Hydroxyprogesterone caproate

From Infogalactic: the planetary knowledge core
Jump to: navigation, search
Hydroxyprogesterone caproate
Hydroxyprogesterone Caproate.gif
Systematic (IUPAC) name
[(8R,9S,10R,13S,14S,17R)-17-acetyl-10,13-dimethyl-
3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-
1H-cyclopenta[a]phenanthren-17-yl] hexanoate
Clinical data
Pregnancy
category
  • B
Routes of
administration		 Intramuscular injection
Pharmacokinetic data
Biological half-life 7.8 days
Identifiers
CAS Number 630-56-8 N
ATC code G03DA03 (WHO)
PubChem CID: 169870
ChemSpider 148552 YesY
UNII 276F2O42F5 YesY
Synonyms 17α-Hydroxyprogesterone caproate, 17α-OHPC, 17-Hydroxyprogesterone caproate, 17-OHPC
Chemical data
Formula C27H40O4
Molecular mass 428.6041 g/mol
  • O=C4\C=C2/[C@]([C@H]1CC[C@@]3([C@@](OC(=O)CCCCC)(C(=O)C)CC[C@H]3[C@@H]1CC2)C)(C)CC4
  • 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 YesY
  • Key:DOMWKUIIPQCAJU-LJHIYBGHSA-N YesY
 NYesY (what is this?)  (verify)

Hydroxyprogesterone caproate (OHPC) (INN, USAN, JAN) (brand names Delalutin, Proluton, Makena, Prodrox, Hylutin, many others), also known as hydroxyprogesterone hexanoate (BANM), is a steroidal progestin and derivative of 17α-hydroxyprogesterone (17-OHP) that is related to other 17-OHP derivatives such as chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, and megestrol acetate.[1] It is an ester of 17-OHP formed from caproic acid (hexanoic acid).[1]

OHPC was previously marketed under the trade name Delalutin by Squibb, which was approved by the United States (U.S.) Food and Drug Administration (FDA) in 1956 and withdrawn from marketing in 1999. It is also sold as Proluton throughout Europe.[1]

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.

Pharmacology

OHPC, unlike many other progestins, is very similar to natural progesterone both structurally and pharmacologically, and is a pure progestogen. However, relative to progesterone, OHPC has improved pharmacokinetics, namely, a much longer duration with depot injection.

The caproate ester is not cleaved from OHPC during metabolism, so it is not converted into 17-OHP, nor into progesterone.[2] OHPC is a much more potent progestogen relative to 17-OHP, but does not have as high of affinity for the progesterone receptor (PR) relative to progesterone.[2] However, despite this, it is more potent than progesterone in vivo, likely due to differences in the pharmacokinetics of the two compounds.[2] OHPC is not as potent as the related ester hydroxyprogesterone acetate.[2]

OHPC, unlike various other progestogens, is a pure progestogen,[3] and has no androgenic or glucocorticoidic properties,[4] nor any estrogenic effects.[3] Due to its lack of androgenic properties, similarly to progesterone, OHPC does not have any teratogenic effects on the fetus, making it safe for use during pregnancy.[4] Regarding glucocorticoid activity, OHPC has been found not to alter cortisol levels in humans even with extremely high dosages via intramuscular (i.m.) injection,[5] which is of relevance because drugs with significant glucocorticoid activity suppress cortisol levels (due to increased negative feedback on the hypothalamic-pituitary-adrenal axis). OHPC has been studied in humans at dosages as high as 5,000 mg per week via i.m. injection (in the treatment of endometrial cancer specifically, with safety and effectiveness observed).[6] Through activation of the PR, OHPC has antigonadotropic effects.[7]

OHPC has a half-life of approximately 7.8 days via intramuscular injection.[8]

Safety

The use of OHPC in pregnancy to prevent preterm birth in women with a history of preterm delivery between 20 weeks and 36 weeks and 6 days is supported by the Society of Maternal Fetal Medicine Clinic Guidelines put out in May 2012 as Level I and III evidence, Level A recommendation.[9] Level I evidence refers to a properly powered randomized controlled trial, and level III evidence is support from expert opinion, while a Level A recommendation confers that the recommendation is made based on good and consistent scientific evidence. OHPC 250 mg IM weekly preferably starting at 16–20 weeks until 36 weeks is recommended. In these women, if the transvaginal ultrasound cervical length shortens to <25 mm at < 24 weeks, cervical cerclage may be offered. In the 2013 study the guideline recommendation is based on by [10] there was also a significant decrease of neonatal morbidity including lower rates of necrotizing enterocolitis (0 in treatment group vs 4 in control), intraventricular hemorrhage (4 in the treatment group compared with 8 in the control for relative risk of 0.25), and need for supplemental oxygen (14% in treatment group vs 24% in placebo for relative risk of 0.42). Furthermore, this study contained 463 patients, 310 of whom received injection. Of these patients, 9 had infants with congenital malformations (2%), but there was no consistent pattern and none involved internal organs.

