The Bioequivalence of Emulsified Isoflurane With a New Formulation of Emulsion: A Single-Center, Single-Dose, Double-Blinded, Randomized, Two-Period Crossover Study

Abstract

Background: Emulsified isoflurane is a novel intravenous general anesthetic obtained by encapsulating isoflurane molecules into emulsion. The formulation of emulsion has been improved according to the latest regulations of the China Food and Drug Administration. This study was designed to compare the bioequivalence of the new and previous formulation emulsion of isoflurane. Methods: In a single-center, single-dose, double-blinded, randomized, two-period crossover study, healthy volunteers received intravenous injection of 30 mg/kg of isoflurane with either previous formulation of emulsion isoflurane (PFEI) or new formulation of emulsion isoflurane (NFEI). Arterial and venous blood samples were obtained for geometric mean test/reference ratios of C_max, AUC_0-t, and AUC_0-∞, as well as their 90% confidence interval (CI90) as the primary outcome. The secondary outcomes were safety measurements such as vital signs, 12-lead electrocardiography, adverse effects, and laboratory tests; and anesthesia efficacy was assessed by Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score, bispectral index (BIS), and loss/recovery of eyelash reflex. Results: 24 subjects were eligible, of which 21 completed the whole experiment (NFEI n = 21, PFEI n = 23). Arterial geometric mean test/reference ratios of C_max, AUC_0-t, and AUC_0-∞ were 104.50% (CI90 92.81%-117.65%), 108.23% (94.51%-123.96%), and 106.53% (93.94%∼120.80%), respectively. The most commonly seen adverse effects for NFEI and PFEI were injection pain (38.1% vs. 34.8%), hypotension (19.0% vs. 13.0%), apnea (14.3% vs. 17.4%), and upper airway obstruction (14.3% vs. 13.0%). No severe adverse effect was observed. The effectiveness of general anesthesia was similar between the two formulations. Conclusion: The CI90 of C_max, AUC_0-t, AUC_0-∞, NFEI, and PFEI were within the range of 80%-125%, suggesting bioequivalence between NFEI and PFEI. The safety and anesthesia effectiveness were also similar.

Keywords: AUC0-t; AUC0-∞; Cmax; bioequivalence; emulsified isoflurane.

FIGURE 1

The consort flow diagram for the patient progress through this trial. 48 subjects were enrolled; 24 met the exclusion criteria. The remaining 24 subjects received randomization; one subject had fever before receiving any drug. 11 subjects received new formulation of emulsified isoflurane (NFEI); the other 12 subjects received previous formulation of emulsified isoflurane (PFEI). During the 72-h washout period, the NFEI group had two subjects dropped out, and the remaining 21 subjects completed the whole trial.

FIGURE 2

The time–concentration curves of subjects receiving venous injection of 30 mg/kg of new formulation of emulsified isoflurane (NFEI) or previous formulation of emulsified isoflurane (PFEI). The actual arterial (A) and venous (C) blood isoflurane concentration over time, and the semi-log of arterial (B) and venous (D) blood drug concentration over time.

FIGURE 3

BIS value (A) and MOAA/s score (B) after intravenous injection of 30 mg/kg of the new formulation of emulsified isoflurane (NFEI) or the previous formulation of emulsified isoflurane (PFEI).