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

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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

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Osteoporosis		••••••••••••		•••• •••• •• ••••••••	•••••••••
Management of	Osteoporosis		••••••••••••		•••••• •••••••••••• •••••••	•••••••••
Management of	Osteoporosis		••••••••••••		••••••••••• •••• •••••••••••• •••••••	•••••••••
Management of	Osteoporosis		••••••••••••	••••••••••••••	•••• •••• •• ••••••••	•••••••••
Management of	Osteoporosis		••••••••••••	••••••••••••••	••••••••••• •••• •••••••••••• •••••••	•••••••••

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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 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.^4,6 Abaloparatide binds to the PTH1R in target cells to activate the G_s-protein-mediated cAMP signalling pathway, thereby stimulating osteoblastic activity.^2,7 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.^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

Target	Actions	Organism
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) C_max was 812 (118) pg/mL and the AUC_0-24 was 1622 (641) pgxhr/mL. The median T_max 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

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
Integrate drug-drug interactions in your software
Acebutolol	The risk or severity of adverse effects can be increased when Acebutolol is combined with Abaloparatide.
Aldesleukin	The risk or severity of adverse effects can be increased when Aldesleukin is combined with Abaloparatide.
Aliskiren	The risk or severity of adverse effects can be increased when Abaloparatide is combined with Aliskiren.
Ambrisentan	Abaloparatide may increase the hypotensive activities of Ambrisentan.
Amifostine	The risk or severity of adverse effects can be increased when Amifostine is combined with Abaloparatide.

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

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Eladynos	Injection, solution	80 mcg/40mcl	Subcutaneous	Theramex Ireland Limited	2023-02-08	Not applicable
Tymlos	Injection, solution	3.12 mg/1.56mL	Subcutaneous	Radius Health, Inc.	2017-05-01	Not applicable

Categories

ATC Codes

H05AA04 — Abaloparatide

• H05AA — Parathyroid hormones and analogues
• H05A — PARATHYROID HORMONES AND ANALOGUES
• H05 — CALCIUM HOMEOSTASIS
• H — SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES AND INSULINS

Drug Categories

• Amino Acids, Peptides, and Proteins
• Analogs/Derivatives
• Biological Factors
• Bone Density Conservation Agents
• Calcium Homeostasis
• Hormones
• Hormones, Hormone Substitutes, and Hormone Antagonists
• Hypotensive Agents
• Intercellular Signaling Peptides and Proteins
• Parathyroid Hormone-Related Protein
• Parathyroid Hormones and Analogues
• Peptide Hormones
• Peptides
• Proteins
• Systemic Hormonal Preparations, Excl. Sex Hormones and Insulins
• Thyroid Products

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]

External Links

PubChem Substance

347909937

ChemSpider

34443170

BindingDB

50246337

RxNav

1921069

ChEMBL

CHEMBL4084894

Wikipedia

Abaloparatide

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Arthroplasties, Replacement, Knee / Osteoporosis	1
4	Not Yet Recruiting	Treatment	Femoral Fractures	1
4	Recruiting	Treatment	Postmenopausal Osteoporosis	1
3	Completed	Treatment	Osteoporosis / Osteoporosis (Senile) / Osteoporosis Fracture / Osteoporosis Localized to Spine / Osteoporosis of Vertebrae / Osteoporosis Risk / Osteoporosis, Age Related / Postmenopausal Osteoporosis	1
3	Completed	Treatment	Osteoporosis / Osteoporosis (Senile) / Osteoporosis Localized to Spine / Osteoporosis of Vertebrae / Osteoporosis, Age Related	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Subcutaneous	80 mcg
Injection, solution	Subcutaneous	80 mcg/40mcl
Injection, solution	Subcutaneous	3.12 mg/1.56mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US8148333	No	2012-04-03	2027-11-08
US7803770	No	2010-09-28	2028-03-26
US8748382	No	2014-06-10	2027-10-03
US10996208	No	2021-05-04	2038-04-30
US11255842	No	2020-01-10	2040-01-10
USRE49444	No	2011-04-28	2031-04-28
US11680942	No	2020-01-10	2040-01-10
US11782041	No	2018-04-30	2038-04-30

Properties

State

Solid

Experimental Properties

Property	Value	Source
water solubility	Soluble	Not Available

Targets

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insights and accelerate drug research.

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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]

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