PubChem compound: 145705876
Abaloparatide is a 34 amino acid peptide that shares 41% homology to parathyroid hormone [PTH] and 76% homology to parathyroid hormone related peptide [PTHrP(1-34)], and is an activator of the PTH1 receptor signalling pathway. Abaloparatide stimulates new bone formation on trabecular and cortical bone surfaces by stimulation of osteoblastic activity.
Abaloparatide causes transient and limited increases in bone resorption and increases bone density.
The median (range) time to peak concentration of abaloparatide 80 micrograms was 0.5 h (0.25 to 0.52 h) following subcutaneous administration. The absolute bioavailability of abaloparatide in healthy subjects after subcutaneous administration of 80 micrograms dose was about 39%.
The in vitro plasma protein binding of abaloparatide was approximately 70%. The volume of distribution was approximately 45 L.
No specific metabolism or excretion studies have been performed with abaloparatide. The metabolism of abaloparatide is consistent with non-specific proteolytic degradation into smaller peptide fragments, followed by elimination by renal clearance. In vitro studies showed that abaloparatide, at clinically relevant concentrations, does not inhibit or induce Cytochrome P450 enzymes.
The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects, and the mean half-life of abaloparatide is about 1 h. The peptide fragments are primarily eliminated through renal excretion. Active secretion of abaloparatide in the kidneys cannot be ruled out.
Abaloparatide is not a substrate of the renal transporters P-gp, OAT1, OAT3, OCT2, MATE1 or MATE2K. Furthermore, abaloparatide does not inhibit P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1 and OATP1B3 transporters in vitro at its clinically relevant concentrations.
Abaloparatide systemic exposure was generally increasing with the increase of its subcutaneous doses from 5 micrograms up to 240 micrograms. There was a general tendency towards less than doseproportional increases, and no further increase in abaloparatide systemic exposure was observed as its dose increased to 280 micrograms and 320 micrograms.
Abaloparatide exposure increased with decreasing CrCl. Subjects with mild, moderate and severe renal impairment had Cmax increases of 3%, 28% and 44%, respectively, and AUC increases of 17%, 68% and 113%, respectively, compared to subjects with normal renal function.
No studies have been performed in patients undergoing dialysis for chronic renal failure.
No studies have been performed in patients with hepatic impairment. Abaloparatide is a peptide and not an inhibitor or an inducer of hepatic drug metabolising enzymes. The elimination is through proteolytic degradation and renal excretion, and it is unlikely that hepatic impairment will have any significant effect on abaloparatide exposure. No dose adjustment is needed for these patients.
No age related differences in abaloparatide pharmacokinetics were detected during clinical studies, including postmenopausal women ranging from 49 to 86 years of age.
In a 2-year rat carcinogenicity study, abaloparatide displayed an increase in the overall incidence of osteosarcomas at doses that were 4 times higher than the systemic exposure observed in humans following a subcutaneous dose of 80 micrograms based on AUC comparisons. Neoplastic changes related to the treatment with abaloparatide consisted of dose-dependent increased incidence of osteosarcomas and osteoblastomas. The incidence and earliest occurrence of tumours was similar in both male and female rats. The relevance of these rat findings to humans is uncertain, thus the use of abaloparatide should be avoided for patients at increased risk of osteosarcoma.
In toxicology studies in rats and monkeys, findings included soft tissue mineralization at doses that were approximately 2 and 3 times, respectively, the exposure in humans at daily subcutaneous doses of 80 micrograms.
Subcutaneous administration of abaloparatide at doses that were approximately 0.3, 2.4 and 3.8 times the exposure in humans at daily subcutaneous doses of 80 micrograms to the conscious dog produced a dosedependent transient increase in heart rate lasting approximately 3 hours, had marginal effects on mean arterial blood pressure. Additionally, abaloparatide had marginal effects on the QTc interval, with a nonsignificant tendency towards a decrease in QTc with increasing dose, which is consistent with its minimal effects on hERG potassium currents and Purkinje fibres at clinically relevent concentrations.
Abaloparatide was not genotoxic or mutagenic in a standard battery of tests.
No embryofoetal development or pre/postnatal development studies have been conducted in female animals because the intended population for abaloparatide is postmenopausal women. Effects on male fertility were evaluated in rats, and no impact on male fertility was observed at doses 27 times the exposure in humans at daily subcutaneous doses of 80 micrograms.
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