Abaloparatide 80micrograms/40microlitres solution for injection 1.5ml pre-filled disposable devices

Abaloparatide is an agonist at the PTH1 receptor (PTH1R), a G-protein-coupled receptor (GPCR) that regulates bone formation and bone turnover, as well as mineral ion homeostasis.[A256793] The PTH1R couples to G_s and G_q, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade.[A256778][A256793] Abaloparatide binds to the PTH1R in target cells to activate the G_s-protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity.[A256753][L740] Abaloparatide also activates G_q and β-arrestin-1 pathway downstream of PTH1R as off-targets in target cells such as the testis and epididymis, which have been associated with anti-inflammatory effects and alleviation of epididymitis and orchitis symptoms.[A256753][A256778][A256783]

The PTH1R has two conformations with distinct ligand binding profiles. The R⁰ conformation is a G protein–independent high-affinity conformation, and upon binding, the ligand induces a longer-lasting signalling response that gradually increases cAMP. Due to the prolonged signalling response, ligands selectively binding to the R⁰ conformation are associated with a risk for increased calcium mobilization and hypercalcemia.[A19105] Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response.[A19105][A256778] Abaloparatide binds to the RG conformation with greater selectivity:[A19105][A256753] it induces more transient signalling responses and favours net bone formation over bone resorption. The drug's relatively low risk for hypercalcemia and osteoclast resorption compared to [teriparatide] is attributed to the preferential binding of abaloparatide to the RG conformation.[A256748][A256753]