SUN-LB47 Extended Release Octreotide Pharmacokinetics in Healthy Subjects After Subcutaneous Injection of MTD201

Abstract

An open-label, randomised, single-dose Phase I study in healthy subjects evaluated octreotide pharmacokinetics after deep-intramuscular (IM) or subcutaneous (SC) injection of MTD201 (30mg). All subjects received Sandostatin® (100μg immediate release; SIR) by deep SC injection 24h before MTD201. MTD201 is manufactured by Q-Sphera™ printing technology to minimize particle size variation and afford simpler reconstitution and less painful injection via a 21G needle. Plasma octreotide concentrations were measured over 63 days to ascertain the potential for a 6- to 8-week dosing interval. MTD201 is being developed as a next generation long-acting somatostatin analogue for maintenance management of acromegaly and neuroendocrine cancer patients. Methods: 28 healthy subjects were randomised to two groups. The reference product SIR (100μg) was injected SC, followed 24 hours later by MTD201 administered by either IM (n=14, 38mm 21G needle) or SC (n=14, 16mm 21G needle) injection. MTD201 was resuspended in WFI to give a final injection volume of 1.5mL. Plasma samples for determination of octreotide and serum samples for IGF-1 and GH levels were drawn pre-dose and over the 63-days post-dosing. Injection site reactions and AEs were recorded, scored and compared across groups. Results: MTD201 was very well tolerated by both groups with 3 mild TEAEs observed per group. Transient and mild injection site reactions were similar after all treatments. Upon MTD201 injection, a low initial burst of octreotide (<1ng/mL) was followed by a sustained period of release that extended beyond the final sampling point at Day 63. Cmax values of 5.42ng/mL (SC) and 3.68ng/mL (IM) were within the plasma exposure range reported for marketed octreotide products. Octreotide bioavailability was 47% (IM) and 62% (SC) relative to SIR. Sustained suppression of IGF-1 concentration was achieved throughout the study period to similar levels for both groups. Octreotide PK profiles and overall exposures were similar between groups, indicating that these routes may be interchangeable in clinical use.Conclusions: MTD201 (30mg) by either IM or SC injection produced continuous octreotide release over a period of at least 63 days at levels predicted to maintain efficacious plasma concentrations at steady state with a dosing interval of up to 8 weeks. Reduced plasma IGF-1 concentrations were maintained throughout the study period. Unlike marketed octreotide depot products, MTD201 can be simply and rapidly reconstituted in WFI to give a stable suspension injectable via 21G needle in a 1.5mL volume. MTD201 can be developed as an easy to inject SC or IM depot for acromegaly and NETs, with an expected dose interval of 8 weeks, and confirmed patient-centric advantages.