Hydroxyprogesterone caproate

Identification

Name
Hydroxyprogesterone caproate
Accession Number
DB06789
Type
Small Molecule
Groups
Approved, Investigational
Description

Hydroxyprogesterone caproate is a synthetic steroid hormone that is similar to medroxyprogesterone acetate and megestrol acetate. It is an ester derivative of 17α-hydroxyprogesterone formed from caproic acid (hexanoic acid). Hydroxyprogesterone caproate was previously marketed under the trade name Delalutin by Squibb, which was approved by the U.S. Food and Drug Administration (FDA) in 1956 and withdrawn from marketing in 1999. The U.S. FDA approved Makena from KV Pharmaceutical (previously named as Gestiva) on February 4, 2011 for prevention of preterm delivery in women with a history of preterm delivery, sparking a pricing controversy.

Structure
Thumb
Synonyms
  • 17-alpha-hydroxy-progesterone caproate
  • 17alpha-Caproyloxypregn-4-ene-3,20-dione
  • 17alpha-Hydroxyprogesterone hexanoate
  • Caproate d'hydroxyprogesterone
  • Caproato de hidroxiprogesterona
  • Hydroxyprogesterone hexanoate
External IDs
NSC-17592
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
MakenaInjection250 mg/1mLIntramuscularAmag Pharmaceuticals Inc2011-02-03Not applicableUs
MakenaInjection250 mg/1mLSubcutaneousAmag Pharmaceuticals Inc2018-02-14Not applicableUs
MakenaInjection250 mg/1mLIntramuscularAmag Pharmaceuticals Inc2011-02-03Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularPrasco, Laboratories2018-07-02Not applicableUs
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularMcGuff Pharmaceuticals, Inc.2016-12-022016-12-02Us
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularAmerican Regent2018-06-28Not applicableUs
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularMylan Institutional2017-09-22Not applicableUs
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularPrasco, Laboratories2018-07-02Not applicableUs
Hydroxyprogesterone CaproateInjection250 mg/1mLIntramuscularANI Pharmaceuticals, Inc.2016-06-032018-07-31Us
International/Other Brands
Delalutin (Bristol-Myers Squibb) / Gestiva (Cytyc) / Hormofort (Kobanyai) / ldrogestene (Farmila) / Makena
Categories
UNII
276F2O42F5
CAS number
630-56-8
Weight
Average: 428.6041
Monoisotopic: 428.292659768
Chemical Formula
C27H40O4
InChI Key
DOMWKUIIPQCAJU-LJHIYBGHSA-N
InChI
InChI=1S/C27H40O4/c1-5-6-7-8-24(30)31-27(18(2)28)16-13-23-21-10-9-19-17-20(29)11-14-25(19,3)22(21)12-15-26(23,27)4/h17,21-23H,5-16H2,1-4H3/t21-,22+,23+,25+,26+,27+/m1/s1
IUPAC Name
(1R,3aS,3bR,9aR,9bS,11aS)-1-acetyl-9a,11a-dimethyl-7-oxo-1H,2H,3H,3aH,3bH,4H,5H,7H,8H,9H,9aH,9bH,10H,11H,11aH-cyclopenta[a]phenanthren-1-yl hexanoate
SMILES
[H][C@@]12CC[C@](OC(=O)CCCCC)(C(C)=O)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CCC2=CC(=O)CC[C@]12C

Pharmacology

Indication

Hydroxyprogesterone caproate is indicated for the prevention of spontaneous preterm births in singleton pregnancies in women who have previously had a spontaneous preterm birth. (1)

Associated Conditions
Pharmacodynamics

No specific pharmacodynamic studies have been performed to assess hydroxyprogesterone caproate injections. (4) However, the mechanism of action is likely related to increased interaction between progesterone and progesterone receptors. (5)

Mechanism of action

The mechanism by which progesterone prevents preterm birth is not well understood, but many pathways are likely involved. (1) Progesterone plays a vital role in regulation of the female reproductive system and is important for successful implantation of the embryo and maintenance of pregnancy. It acts by binding to progesterone receptors in the uterus, ovaries, breasts and in the central nervous system. These receptors exist in 2 isoforms, PR-A and PR-B. Progesterone binding to these receptors ultimately leads to regulation of gene transcription. (2) This results in an anti-inflammatory effect which blunts the proinflammatory state that occurs with initiation of labor, and maintains uterine queiscence by stabilizing progesterone acting on the myometrium. (2)

