To be a realistic competitor to existing drugs, a new hypnotic agent must have a clinical pharmacology profile that is a closer approximation to the ideal agent. From a pharmaceutical perspective, the new agent would be water soluble, thus avoiding the problems associated with lipid formulations (i.e., hyperlipidemia, growth of microorganisms). In the pharmacokinetic (PK) domain, the new agent would have an exceptionally high clearance, ensuring that, when administered by infusion, the drug rapidly reaches a steady-state concentration and that the concentrations decline quickly when the infusion is terminated. A rapid equilibration between plasma and effect-site concentrations is also an ideal kinetic feature. In terms of pharmacodynamic (PD) attributes, nominal cardiovascular effects, improved safety (i.e., a large therapeutic index), minimal ventilatory depression, a low incidence of nausea and vomiting, no pain on injection, and evidence of cerebral protection would be ideal. Are the drugs currently in use falling well short of the ideal?
No currently available IV sedative-hypnotic closely approximates the ideal. Recognizing its popularity for both induction and maintenance of anesthesia in modern practice, propofol is the obvious comparator drug for any new agent. Despite its widespread use, propofol has numerous shortcomings. For starters, there are propofol supply shortages, especially in the United States. These partly relate to difficulties with manufacture of the lipid formulation of propofol.1 There have been issues over bacterial and viral contamination of propofol solutions that have resulted in serious infections.2,3 Propofol causes cardiorespiratory depression; the cardiovascular depression is seriously exacerbated in hemorrhagic shock.4 Propofol is notorious for pain on injection, and its use for long-term sedation in the intensive care unit is compromised by propofol infusion syndrome, which is often lethal. Existing alternatives to propofol also have unique adverse effects, such as adrenal suppression associated with etomidate.5
Propanidid [(4-diethylcarbamoylmethoxy-3- methoxy-phenyl)-acetic acid propyl ester] is a short-acting sedative-hypnotic agent containing an ester moiety that was available in some countries in the 1960s and 1970s.6 Propanidid was withdrawn in 1984 because of a high incidence of anaphylactic reactions, believed to be due to the polyoxyethylated castor oil solvent, Cremophor EL (BASF, Ludwigshafen, Germany).7,8 AZD-3043 ([4-[(N,N-diethylcarbamoyl)methoxy]-3-ethoxyphenyl]acetic acid propyl ester) is another metabolically labile ester similar to the propanidid molecule that has been the focus of recent development efforts. Formerly known as THRX-918861 and TD-4756, AZD-3043 is formulated in a lipid emulsion similar to that used for propofol.
During preclinical animal studies, the time to emergence from AZD-3043-induced hypnosis was rapid and relatively unaffected by the duration of infusion, in contrast to propofol.9 Compared with propofol, the infusion rate of AZD-3043 required less alteration to maintain a consistent depth of hypnosis throughout anesthesia (as monitored by the, admittedly subjective, observation of noxious stimulus-induced paw withdrawal). This may be because the drug has a wide therapeutic window. The infusion data for AZD-3043 demonstrate a short, time-independent 50% or 80% decrement time. However, making predictions about a drug’s human pharmacology from animal studies has well-known limitations. Hence, the studies in the current 3 articles were aimed at confirming AZD-3043’s clinical pharmacologic behavior in humans.
The studies in this issue of Anesthesia & Analgesia examine a number of different aspects of AZD-3043’s clinical pharmacology in volunteers:
- The efficacy and safety of a 30-minute infusion of 1 to 81 mg/kg/h;
- Development of a recirculatory model examining the PKs and effects of the drug on the bispectral index; and
- An infusion study investigating the sedation profile and the drugs’ safety after either a single bolus (1–6 mg/kg) or a bolus-infusion protocol (0.8–4.0 mg/kg followed by 10–40 mg/kg/h for 30 minutes).
