History of Alfaxalone

History of Alfaxalone

The anesthetic properties of steroids have been known for more than 70 years.  In the 1940s, the Hungarian-born endocrinologist Hans Selye showed that reversible unconsciousness could be produced in rats administered intraperitoneal injections of large quantities of steroid hormones.4  Of the steroids injected, pregnanedione was the most potent and devoid of hormonal acivity.5

In 1955, P’an and colleagues reported that a close structural analog of pregnaendione, hydroxydione, was more potent and safer than the thiobarbiturate, thiopentone.6  However, hydroxydione was not an ideal anesthetic induction agent as it produced a delayed induction of up to three minutes and had to be solubilized in an alkaline pH causing venous thrombosis.  Further research on the structure/activity relationship of neurosteroids showed that manipulation of the 3 and 21 carbon positions altered anesthetic potency.7,8

Eventually, the active molecule 3α-hydroxy-5α-pregnane-11, 20-dione [alfaxalone] was discovered by the Glaxo UK Pharmacology Department.  Similar to the barbiturates, benzodiazepines, propofol and isoflurane, it is thought that alfaxalone’s main mechanism of action is through the gamma-aminobutyric acid type A [GABAA] receptor, which belongs to a superfamily of ligand-gated, pentameric, ion-pore-forming, cell surface receptors found in neurones and other excitable cells [see Figure 3].9 

Alfaxalone was later combined with alfadolone 921-acetoxy-3α-hydroxy-5-α-pregnane-11, 20-dione], Cremophor EL and sodium chloride to yield formulation CT1341. The alfadolone was placed in the formulation to improve the solubility of the alfaxalone.10  Child et al performed a a battery of pharmacological tests on CT1341 in laboratory animals and found it offered significant advantages over the other injectable anesthetics as it had a higher margin of safety, it was non-irritating to tissues including veins, it was compatible with the adjuvant and pre-anesthetic drugs, it did not accumulate and it produced a pleasant anesthetic experience for the patient.11

In the early 1970s, CT1341 was introduced as an intravenous (IV) anesthetic induction agent for humans (Althesin) and as an intramuscular anesthetic (Saffran) for cats and monkeys.  Saffran was not licensed in dogs because in dogs polyoxyethylated emulsifying agents like Cremophor EL cause histamine release and potential anaphylaxis.12

In an effort to remove the side effects observed with drug carriers like Cremophor EL, Brewster et al found that alfaxalone and other drugs could be solubilized in safe carriers like hydroxypropyl-beta-cyclodextrin [HP-β-CD].1314

In 2000, alfaxalone was formulated by Jurox Pty Limited in 2-HPCD as an anesthetic for intravenous injection as Alfaxan.  HPCD is inert, does not cause histamine release and is excreted in its parent form through the kidneys.15  In 2018, Jurox successfully added a preservative to Alfaxan resulting in a new product, Alfaxan Multidose. Alfaxan Multidose is pharmacokinetically and pharmacodynamically identical to original Alfaxan and has an FDA-registered 28 day shelf life after the initial vial broaching. 

Alfaxan Multidose is approved for the induction and maintenance of anesthesia in dogs and cats internationally, including Australia, New Zealand, South Africa, Canada, France, Germany, Republic of Ireland, Spain, Belgium, United Kingdom and the United States of America.