TargetActionsOrganism
UProgesterone receptor
agonist
Human
Absorption

Absorption of 17-hydroxyprogesteron caproate is slow, occurring over a long period of time. (3)

Volume of distribution

Hydroxyprogesterone caproate has a high volume of distribution. (3)

Protein binding

Hydroxyprogesterone caproate is extensively protein bound in the plasma. (3)

Metabolism

The main enzymes involved in metabolism of hydroxyprogesterone caproate are cytochrome P450 (CYP) 3A4 and to a lesser extent CYP3A5. (3)

Route of elimination

Following intramuscular injection, approximately 50% of hydroxyprogesterone caproate metabolites are eliminated in the feces, while approximately 30% of metabolites are eliminated in the urine. (3)

Half life

Half-life = 16 days (±6 days). (3)

Clearance

Clearance is highly variable from patient to patient. (3)

Toxicity

Injection site pain is the most common adverse effect associated with hydroxyprogesterone caproate. Other commonly reported adverse effects include: injection site swelling, urticaria, pruritus, injection site pruritus, nausea, injection site nodule, and diarrhea. (4)

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

Interactions

Drug Interactions
DrugInteraction
(1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINEThe therapeutic efficacy of (1S,6R)-3-{[3-(TRIFLUOROMETHYL)-5,6-DIHYDRO[1,2,4]TRIAZOLO[4,3-A]PYRAZIN-7(8H)-YL]CARBONYL}-6-(2,4,5-TRIFLUOROPHENYL)CYCLOHEX-3-EN-1-AMINE can be decreased when used in combination with Hydroxyprogesterone caproate.
2,4-thiazolidinedioneThe therapeutic efficacy of 2,4-thiazolidinedione can be decreased when used in combination with Hydroxyprogesterone caproate.
AbciximabHydroxyprogesterone caproate may decrease the anticoagulant activities of Abciximab.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Hydroxyprogesterone caproate.
AcenocoumarolHydroxyprogesterone caproate may decrease the anticoagulant activities of Acenocoumarol.
AcetohexamideThe therapeutic efficacy of Acetohexamide can be decreased when used in combination with Hydroxyprogesterone caproate.
Acetyl sulfisoxazoleThe metabolism of Hydroxyprogesterone caproate can be decreased when combined with Acetyl sulfisoxazole.
AcetyldigitoxinAcetyldigitoxin may decrease the cardiotoxic activities of Hydroxyprogesterone caproate.
AcetyldigoxinAcetyldigoxin may decrease the cardiotoxic activities of Hydroxyprogesterone caproate.
Acetylsalicylic acidHydroxyprogesterone caproate may decrease the anticoagulant activities of Acetylsalicylic acid.
Food Interactions
Not Available

References

Synthesis Reference

U.S. Patent 2,753,360.

General References
  1. Goodnight W: Clinical Application of Progesterone for the Prevention of Preterm Birth, 2016. Am J Perinatol. 2016 Feb;33(3):253-7. doi: 10.1055/s-0035-1570378. Epub 2016 Jan 20. [PubMed:26788788]
  2. Ruan X, Mueck AO: Systemic progesterone therapy--oral, vaginal, injections and even transdermal? Maturitas. 2014 Nov;79(3):248-55. doi: 10.1016/j.maturitas.2014.07.009. Epub 2014 Jul 22. [PubMed:25113944]
  3. Feghali M, Venkataramanan R, Caritis S: Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations. Semin Perinatol. 2014 Dec;38(8):516-22. doi: 10.1053/j.semperi.2014.08.013. Epub 2014 Sep 23. [PubMed:25256193]
  4. O'Brien JM, Lewis DF: Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety. Am J Obstet Gynecol. 2016 Jan;214(1):45-56. doi: 10.1016/j.ajog.2015.10.934. Epub 2015 Nov 10. [PubMed:26558340]
External Links
KEGG Drug
D00949
KEGG Compound
C08148
PubChem Compound
169870
PubChem Substance
310264886
ChemSpider
148552
BindingDB
70293
ChEBI
5812
ChEMBL
CHEMBL1200848
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Hydroxyprogesterone_caproate
FDA label
Download (383 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedNot AvailablePregnancy1
1CompletedTreatmentComparing Bioavailability When Makena® is Administered in Healthy Post-menopausal Women1
2, 3CompletedPreventionPreterm Delivery1
2, 3RecruitingTreatmentPremature Births1
3Active Not RecruitingPreventionPremature Births1
3CompletedTreatmentAssessing Injection Pain of Makena® (Hydroxyprogesterone Caproate Injection, 250 mg/mL) in Healthy Post-menopausal Women1
4RecruitingPreventionPremature Births1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntramuscular250 mg/1mL
InjectionSubcutaneous250 mg/1mL
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
USRE44846No1999-08-102019-08-10Us
US8021335No2006-10-042026-10-04Us
US8562564No2006-01-242026-01-24Us
US9533102No2006-01-242026-01-24Us
US9629959No2006-01-242026-01-24Us
US9844558No2016-05-022036-05-02Us
US9180259No2006-01-242026-01-24Us
US9789257No2014-02-112034-02-11Us

