Pharmacokinetic and pharmacodynamic properties of ciprofol emulsion in Chinese subjects: a single center, open-label, single-arm dose-escalation phase 1 study

Abstract

We conducted a single-center, single-arm, open-label, dose-escalation phase 1 clinical trial to evaluate the tolerability of a single intravenous injection of ciprofol emulsion for the induction of short-term general anesthesia. Four doses of ciprofol (0.15 mg/kg, n = 2; 0.4 mg/kg, n = 10; 0.6 mg/kg, n = 6; 0.9 mg/kg, n = 6) were administered. Twenty-four subjects were enrolled, with 18 subjects in the 0.4 to 0.9 mg/kg dosage groups included in the data analysis. In total, 37 mild and 4 moderate adverse events (AEs), including 9 abnormal limb movements (3 moderate cases), 8 cases of sinus bradycardia, 11 cases of prolonged QTcF interval (including 1 moderate case), and 1 case of hypotension, were found, but no serious AEs were reported. The Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores rapidly decreased after ciprofol administration. The duration of recovery of the verbal response, loss of verbal response duration, the duration of MOAA/S ≤1 and the duration until the return of responsiveness were all increased in a dose-dependent manner. The durations of bispectral index values <60 (6, 8 and 12 min) were similar to the durations of loss of verbal response (6, 8 and 14 min) and MOAA/S ≤1 (5, 5.5 and 13.5 min) in the 0.4, 0.6 and 0.9 mg/kg dose groups, respectively. The plasma concentration reached a peak value approximately 2 min after injection in the 0.4-0.9 mg/kg groups and all subjects fully recovered after ciprofol administration, with the shortest time being 9.2 min in the 0.4 mg/kg group. A ciprofol dosing regimen of 0.4-0.9 mg/kg was well-tolerated and exhibited rapid onset and recovery properties.

Keywords: Anesthetic; ciprofol; pharmacodynamics; pharmacokinetics; sedation.

Figure 1

Flow diagrams of the study. A. Scheme of the study periods. B. Scheme of the study subjects. *At the beginning of the experiment, 2 subjects in the 0.15 mg/kg group and 4 subjects in the 0.4 mg/kg group received ciprofol by infusion pump, but the subsequent administrations were changed to manual injections, which were completed within 1 min. Subjects administered medication with an infusion pump were excluded from the PK and PD analyses.

Figure 2

Changes in (A) mean MAP (mmHg), (B) mean HR (beats/min) for each ciprofol group.

Figure 3

Changes in (A) ciprofol plasma concentrations, (B) MOAA/S scores, and (C) BIS values for each ciprofol group.