate of adverse events ranged from 71% to 100% across the formulations, said Roberts, with 71% of subjects randomized to octreotide LAR and 86% to 100% randomized to octreotide subcutaneous depot reporting an adverse event.
The most frequent adverse events for all formulations were mild-to-moderate gastrointestinal event, headache, and administration–site reactions. Six of the 122 subjects had adverse events that led to study discontinuation, which occurred after the first or second injection.
“Getting an intramuscular injection once a month for several years can be hard on patients in terms of their quality of life, and a subcutaneous injection with a little less fluid that you’re injecting could be helpful for our patients,” commented Diane Reidy-Lagunes, MD, a gastrointestinal oncologist at Memorial Sloan Kettering Cancer Center. “If anything, it’s probably the same, if not a little better, when it comes to PK/PD. Certainly, we need more data to confirm the safety but, it’s promising for the ease for the patient. Cost is going to be an issue.”
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