Abaloparatide

Identification

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Name
Abaloparatide
Accession Number
DB05084
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Hormones
Description

Abaloparatide is an analog of PTHrP (parathyroid hormone-related protein). It was approved in April 28, 2017 by the FDA (as Tymlos) for the treatment of postmenopausal women with osteoporosis at high risk for fracture. Abaloparatide is a synthetic peptide that is related to hPTHrP and has demonstrated in preclinical testing the potential to widen the anabolic window for bone therapeutics, stimulating bone formation with a limited effect on bone resorption and mineral mobilization. This could enable improved convenience over currently available anabolic therapies, resulting in greater compliance and, ultimately, greater benefit to patients.

Protein chemical formula
C174H300N56O49
Protein average weight
3961.0 Da
Sequences
>Abaloparatide N-terminal peptide sequence
AVSEHQLLHDKGKSIQDLRRRELLEKLLXKLHTA
Download FASTA Format
Synonyms
Not Available
External IDs
BA-058 / BA058 / BIM-44058 / BIM44058
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
TymlosInjection, solution2000 ug/1mLSubcutaneousRadius Health, Inc.2017-05-01Not applicableUs
Additional Data Available
  • Application Number
    Application Number

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  • Product Code
    Product Code

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Categories
UNII
AVK0I6HY2U
CAS number
247062-33-5

Pharmacology

Indication

Investigated for use/treatment in postmenopausal osteoporosis to reduce vertebral and/or non-vertebral fractures.

Associated Conditions
Pharmacodynamics

Abaloparatide (BA058), a proprietary analog of human parathyroid hormone-related protein (hPTHrP), is currently undergoing clinical trials by the company for the treatment of osteoporosis in postmenopausal women. PTHrP is a critical peptide for promoting new bone formation, with a distinct role from parathyroid hormone, or PTH, which primarily regulates calcium homeostasis and bone resorption. Clinical studies show increased bone mineral density (BMD) and levels of bone formation markers in a dose-response relationship.

Mechanism of action

In target cells, abaloparatide acts as an agonist on PTH type 1 receptor (PTH1R) and activates both G protein–mediated cAMP signaling and β-arrestin-mediated ERK-1/2 signaling pathways with similar potency [A19105]. Abaloparatide binds to RG conformation of PTH1R with greater selectivity that results in more transient cell signalling responses.

TargetActionsOrganism
AParathyroid hormone/parathyroid hormone-related peptide receptor
ligand
Humans
Additional Data Available
Adverse Effects

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Contraindications

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Blackbox Warnings

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Absorption

The time it takes to reach peak concentration following subcutaneous administration of 80 mcg abaloparatide ranges from 0.25 to 0.52 hr, with the median time of 0.51hr. The bioavailability in healthy women is 36% following administration.

Volume of distribution

Vd is approximately 50L.

Protein binding

In vitro plasma protein binding is approximately 70%.

Metabolism

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

Route of elimination

Metabolized products are mainly eliminated via renal excretion. Patients with severe renal impairment should be monitored with increased risk of adverse effects however there are no recommended dosage adjustments in patients with mild, moderate or severe renal impairment.

Half life

The mean (SD) half-life if 1.7 (0.7) hrs.

Clearance
Not Available
Toxicity

Abaloparatide has shown to induce higher incidences of osteosarcoma in a dose-dependent manner in a 2 year carcinogenicity study with female and male rats. This correlation is not known to be reflected in humans, however patients with increased risk of osteosarcoma including Paget's disease, open epiphyses, and skeletal malignancies should avoid this treatment. Abaloparatide may also cause hypercalcemia so should be avoided in patients with pre-existing conditions of primary hyperthyroidism or hypercalcemia. Overdose is commonly associated with hypercalcemia, nausea, vomiting, dizziness, tachycardia, orthostatic hypotension and headache. There is no known antidote for abaloparatide.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinAbaloparatide may increase the anticoagulant activities of (R)-warfarin.
(S)-WarfarinAbaloparatide may increase the anticoagulant activities of (S)-Warfarin.
2,5-Dimethoxy-4-ethylamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylamphetamine is combined with Abaloparatide.
2,5-Dimethoxy-4-ethylthioamphetamineThe risk or severity of adverse effects can be increased when 2,5-Dimethoxy-4-ethylthioamphetamine is combined with Abaloparatide.
3-isobutyl-1-methyl-7H-xanthineThe serum concentration of 3-isobutyl-1-methyl-7H-xanthine can be increased when it is combined with Abaloparatide.
4-Bromo-2,5-dimethoxyamphetamineThe risk or severity of adverse effects can be increased when 4-Bromo-2,5-dimethoxyamphetamine is combined with Abaloparatide.
4-hydroxycoumarinAbaloparatide may increase the anticoagulant activities of 4-hydroxycoumarin.
6-O-benzylguanineThe serum concentration of 6-O-benzylguanine can be increased when it is combined with Abaloparatide.
7-DeazaguanineThe serum concentration of 7-Deazaguanine can be increased when it is combined with Abaloparatide.
7,9-DimethylguanineThe serum concentration of 7,9-Dimethylguanine can be increased when it is combined with Abaloparatide.
Additional Data Available
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Food Interactions
Not Available

References

General References
  1. Chew CK, Clarke BL: Abaloparatide: Recombinant human PTHrP (1-34) anabolic therapy for osteoporosis. Maturitas. 2017 Mar;97:53-60. doi: 10.1016/j.maturitas.2016.12.003. Epub 2016 Dec 15. [PubMed:28159062]
  2. Gonnelli S, Caffarelli C: Abaloparatide. Clin Cases Miner Bone Metab. 2016 May-Aug;13(2):106-109. Epub 2016 Oct 5. [PubMed:27920805]
  3. TYMLOS (abaloparatide) injection Label [Link]
  4. Radius Health, Inc. Pipeline [Link]
External Links
PubChem Substance
347909937
ChemSpider
34443170
ChEMBL
CHEMBL3301581
Wikipedia
Abaloparatide
FDA label
Download (1.51 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1RecruitingTreatmentChronic Myelomonocytic Leukemia / Myelodysplastic Syndromes1
2CompletedTreatmentOsteoporosis1
2CompletedTreatmentPostmenopausal Osteoporosis (PMO)1
2Not Yet RecruitingTreatmentDegeneration Disc Intervertebral1
2Not Yet RecruitingTreatmentFusion of Spine (Disease)1
3CompletedTreatmentOsteoporosis / Postmenopausal Osteoporosis (PMO)1
3RecruitingTreatmentAge Related Osteoporosis / Osteoporosis / Osteoporosis Localized to Spine / Osteoporosis of Vertebrae / Osteoporosis Senile / Osteoporosis, Age-Related1
3RecruitingTreatmentOsteoporosis / Osteoporosis Localized to Spine / Osteoporosis of Vertebrae / Osteoporosis Risk / Osteoporosis Senile / Osteoporosis Vertebral / Osteoporosis, Age-Related / Osteoporotic Fractures / Postmenopausal Osteoporosis (PMO)1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Injection, solutionSubcutaneous2000 ug/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8148333No2012-04-032027-11-08Us
US7803770No2010-09-282028-03-26Us
US8748382No2014-06-102027-10-03Us
Additional Data Available
  • Filed On
    Filed On

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Properties

State
Liquid
Experimental Properties
PropertyValueSource
water solubilitySolubleNot Available

Taxonomy

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

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Ligand
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. [PubMed:28389324]
  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. [PubMed:26562265]

Drug created on October 21, 2007 16:23 / Updated on June 04, 2019 06:14