Population Pharmacokinetics and Pharmacodynamics of Ciprofol

Elderly patients undergoing orthopedic limb surgery represent a growing population with unique perioperative challenges. Age-related physiological changes-including reduced hepatic and renal function, altered body composition, and decreased cardiac output-significantly affect the pharmacokinetics (PK) and pharmacodynamics (PD) of anesthetic drugs. These changes increase the difficulty of maintaining adequate anesthesia depth and hemodynamic stability.

Ciprofol, a novel intravenous anesthetic, has shown promising efficacy and safety in clinical practice. However, existing PK/PD models are largely derived from healthy volunteers or younger patients, and cannot adequately predict drug behavior in elderly orthopedic patients who often present with comorbidities and heightened surgical stress. This gap may lead to risks such as drug accumulation and circulatory depression, or insufficient dosing and intraoperative awareness.

This single-center, observational, prospective study at Shanghai Geriatric Medical Center aims to construct and validate a population PK/PD model of ciprofol specifically for elderly patients undergoing orthopedic limb surgery. The model will support precise control of effect-site concentration via Target-Controlled Infusion (TCI) systems, enabling individualized anesthesia management.

Study Objectives 1.Primary Objective: To develop and validate a population PK/PD model of ciprofol tailored to elderly orthopedic patients, and to evaluate its accuracy in predicting effect-site concentrations.

2.Secondary Objectives:

• To simulate recommended TCI dosing regimens based on the new model and compare them with current drug label recommendations, assessing clinical value and optimization potential.
• To evaluate the anesthetic efficacy and safety of ciprofol in this patient population.

3.Exploratory Objectives: To investigate the influence of covariates (e.g., age, sex, BMI, hepatic and renal function) on PK/PD parameters, and to explore correlations between individual PK/PD parameters and recovery outcomes such as Aldrete score and postoperative delirium incidence.

Study Design

1.Type: Single-center, observational, biosample-utilization study. 2.Population: 45 elderly patients (≥65 years, ASA I-III) scheduled for elective orthopedic limb surgery under general anesthesia.

3.Procedures:

• Collection of perioperative clinical data (vital signs, BIS monitoring, anesthesia-related indicators).
• Serial blood sampling at predefined time points for plasma concentration measurement.
• Monitoring of anesthetic efficacy (induction success, BIS values, recovery times) and safety endpoints (hypotension, bradycardia, hypoxemia, injection pain).

4.Endpoints:

• Primary Endpoint: Accuracy of the population PK/PD model in predicting effect-site concentrations.
• Secondary Endpoints: Differences between model-recommended dosing and label-based dosing; incidence of ciprofol-related adverse events; anesthetic efficacy indicators.
• Exploratory Endpoints: Covariate effects on PK/PD parameters; correlation of PK/PD parameters with Aldrete score recovery and postoperative delirium.

Data Management and Analysis All perioperative data will be recorded and stored electronically, with double-entry verification and query resolution procedures to ensure accuracy. PK/PD modeling will be performed using nonlinear mixed-effects modeling (NONMEM). Model evaluation will include goodness-of-fit plots, visual predictive checks, and bootstrap validation. Simulations will be conducted to compare TCI dosing regimens derived from the new model with standard recommendations.

Expected Significance This study will fill an important gap in anesthetic pharmacology by providing a validated PK/PD model of ciprofol for elderly orthopedic patients. The findings are expected to improve perioperative anesthesia management, enhance patient safety, and support individualized dosing strategies in clinical practice.

Inclusion criteria

• Age ≥65 years;
• BMI: 18-30 kg/m²;
• ASA physical status classification I-III;
• Scheduled for elective orthopedic limb surgery under general anesthesia;
• Expected duration of surgery >30 minutes;
• Willing to participate and able to provide written informed consent.

Exclusion criteria

• Known allergy to ciprofol or related medications, or any contraindication to their use;
• Preoperative cognitive impairment;
• History of severe cerebrovascular disease or related complications;
• History of neuromuscular system diseases or psychiatric disorders;
• History of sedative medication use;
• History of alcohol abuse or substance use disorder;
• Bradycardia (heart rate <60 beats per minute);
• Hypotension (mean arterial pressure <55 mmHg);
• QT interval prolongation;
• Uncooperative or unable to communicate effectively.