First in Man Studies of Pharmacokinetic Profiles of a Novel Oral PTH(1-34)

Background: PTH(1-34) (Teriparatide) is an anabolic agent used in treatment of osteoporosis. It promotes bone formation and reduces the risk of vertebral and some non-vertebral fractures. The route of administration by daily subcutaneous (sc) injection can cause problems in certain patients. A new oral delivery system for human PTH(1-34) has been developed as a possible treatment option. Galitzer et al. presented pre-clinical data (ASBMR 2012, MO0402) and first-in-human results (ASBMR 2013, FR0378) on safety, tolerability and absorption dynamics of oral PTH(1-34) in various dosages. We now describe the pharmacokinetics (PK) of oral PTH(1-34) compared to sc and placebo in healthy subjects.
Objective: A single-center, double blinded, triple crossover study was designed to compare the 1.8 mg optimal dose of oral PTH(1-34) against standard dosage of teriparatide injection and oral placebo.
Method: The study was conducted following and in accordance with the Hadassah Medical Center ethical approval committee. 12 healthy volunteers (6m/6f), 18-50y, received three treatments: single sc injection of 20µg FORTEO®, 1.8 mg oral PTH(1-34), or placebo. Blood samples were collected at time 0, 10, 15, 20, 30, 45, 60, 75, 90, 120, 180, 240, 300 minute post dose. Plasma concentration of PTH(1-34) (IDS, Tyne and Wear, UK) and cyclic adenosine 3’,5’monophosphate (cAMP) were measured on all samples.
Results: All 12 subjects on oral PTH(1-34) showed rapid, post dose increase then decrease of PTH(1-34), from baseline mean (±SD) of 5.9 (1.8) pg/mL to peak mean of 185.3 (±128.8) pg/mL. PK profiles of oral PTH(1-34) showed Cmax (pg/mL), Tmax (mins), AUC0-last of 238.3 (110.8), 17.5 (5.4) and 6161.7 (2726.7), respectively; whereas sc showed mean Cmax (pg/mL), Tmax (mins), AUC0-last of 172.3 (55.7), 20.8 (8.7) and 13965.9 (2984.8), respectively. Plasma cAMP increased in all subjects in response to oral PTH(1-34) and sc treatment. Serum adjusted calcium in all subjects remained within normal limits throughout the studies.
Conclusion: PK profiles showed a single oral dose of 1.8 mg PTH(1-34) is rapidly absorbed, and no significant difference in Cmax and Tmax when compared with 20µg of sc teriparatide. A significant difference in the rate of plasma clearance and AUC0-last value was observed (fig.1). These differing profiles and modality of administration of PTH(1-34) could offer unique advantages in the treatment of calcium and metabolic bone disorders.