NAV

Abaloparatide

Identification

Summary

Abaloparatide is a parathyroid hormone-related protein (PTHrP) analog used for the treatment of osteoporosis in patients with a high risk of fracture.

Brand Names
Tymlos
Generic Name
Abaloparatide
DrugBank Accession Number
DB05084
Background

Abaloparatide is an N-terminal analog of parathyroid hormone-related protein (PTHrP) 4 and an agonist at the parathyroid hormone type 1 (PTH1) receptor.7 It is a synthetic 34 amino acid peptide with 41% homology to human parathyroid hormone 1-34 and human PTHrP 1-34.7 Abaloparatide and PTHrP share the first 21 amino acids and the receptor-activating domain.4

Abaloparatide is an osteoanabolic agent that stimulates bone formation.7 It was first approved by the FDA on April 28, 2017,1 for the treatment of osteoporosis in postmenopausal women and is also used to increase bone density in men with osteoporosis.7 In October 2022, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended abaloparatide be granted marketing authorization in Europe 8 and the drug was fully authorized by the European Commission on December 19, 2022.10

Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Hormones
Protein Chemical Formula
C174H300N56O49
Protein Average Weight
3961.0 Da
Sequences
>Abaloparatide N-terminal peptide sequence
AVSEHQLLHDKGKSIQDLRRRELLEKLLXKLHTA
References:
  1. FDA Approved Drug Products: TYMLOS (abaloparatide) injection, for subcutaneous use (December 2022) [Link]
Download FASTA Format
Synonyms
  • Abaloparatide
External IDs
  • BA-058
  • BA058
  • BIM-44058
  • BIM44058

Pharmacology

Indication

Abaloparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) 7,9 or patients who have failed or are intolerant to other available osteoporosis therapy.7 In postmenopausal women with osteoporosis, abaloparatide reduces the risk of vertebral and nonvertebral fractures.7

Abaloparatide is also indicated to increase bone density in men with osteoporosis at high risk for fracture (defined as a history of osteoporotic fracture or multiple risk factors for fracture) or patients who have failed or are intolerant to other available osteoporosis therapy.7

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Associated Conditions
Contraindications & Blackbox Warnings
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Pharmacodynamics

Abaloparatide stimulates bone formation on periosteal, trabecular, and cortical bone surfaces.2 It increases bone mineral density and bone formation markers in a dose-dependent manner.1,7 Abaloparatide causes transient and limited increases in osteoclast bone resorption and increases bone density.2,9 In rats and monkeys, abaloparatide exerted anabolic effects, increasing bone mineral density and mineral content correlating with increases in bone strength at vertebral and nonvertebral sites.7

Mechanism of action

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.6 The PTH1R couples to Gs and Gq, which stimulates adenylyl cyclase (AC), which activates the cAMP/PKA signalling cascade, and phospholipase C (PLC), which activates the IP/PKC signalling cascade.4,6 Abaloparatide binds to the PTH1R in target cells to activate the Gs-protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity.2,7 Abaloparatide also activates Gq 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.2,4,5

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.3 Conversely, the RG conformation is G-protein–dependent (GTPγS-sensitive) with a shorter signalling response.3,4 Abaloparatide binds to the RG conformation with greater selectivity:3,2 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.1,2

TargetActionsOrganism
AParathyroid hormone/parathyroid hormone-related peptide receptor
agonist
Humans
Absorption

The absolute bioavailability of abaloparatide in healthy women after subcutaneous administration of an 80 mcg dose was 36%. Following subcutaneous administration of 80 mcg abaloparatide in postmenopausal women with osteoporosis for seven days, the mean (SD) Cmax was 812 (118) pg/mL and the AUC0-24 was 1622 (641) pgxhr/mL. The median Tmax was 0.51 hours, with a range from 0.25 to 0.52 hours.7

