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Drug Development

Heat-stable peptide might save thousands of mothers from excessive bleeding after childbirth

Massive clinical trial including developing nations demonstrates carbetocin is no less effective or safe than oxytocin

by Carmen Drahl
July 3, 2018 | APPEARED IN VOLUME 96, ISSUE 28

 

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Credit: Joni Kabana, Kabana Photography/Concept Foundation/Ferring Pharmaceuticals/MSD for Mothers
In a hospital in Nepal, a mother lies next to her newborn.

After a mother gives birth to a healthy baby, she’s far from out of the woods. Losing too much blood postpartum accounts for about 70,000 deaths worldwide every year, with 99% of deaths occurring in developing nations. Doctors can prevent excessive bleeding by administering oxytocin, a drug and naturally-occurring hormone. But oxytocin, a peptide, degrades after prolonged heat exposure, so the drug is not reliable in nations lacking consistently climate-controlled hospitals and refrigerated supply chains.

Now, the World Health Organization (WHO) is reporting that a heat-stable formulation of an oxytocin analog—carbetocin—is an effective way around the problem (N. Engl. J. Med. 2018, DOI: 10.1056/NEJMoa1805489).

“This is one of the most important public health issues for women in the developing world,” says Jeffrey M. Smith, an obstetrician-gynecologist at Jhpiego, an international health nonprofit group, who was not involved with the study. “And it’s solved by using chemistry.”

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Carbetocin is not a new drug. It first appeared in the literature in the 1980s and has been used to prevent excessive bleeding during Caesarean sections since 1997. But recently, researchers at Ferring Pharmaceuticals reported a formulation that remains stable for three years at 30 °C (J. Pep. Sci. 2018, DOI: 10.1002/psc.3082). Guidelines recommend that oxytocin be stored at 2 to 8 °C, says A. Metin Gülmezoglu, the WHO researcher who led the study. Oxytocin degrades at higher temperatures largely due to a disulfide bond and a nearby amine group. Carbetocin lacks these groups. On top of making carbetocin more intrinsically stable than oxytocin, those omissions allowed formulation experts to explore wide pH ranges to minimize minor breakdown pathways.

Representatives from Ferring and a philanthropic initiative of Merck & Co. approached WHO in 2013 to launch a clinical trial comparing oxytocin and heat-stable carbetocin. The randomized, double-blind study enrolled nearly 30,000 women in 10 countries. About half received a shot of oxytocin following vaginal delivery, and about half received carbetocin.

Carbetocin was no less effective than oxytocin at preventing over half a liter of blood loss after labor. The trial didn’t have enough statistical power to conclude that carbetocin was no less effective than oxytocin at preventing over a liter of blood loss. The Royal College of Obstetricians & Gynecologists defines severe hemorrhage as a loss of over 2 liters of blood. Side effects were infrequent in both groups, with no statistically significant difference detected.

As a result of this study, “WHO will now update its recommendations for drugs to prevent excessive bleeding after childbirth,” to include carbetocin, Gülmezoglu says. Oxytocin can still be used if refrigeration throughout its supply chain and storage is available, he adds.

Smith says educating policy-makers and getting the drug into the hands of midwives are the next steps. As an example of how challenging those steps can be, he points to another drug, tranexamic acid, that reduces traumatic bleeding from tears of the cervix and other injuries. Though it’s inexpensive and has been demonstrated to be effective, he says it isn’t as widely used as it could be.

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“Maternal mortality is one of the great injustices of our time. Where a woman lives determines whether a woman lives,” Smith says. “Implementation is critical. Unless you put equal energy into implementation, nothing’s gonna happen.”

Representatives from WHO, Ferring, and Merck have signed a memorandum of understanding stating that if carbetocin were proven noninferior to oxytocin, then the drug would be made available at an affordable price. Ferring did not respond to C&EN’s inquiries about carbetocin pricing as of press time.

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