Haiping Xu 1, Xue Zhang 2, Xinyi Tang 1, Hao Fang 2,3, Xiao Zhu 1
1 Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University (Shanghai, China), 2 Department of Anesthesiology, Shanghai Geriatic Medical Center (Shanghai, China), 3 Department of Anesthesiology, Zhongshan Hospital, Fudan University (Shanghai, China)
Introduction:
Ciprofol is a novel γ-aminobutyric acid type A (GABA A) receptor agonist with 4–5 fold greater potency than propofol [1, 2]. Its high potency necessitates precise titration of both induction and maintenance doses to maintain anesthetic stability, as minor dosage variations can significantly impact sedation depth in geriatric patients [3]. Although drug labels recommend empirical dose reductions for elderly patients, these guidelines lack a model-based foundation for precise dosing. While population pharmacokinetic-pharmacodynamic (PopPK–PD) models have been developed to optimize ciprofol dosing, existing studies primarily rely on healthy volunteers or intensive care unit (ICU) cohorts [4, 5]. Consequently, there remains a gap for a model specifically tailored to geriatric orthopedic patients.
Objectives:
This study aimed to optimize ciprofol administration for Chinese geriatric orthopedic patients during general anesthesia by: (1) developing a ciprofol PopPK–PD model and (2) providing model-based recommendations for individualized anesthetic induction and maintenance infusion regimens.
Method:
A prospective study was conducted in Chinese geriatric patients (aged ≥65 years) undergoing elective orthopedic surgery. Ciprofol plasma concentrations were sampled intraoperatively and postoperatively to characterize PK, while bispectral index (BIS) were recorded intraoperatively as the PD endpoint. Two- and three-compartment models were evaluated for PopPK model development. To account for body size, the scaling of all PK parameters was evaluated using body weight, body surface area [6], body mass index (BMI), and fat-free mass (FFM) [7]. Subsequently, several PD candidate models (effect-compartment, indirect response (IDR), and integrated effect-compartment-IDR model) were systematically evaluated to characterize the exposure–BIS relationship. Candidate covariates reflecting geriatric vulnerability (chronological age, FRAILE scale, and age-adjusted Charlson Comorbidity Index) and laboratory biomarkers (alkaline phosphatase, albumin, and creatinine) were screened for effects on key model parameters. The nonlinear mixed-effects modeling software NONMEM (version 7.5) and Perl-speaks-NONMEM (PsN, version 5.2.6) were used for PopPK–PD model development. Statistical analysis, data visualization, and exploratory analysis were conducted in R (version 4.5.2). Model evaluation was based on goodness of fitting and prediction-corrected visual predictive checks. The final PopPK/PD model was used to simulate target-controlled infusion (TCI) regimens for typical subjects (e.g., 170 cm, 70 kg). Simulated induction and maintenance dosages across sex and age subgroups (65, 75, and 90 years) were compared with ciprofol label-based recommendations.
Results:
A total of 643 ciprofol plasma concentrations (92% arterial) and 4,173 BIS observations from 40 patients were included in the PopPK-PD modeling. The median age was 74 years (range: 65–90), with a median BMI of 25 kg/m² (range: 18–31). Ciprofol PK was best described by a three-compartment model with first-order elimination, with all PK parameters allometrically scaled to FFM. The BIS response was adequately captured by an IDR model integrated with an effect-site compartment, consistent with the observed hysteresis. A representative 75-year-old, 170 cm, 70 kg male has a clearance of 1.08 L/min, a half-maximal inhibitory concentration (IC50) of 313.2 ng/mL, a response production rate constant (kout) of 0.176 min-1, and an effect-site equilibration rate constant (ke0) of 0.162 min-1. Age was identified as a significant covariate for both the central volume of distribution (V1) and IC50, with increasing age associated with higher V1 and lower IC50. TCI simulations showed higher induction and maintenance doses for males than females, with requirements decreasing as age increased. For patients over 65 years, model-based induction doses were lower than label specifications, and the simulated maintenance doses for a 90-year-old male similarly fell below the labeled dosing regimen. These findings indicate that further dosage adjustments based on sex and age are required to optimize ciprofol administration in geriatric patients.
Conclusion:
The FFM-scaled PopPK–PD model well described the relationship across ciprofol concentrations and BIS in geriatric orthopedic patients by capturing geriatric body composition and age-dependent sensitivity. Model-based simulations indicate lower dose requirements than label recommendations and support the development of effect-site TCI dosing algorithms for this population.
References:
[1] Li X et al., Front Pharmacol. 2021;12:735700.
[2] Bian Y et al., Br J Clin Pharmacol. 2021;87(1):93-105.
[3] Nagapadma M et al., Journal of Contemporary Clinical Practice. 2024;10:499-503.
[4] Liu L et al., J Clin Anesth. 2024;92:111317.
[5] Liu L et al., CPT Pharmacometrics Syst Pharmacol. 2024;13(5):823-836.
[6] Du Bois D et al., Nutrition. 1989;5(5):303-311; discussion 312-313.
[7] Janmahasatian S et al. Clin Pharmacokinet. 2005;44(10):1051-1065.
Reference: PAGE 34 (2026) Abstr 12192 [www.page-meeting.org/?abstract=12192]
Poster: Drug/Disease Modelling - CNS