A Phase 1c Trial Comparing the Efficacy and Safety of a New Aqueous Formulation of Alphaxalone with Propofol.

Alphaxalone is an analog of progesterone and its metabolite 3α-hydroxy-5α-pregnan-20-one (allopregnanolone). Allopregnanolone is a neurosteroid that has sedating, anesthetic, anticonvulsant, and neuroprotective properties.1–4 Alphaxalone also has these attributes5–9 and the same receptor-binding properties and actions at GABAA receptors.10,11 However, it is devoid of progestational, estrogenic, mineralocorticoid or thymolytic activity.12 Althesin® (Glaxo Laboratories Ltd., Greenford, Middlesex, UK) was a mixture of alphaxalone with a small amount of a related compound, alphadolone dispersed in water with the aid of Cremophor EL® (CAS registry 61791-12-6). It was used in clinical anesthetic practice for induction and maintenance of anesthesia from 1972 to 1984 in many countries. The anesthetic properties of this preparation were ascribed to the alphaxalone content. The properties of Althesin®, also known as alfadione, were reviewed by Gyermek and Soyka13 in Anesthesiology in 1975, and later in an editorial in the British Journal of Anaesthesia in 1980 by Prys-Roberts and Sear.14 The common view was that Althesin anesthesia was characterized by rapid onset and offset of action, no irritating effects on blood vessels, and minor cardiovascular and respiratory depression with a wide safety margin. Althesin was withdrawn from the market in 1984 because of hypersensitivity reactions caused by the Cremophor EL excipient. There were 3 main types of reactions: Histaminoid: Peripheral vasodilatation, skin flushes, edema, and wheals Bronchospasm: Usually accompanied by vasodilatation or hypotension Cardiovascular collapse not usually accompanied by other features of histaminoid reactions. The hypersensitivity reactions were investigated extensively. Activation of complement by the classic and indirect pathways was found to be common in cases of hypersensitivity reactions to Althesin.15 Gyermek and Soyka13 had suggested before this that alphaxalone should be reformulated in a water base to avoid the Cremophor EL excipient and the hypersensitivity reactions it caused. Dissolution of neuroactive steroid anesthetics in an alternative vehicle suitable for human use has proved to be difficult. Lipid emulsions were tried, but failed to produce an agent with suitable onset and offset characteristics.16,17 When Althesin was withdrawn, 2,6, di-isopropyl phenol (also formulated previously in Cremophor EL) was reformulated successfully using lipid emulsion to produce propofol (Diprivan®, AstraZeneca, New South Wales, Australia). Propofol lipid emulsion is the current standard against which all new anesthetic and sedative drugs must be measured. The reformulated propofol has fulfilled the need for a fast-onset, short-action drug, but with the disadvantage of greater cardiovascular and respiratory depression compared with Althesin.18 Further, the lipid in that formulation has caused new safety issues with infections, contamination, and lipid toxicity.19–22 An alternative excipient for lipid-soluble IV anesthetics is clearly warranted. 7-Sulfobutylether β-cyclodextrin (SBECD) is an excipient with a low toxicity and hypersensitivity profile, which has been used to dissolve hydrophobic drugs in water for IV injections suitable for human use.23–27 It has not been previously investigated as an excipient for alphaxalone. Such a preparation, alphaxalone in aqueous solution with SBECD, Phaxan™ (PHAX), has been made and tested in preclinical studies.28 These revealed that PHAX is a fast-onset, short-duration IV anesthetic with times to induce anesthesia and recover that are equal with propofol and Althesin. Furthermore, those studies revealed that PHAX has a higher safety profile (higher therapeutic index) than propofol or Althesin and, in particular, PHAX was shown to cause less cardiovascular depression than propofol.28 The phase 1c human study reported here set out to compare the anesthetic properties of PHAX with the standard lipid preparation of propofol in common clinical use. The following objectives were addressed in this double-blind, dose-finding comparison of PHAX with propofol: What doses of PHAX and propofol cause the same depth of anesthesia (a BIS value <50)? When those equivalent doses of PHAX and propofol are administered, is there a difference between the 2 drug treatments for: Time to induce hypnosis and recover, Cardiovascular effects, Respiratory depression and airway obstruction, Pain on injection, Involuntary movements or, Speed and quality of recovery? Apart from routine biochemical screening, subjects were also screened for complement activation because the previous alphaxalone preparation (Althesin) caused hypersensitivity reactions.15