Volume of distribution

The volume of distribution was approximately 50 L.7

Protein binding

In vitro, abaloparatide was approximately 70% bound to plasma proteins.7

Metabolism

Abaloparatide is metabolized into smaller peptide fragments via non-specific proteolytic degradation.7

Route of elimination

The peptide fragments of abaloparatide are primarily eliminated through renal excretion.7

Half-life

The mean half-life of abaloparatide is approximately one hour.7

Clearance

The mean apparent total plasma clearance for subcutaneous administration is 168 L/h in healthy subjects.9

Adverse Effects
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Toxicity

The LD50 in rats and mice following intravenous or subcutaneous administration was 42 mg/kg.11

One clinical study reported an accidental overdose in a patient who received 400 mcg in one day, which is five times the recommended clinical dose. This patient experienced asthenia, headache, nausea, and vertigo. Serum calcium was not assessed on the day of the overdose, but on the following day, the patient’s serum calcium was within the normal range. Other symptoms of overdose may include hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension, and headache. Since there is no specific antidote for abaloparatide overdose, it is recommended that overdose is managed with drug discontinuation, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures, such as hydration. Based on the molecular weight, plasma protein binding and volume of distribution, abaloparatide is not expected to be dialyzable.7

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
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interactions in your software
AcebutololThe risk or severity of adverse effects can be increased when Acebutolol is combined with Abaloparatide.
AldesleukinThe risk or severity of adverse effects can be increased when Aldesleukin is combined with Abaloparatide.
AliskirenThe risk or severity of adverse effects can be increased when Abaloparatide is combined with Aliskiren.
AmbrisentanAbaloparatide may increase the hypotensive activities of Ambrisentan.
AmifostineThe risk or severity of adverse effects can be increased when Amifostine is combined with Abaloparatide.
AmilorideThe risk or severity of adverse effects can be increased when Amiloride is combined with Abaloparatide.
AmiodaroneThe risk or severity of adverse effects can be increased when Amiodarone is combined with Abaloparatide.
AmlodipineThe risk or severity of adverse effects can be increased when Amlodipine is combined with Abaloparatide.
AmobarbitalAmobarbital may increase the hypotensive activities of Abaloparatide.
Amphotericin BThe risk or severity of adverse effects can be increased when Amphotericin B is combined with Abaloparatide.
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Food Interactions
  • Administer vitamin supplements. If dietary intake is inadequate, patients should receive supplemental calcium and vitamin D.
  • Take at the same time every day.
  • Take with or without food.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
TymlosInjection, solution2000 ug/1mLSubcutaneousRadius Health, Inc.2017-05-01Not applicableUS flag

Categories

ATC Codes
H05AA04 — Abaloparatide
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
AVK0I6HY2U
CAS number
247062-33-5

References

General References
  1. Shirley M: Abaloparatide: First Global Approval. Drugs. 2017 Aug;77(12):1363-1368. doi: 10.1007/s40265-017-0780-7. [Article]
  2. Akel M, Parmar M: Abaloparatide. . [Article]
  3. Hattersley G, Dean T, Corbin BA, Bahar H, Gardella TJ: Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling. Endocrinology. 2016 Jan;157(1):141-9. doi: 10.1210/en.2015-1726. Epub 2015 Nov 12. [Article]
  4. Bhattacharyya S, Pal S, Chattopadhyay N: Abaloparatide, the second generation osteoanabolic drug: Molecular mechanisms underlying its advantages over the first-in-class teriparatide. Biochem Pharmacol. 2019 Aug;166:185-191. doi: 10.1016/j.bcp.2019.05.024. Epub 2019 May 25. [Article]
  5. Wang MW, Yang Z, Chen X, Zhou SH, Huang GL, Sun JN, Jiang H, Xu WM, Lin HC, Yu X, Sun JP: Activation of PTH1R alleviates epididymitis and orchitis through Gq and beta-arrestin-1 pathways. Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2107363118. doi: 10.1073/pnas.2107363118. [Article]
  6. Bastepe M, Turan S, He Q: Heterotrimeric G proteins in the control of parathyroid hormone actions. J Mol Endocrinol. 2017 May;58(4):R203-R224. doi: 10.1530/JME-16-0221. [Article]
  7. FDA Approved Drug Products: Tymlos (abaloparatide) for subcutaneous injection [Link]
  8. EMA Summary of Opinion: Eladynos (abaloparatide) [Link]
  9. EMA Approved Drug Products: Eladynos (abaloparatide) Subcutaneous Injection [Link]
  10. Radius Health: European Commission Approves ELADYNOS (Abaloparatide) for the Treatment of Osteoporosis in Postmenopausal Women at Increased Risk of Fracture [Link]
  11. The Center for Drug Evaluation and Research: Abaloparatide Pharmacology Review [Link]
PubChem Substance
347909937
ChemSpider
34443170
BindingDB
50246337
RxNav
1921069
ChEMBL
CHEMBL4084894
Wikipedia
Abaloparatide