OHPC is currently (as of June 2014) pregnancy category B, meaning there is no evidence of fetal risk with use of this drug during pregnancy. Although this is now the recommendation, this has not always been the case. A 2006 Cochrane Review concluded "...important maternal and infant outcomes have been poorly reported to date... information regarding the potential harms of progesterone therapy to prevent preterm birth is limited".[11] There was a similar conclusion from a review by Marc Keirse of Flinders University.[12] Three clinical studies in singleton pregnancies of 250 mg/week of intramuscular OHPC have all shown a trend for an increase in pregnancy loss due to miscarriage compared to placebo.[13][14][15][16] The FDA expressed concern about miscarriage at the 2006 advisory committee meeting; the committee voted unanimously that further study was needed to evaluate the potential association of OHPC with increased risk of second trimester miscarriage and stillbirth.[17] A toxicology study in rhesus monkeys resulted in the death of all rhesus fetuses exposed to 1 and 10 times the human dose equivalent of OHPC.[18] as of 2008, OHPC was a category D progestin according to the FDA (that is, there is evidence of fetal harm). There is speculation that the castor oil in the OHPC formulation may not be beneficial for pregnancy.[19][20] Of note, the above-mentioned NEJM study by Meirs et al. compares the effect of OHPC (with the castor oil component) to castor oil injection as the placebo.

A study published in February 2016 in the Lancet stated the below amongst other findings

"OPPTIMUM strongly suggests that the efficacy of progesterone in improving outcomes is either non-existent or weak. Given the heterogeneity of the preterm labour syndrome we cannot exclude benefit in specific phenotypic or genotypic subgroups of women at risk. However, the subgroups of women who might benefit do not appear to be easily identifiable by current selection strategies, including cervical length measurement and fibronectin testing.

Reassuringly, our study suggests that progesterone is safe for those who wish to take it for preterm birth prophylaxis. The overall rate of maternal or child adverse events was similar in the progesterone and placebo groups. There were few differences in the incidence of adverse secondary outcomes in the two groups, with the exception of a higher rate of renal, gastrointestinal, and respiratory complications in childhood in the progesterone groups. Importantly, the absolute rates of these complications was low. Follow-up of other babies exposed in utero to vaginal progesterone would be helpful in determining whether the increased rate of some renal, gastrointestinal, and respiratory complications is a real effect or a type I error."[21]

The journal reviewer Richard Lehman, senior Research Fellow at the Department of Primary Health Care at the University of Oxford made the following notable commentary on the OPPTIMUM study, "That’s it. This story is ended, and nobody need ever use vaginal progesterone again to prevent preterm birth."[22]

Makena pricing controversy

<templatestyles src="Module:Hatnote/styles.css"></templatestyles>

See also: KV Pharmaceutical § Makena pricing controversy

A 2011 decision by the USFDA was going to result in driving "up the [US] cost of an available medication from about $300 to $30,000 — about a 100-fold increase — with minimal added clinical benefit".[23] However, the USFDA said it would not go after compounding pharmacies that filled prescriptions, and KV Pharmaceutical announced a lower price.[23]

Synthesis

OHPC can be prepared by the following sequence:[24]

Hydroxyprogesterone caproate.png

It is made from 16-dehydropregnenolone acetate,[25] a product of the Marker degradation.

See also

Notes

  1. ↑ 1.0 1.1 1.2 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 2.2 2.3 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ 3.0 3.1 Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ 4.0 4.1 Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Varga A, Henriksen E. Clinical and Histopathologic Evaluation of the Effect of 17-alpha-Hydroxyprogesterone-17-n-caproate on Endometrial Carcinoma. Obstetrics & Gynecology. December 1961. Volume 18. Issue 6. pp. 658-672.
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ SMFM Clinical Guideline: Progesterone and preterm birth prevention: translating clinical trials data into clinical practice, AJOG May 2012
  10. ↑ Meirs et al. NEJM 2003
  11. ↑ Dodd JM, Flenady V, Cincotta R, Crowther CA; The Cochrane Database of Systematic Reviews 2006 Issue 1
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Meis PJ et al. Prevention of Recurrent Preterm Delivery by 17 Alpha-hydroxyprogesterone Caproate. NEJM, 2003: vol 348, no 24, pg 2379-2385.
  16. ↑ Keirse MJNC, Progestogen administration in pregnancy may prevent preterm delivery. Br J Obstet Gynecol 1990 February; 97:149.
  17. ↑ Advisory Committees: CDER 2006 Meeting Documents
  18. ↑ Hendrix AG, et al. Embriotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate. Teratology 1987 February. 35 (1): 129.
  19. ↑ Duke University Medical Center, New England Journal of Medicine, correspondence, vol 349.
  20. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  21. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  22. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  23. ↑ 23.0 23.1 Lua error in package.lua at line 80: module 'strict' not found.
  24. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  25. ↑ Lua error in package.lua at line 80: module 'strict' not found.

Sources

Retrieved from "https://infogalactic.com/w/index.php?title=Hydroxyprogesterone_caproate&oldid=723077230"