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)119-121U.S. Patent 2,753,360.
Predicted Properties
PropertyValueSource
Water Solubility0.000866 mg/mLALOGPS
logP4.81ALOGPS
logP5.88ChemAxon
logS-5.7ALOGPS
pKa (Strongest Acidic)17.75ChemAxon
pKa (Strongest Basic)-4.8ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area60.44 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity121.69 m3·mol-1ChemAxon
Polarizability50.28 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability1ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-qTof , PositiveLC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-0aba-3940000000-835c32531e48d578d8ee

Taxonomy

Description
This compound belongs to the class of organic compounds known as gluco/mineralocorticoids, progestogins and derivatives. These are steroids with a structure based on a hydroxylated prostane moiety.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Steroids and steroid derivatives
Sub Class
Pregnane steroids
Direct Parent
Gluco/mineralocorticoids, progestogins and derivatives
Alternative Parents
Steroid esters / 20-oxosteroids / 3-oxo delta-4-steroids / Delta-4-steroids / Cyclohexenones / Alpha-acyloxy ketones / Carboxylic acid esters / Monocarboxylic acids and derivatives / Organic oxides / Hydrocarbon derivatives
Substituents
Progestogin-skeleton / Steroid ester / 20-oxosteroid / 3-oxo-delta-4-steroid / 3-oxosteroid / Oxosteroid / Delta-4-steroid / Cyclohexenone / Alpha-acyloxy ketone / Carboxylic acid ester
Molecular Framework
Aliphatic homopolycyclic compounds
External Descriptors
corticosteroid hormone (CHEBI:5812)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Agonist
General Function
Zinc ion binding
Specific Function
The steroid hormones and their receptors are involved in the regulation of eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues. Progesterone receptor ...
Gene Name
PGR
Uniprot ID
P06401
Uniprot Name
Progesterone receptor
Molecular Weight
98979.96 Da
References
  1. O'Brien JM, Lewis DF: Prevention of preterm birth with vaginal progesterone or 17-alpha-hydroxyprogesterone caproate: a critical examination of efficacy and safety. Am J Obstet Gynecol. 2016 Jan;214(1):45-56. doi: 10.1016/j.ajog.2015.10.934. Epub 2015 Nov 10. [PubMed:26558340]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. Feghali M, Venkataramanan R, Caritis S: Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations. Semin Perinatol. 2014 Dec;38(8):516-22. doi: 10.1053/j.semperi.2014.08.013. Epub 2014 Sep 23. [PubMed:25256193]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Substrate
General Function
Oxygen binding
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Feghali M, Venkataramanan R, Caritis S: Prevention of preterm delivery with 17-hydroxyprogesterone caproate: pharmacologic considerations. Semin Perinatol. 2014 Dec;38(8):516-22. doi: 10.1053/j.semperi.2014.08.013. Epub 2014 Sep 23. [PubMed:25256193]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inducer
Curator comments
The data supporting CYP2C19 enzyme induction currently available is limited to in vitro studies.
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Zhao Y, Alshabi AM, Caritis S, Venkataramanan R: Impact of 17-alpha-hydroxyprogesterone caproate on cytochrome P450s in primary cultures of human hepatocytes. Am J Obstet Gynecol. 2014 Oct;211(4):412.e1-6. doi: 10.1016/j.ajog.2014.03.048. Epub 2014 Mar 26. [PubMed:24681287]

Drug created on September 14, 2010 10:21 / Updated on September 19, 2018 01:21