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Not Yet RecruitingTreatmentFemoral Fractures1
4RecruitingTreatmentArthroplasties, Replacement, Knee / Osteoporosis1
4RecruitingTreatmentPostmenopausal Osteoporosis1
3CompletedTreatmentOsteoporosis / Osteoporosis (Senile) / Osteoporosis Localized to Spine / Osteoporosis of Vertebrae / Osteoporosis Risk / Osteoporosis Vertebral / Osteoporosis, Age Related / Osteoporotic Fractures / Postmenopausal Osteoporosis1
3CompletedTreatmentOsteoporosis / Osteoporosis (Senile) / Osteoporosis Localized to Spine / Osteoporosis of Vertebrae / Osteoporosis, Age Related1
3CompletedTreatmentOsteoporosis / Postmenopausal Osteoporosis1
3CompletedTreatmentPostmenopausal Osteoporosis1
2CompletedTreatmentOsteoporosis1
2CompletedTreatmentPostmenopausal Osteoporosis1
2RecruitingTreatmentFracture of Pelvis (Disorder)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
Injection, solutionSubcutaneous2000 ug/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US8148333No2012-04-032027-11-08US flag
US7803770No2010-09-282028-03-26US flag
US8748382No2014-06-102027-10-03US flag
US10996208No2021-05-042038-04-30US flag
US11255842No2020-01-102040-01-10US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
water solubilitySolubleNot Available

Targets

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Details1. Parathyroid hormone/parathyroid hormone-related peptide receptor
Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Protein self-association
Specific Function
This is a receptor for parathyroid hormone and for parathyroid hormone-related peptide. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and also a phosphatid...
Gene Name
PTH1R
Uniprot ID
Q03431
Uniprot Name
Parathyroid hormone/parathyroid hormone-related peptide receptor
Molecular Weight
66359.98 Da
References
  1. Jolette J, Attalla B, Varela A, Long GG, Mellal N, Trimm S, Smith SY, Ominsky MS, Hattersley G: Comparing the incidence of bone tumors in rats chronically exposed to the selective PTH type 1 receptor agonist abaloparatide or PTH(1-34). Regul Toxicol Pharmacol. 2017 Apr 4;86:356-365. doi: 10.1016/j.yrtph.2017.04.001. [Article]
  2. Hattersley G, Dean T, Corbin BA, Bahar H, Gardella TJ: Binding Selectivity of Abaloparatide for PTH-Type-1-Receptor Conformations and Effects on Downstream Signaling. Endocrinology. 2016 Jan;157(1):141-9. doi: 10.1210/en.2015-1726. Epub 2015 Nov 12. [Article]
  3. FDA Approved Drug Products: Tymlos (abaloparatide) for subcutaneous injection [Link]
  4. EMA Approved Drug Products: Eladynos (abaloparatide) Subcutaneous Injection [Link]

Drug created at October 21, 2007 22:23 / Updated at February 02, 2023 07:21