The studies include 125 subjects,10–12 and the main findings are that AZD-3043 is a sedative-hypnotic drug with a short duration of action that does not hurt on injection. PK analysis confirmed high systemic clearance (mean, 2.2 L/min) and low volume of distribution (15 L at low doses, to 37 L at highest doses), consistent with the rapid onset/offset profile. The main breakdown products of AZD-3043 are a carboxylic acid metabolite (THRX-108893) and 1-propanol. Only a tiny fraction of the parent drug (0.02%) is excreted unchanged in the urine. These metabolites are either inactive or have only weak hypnotic actions.
As well as assessing recovery by established clinical end points (spontaneous opening of the eyes, response to oral command, and assessment of full orientation using a sedation score [the Modified Observer's Assessment of Alertness/Sedation Scale]), the investigators also looked at the effect of the drug on the processed electroencephalogram (i.e., bispectral index). The 50% effective concentration was about 15.6 μg/mL (i.e., not very potent). The T1/2 ke0 was 1.1 minutes, suggesting rapid blood-effect site equilibration. The slope of the concentration–effect relationship (γ) was 1.7. There were no apparent differences in the drug’s PKs or PDs between men and women, and none of the volunteers complained of pain on injection.
However, AZD-3043 has potentially undesirable properties. It is formulated in a lipid, so the problems associated with the lipid are to some degree inevitable.13 One or more adverse effects occurred in 21 of 72 (29%) patients included in the PD study. Of greatest concern, perhaps, was the observation in 3 patients of episodes of erythema, chest discomfort, and dyspnea after drug administration. In 1 of the 3 subjects, serial samples were taken for plasma tryptase, which proved to be negative. There was an increased heart rate (dose related) at infusion rates >18 mg/kg/h, for reasons that are unclear. In patients receiving the drug by infusion, there were also sporadic episodes of involuntary movements and increased muscle tone, especially during the recovery phase.
Is a drug that is shorter acting than propofol and does not produce pain on injection sufficiently attractive to merit further development? Can AZD-3043 be the David that brings down the propofol Goliath? This is the vexing “go or no-go” decision that perplexes pharmaceutical board rooms. The financial stakes of these decisions are astronomically high, and outcomes are notoriously uncertain.
Part of what makes propofol the Goliath of IV hypnotics goes beyond the clinical profile of the drug itself. The considerable technology built around propofol helps sustain its popularity. Chief among these is propofol delivery by target-controlled infusion. This kinetic model–based infusion technology is firmly entrenched and well received in many parts of the world.14 Decision-support display systems based on the models of the interaction between propofol and remifentanil are marketed to simulate the probability of important anesthetic effects and to aid drug-dosing strategy.15–17 The ability to measure propofol concentration in the expired gas of the anesthetic breathing circuit is under development, although progress seems slow.18,19 Although these technologies can be developed theoretically for any propofol wannabe, the devices and the underpinning clinical pharmacology studies that support them could be realized only at considerable cost.
The clinical potential of AZD-3043 must also be interpreted in the context of the other contenders in development, and there is considerable drug development in this arena.20 Following the pattern illustrated by AZD-3043, many of the agents under development are applying the “soft-drug” concept in anesthesia, wherein a drug’s ultrarapid kinetic profile is based on a labile parent molecule, usually an ester.21 Descriptions of soft, short-acting etomidate and benzodiazepine analogs have already appeared in the literature.22,23 How these will ultimately compare with AZD-3043 and propofol remains to be seen. Any propofol wannabe will have to be evaluated not just as it compares with propofol, but also in terms of how it competes with the other potential propofol replacements.22–25
Which brings us to the key question: Is AZD-3043 the David that brings down the Goliath of propofol? That’s a tricky question—one that pharmaceutical executives get paid to answer. The challenge is that propofol is a firmly entrenched, fabulously successful drug. It’s going to take a very special molecule to bring the giant down.
Name: John W. Sear, MA, BSc, PhD, MBBS, FFARCS, FANZCA.
Contribution: This author helped write the manuscript.
Attestation: John W. Sear approved the final manuscript.
Name: Talmage D. Egan, MD.
Contribution: This author helped write the manuscript.
Attestation: Talmage D. Egan approved the final manuscript.
This manuscript was handled by: Steven L. Shafer, MD.
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