SAT236 Pharmacokinetics (PK) And Pharmacodynamics (PD) Of The Parathyroid Hormone Analog PTH (1-34) (Teriparatide) Delivered Via An Orally Administered Robotic Pill (RT-102)
Authors: Horlen Kyle , Kaminskaya Kristina , Yamaguchi Alyson , Fung Leonard C , Kennedy Heather , Nguyen Son , Dasari Anvesh , Toledo Vo April , Archana Battiwala , Patel Nidhi , Mohan Deepa , Syed Baber , Dhalla Arvinder K , Imran Mir , Hashim Mir A 
Published: October 2023

Abstract
Disclosure: K. Horlen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. K. Kaminskaya: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Yamaguchi: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. L.C. Fung: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. H. Kennedy: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. S. Nguyen: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Dasari: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A. Toledo Vo: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. B. Archana: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. N. Patel: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. D. Mohan: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. B. Syed: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. A.K. Dhalla: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M. Imran: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics. M.A. Hashim: Employee; Self; Rani Therapeutics. Stock Owner; Self; Rani Therapeutics.
Background: An orally administered robotic pill (RP) protects the drug from digestion during transit through the gastrointestinal tract before painlessly injecting the drug trans-enterically into the peritoneal space. Although parenteral, this unique delivery route can result in altered PK/PD profiles as drug absorption is primarily via mesenteric vasculature which drains into the portal vein. Here we report on two nonclinical studies which, 1) in awake canines, compared the PK profiles of orally delivered teriparatide via the RP (RT-102) versus subcutaneous (SC) injections; and 2) in an ovariectomized (OVX) rat model of osteoporosis, compared the PD (osteoanabolic) effect of intraperitoneal (IP) vs SC administered teriparatide on bone mineral density (BMD).Methods:PK Study: Beagle dogs (n = 43) received a single RT-102 capsule orally containing 20, 40, 80, or 160µg of teriparatide or a SC or intravenous (IV) injection of 20µg of the FDA-approved PTH(1-34) commercial product (Forteo®). Teriparatide concentrations in serial blood samples (collected for up to 300 minutes) were quantitated via a validated ELISA.PD Study: OVX Sprague-Dawley rats (n=50) underwent an 8-week bone depletion period followed by 6-weeks of daily treatment with teriparatide at a dose of 2, 5, or 15 µg/kg via IP injection or 5 µg/kg via SC injection (Forteo®) (n = 10 per treatment). A sham-operated control group received daily saline injections. BMD was assessed via dual-energy X-ray absorptiometry (DXA). Results:PK Study: RT-102 yielded steep increases in serum PTH concentrations followed by rapid declines to baseline levels, similar to the overall PK profile of Forteo® SC. RT-102 yielded more sustained exposures resulting in a prolonged Tmax compared to Forteo® SC (Tmax 37 to 48 vs 21 min). At 80 µg, PK curves of RT-102 tracked closely with SC, albeit with RT-102 yielding higher peak concentrations (Cmax = 3511 vs 1342 pg/mL). PD Study: DXA imaging of whole-body skeleton, femur, femur diaphysis, and lumbar vertebrae showed that intraperitoneally administered teriparatide yielded dose dependent increases in BMD in all areas examined. Animals receiving teriparatide via either IP or SC injections at equivalent doses showed no significant differences in the BMD increases between the two routes of administration. Conclusions: Orally administered RT-102 capsules to canines yielded steep rises in serum teriparatide concentrations followed by rapid elimination within three hours. When administered intraperitonially to mimic RT-102 delivery in a rodent model of osteoporosis, teriparatide was osteoanabolic similar to equivalent drug doses injected SC. These data provide the PK/PD proof-of-concept data for oral RT-102 capsules indicating their potential to replace current injection therapy for the treatment of osteoporosis.
Presentation: Saturday, June 17, 2023