Pharmacokinetics and exposure-safety relationship of ciprofol for sedation in mechanically ventilated patients in the intensive care unit

Abstract

Ciprofol (HSK3486) is a newly developed, highly selective γ-aminobutyric acid-A (GABA_A) receptor potentiator that is recently approved for a new indication of sedation for patients in the intensive care unit (ICU) in China. This analysis aimed to characterize the population pharmacokinetics (PopPKs) of ciprofol and evaluate the relationship of exposure with hypotension in mechanically ventilated patients in the ICU. A total of 462 subjects with 3918 concentration measurements from two clinical trials of mechanically ventilated patients in the ICU, four clinical trials of elective surgical patients, and six clinical trials of healthy subjects were used in the PopPK analysis. Exposure-safety relationship for hypotension was evaluated based on the data gathered from 112 subjects in two clinical trials of mechanically ventilated patients in the ICU. Ciprofol pharmacokinetics (PKs) was adequately described by a three-compartment linear disposition model with first-order elimination. Body weight, age, sex, blood sampling site (vein vs. arterial), study design (long-term infusion vs. short-term infusion), and patient population (ICU vs. non-ICU) were identified as statistically significant covariates on the PKs of ciprofol. Within the exposure range of the mechanically ventilated ICU patient population, no meaningful association was observed between ciprofol exposure and the incidence of hypotension. These results support the dosing regimen currently used in mechanically ventilated patients in the ICU.

FIGURE 1

Ciprofol PK parameter–covariate relationships. Circles are the empirical Bayes estimates of individual PK parameters after correcting for all other covariates except for the one plotted in the x‐axis. Blue squares represent the geometric mean within the group for categorical covariates. Red lines represent the typical (population) predicted parameter–covariate relationship based on the model. The model‐estimated shrinkages on CL, V _1, Q ₂, V ₂, Q ₃, and V ₃ were 24.7%, 30.9%, 40.5%, 43.4%, 49.0%, and 50.3%, respectively. CL, clearance from the central compartment; PK, pharmacokinetic; Q₃, atrioventricular clearance between the central compartment and shallow peripheral compartment; V ₁, central compartment volume of distribution; V ₂ and V ₃, deep and shallow peripheral compartmental volumes of distribution; Study design, 0 for long‐term infusion, 1 for short‐term infusion.

FIGURE 2

The pcVPC of ciprofol plasma concentration–time profiles across all studies. Blue circles are individual observed concentrations, solid red lines represent the median observed concentrations and dashed red lines represent the 2.5th and 97.5th percentiles of the observed concentrations over time. Pink‐shaded areas represent the 95% CI of the predicted median concentrations, and purple‐shaded areas represent the 95% CI of the predicted 2.5th and 97.5th percentiles of the concentrations over time. CI, confidence interval; pcVPC, prediction‐corrected visual predictive check.

FIGURE 3

Simulated concentrations versus RASS score. Circles are the model predicted plasma concentration ranges corresponding to different RASS values in individual mechanically ventilated ICU patients. The boxes represent the 25th to 75th percentiles (the interquartile range). The solid black horizontal line in the middle of each box represents the median. The whiskers represent the range of data points within 1.5 times the interquartile range. ICU, intensive care unit; RASS, Richmond agitation sedation scale.

FIGURE 4

Simulated concentration‐time profiles for a loading dose of 0.1 mg/kg over 0.5–5 mins followed by a maintenance dose of 0.3 mg/kg/h. Solid blue lines represent the simulated concentration‐time profile of individual subjects. The solid red line represents the median of the target concentration (143.3 ng/mL) and the dashed red lines represent the 5th and 95th percentiles of the target concentrations (77.0–215.6 ng/mL). DUR, infusion duration; LD, loading dose; min, minute.

FIGURE 5

Simulated concentration‐time profiles for a loading dose of 0.1 mg/kg over 4 min followed by maintenance doses of 0.06–0.3 mg/kg/h. Solid blue lines represent the simulated concentration‐time profile of individual subjects. The solid red line represents the median of the target concentration (143.3 ng/mL) and the dashed red lines represent the 5th and 95th percentiles of the target concentrations (77.0–215.6 ng/mL). MD, maintenance dose.