Sheng Xu1, Yuanyuan Huang1, Nassim DJEBLI2, Hao Jiang1
1Jiangsu Hengrui Pharmaceuticals, 2Luzsana Biotechology
Introduction: Dexmedetomidine, a selective a2 receptor agonist, has emerged as a vital component in the field of anesthesia and sedation due to its unique properties1. It induces easily reversible, sleep-like sedation with minimal respiratory effects and has a short elimination half-life2,3. Due to these advantages, it is widely used as a pre-anesthetic sedative for children in both non-invasive and invasive procedures4.The world’s first dexmedetomidine nasal spray was developed by Jiangsu Hengrui Medicine Co., Ltd., and was approved in China in 2023 for preoperative sedation and anxiety relief in adults and children. This innovative formulation significantly improves patient compliance, especially among pediatric populations who may have difficulty with oral or intravenous administration5. Objective: This analysis aimed at characterizing the population pharmacokinetics (PopPK) of dexmedetomidine hydrochloride nasal spray for preoperative sedation in adults and children. Additionally, the study aimed at analyzing the exposure-efficacy relationship in pediatric patients via the prediction of Ramsay scale. Methods: The PopPK model was developed based on data from two studies involving healthy Chinese adults, one study with Chinese adult patients undergoing elective general anesthesia surgery, and one study with pediatric patients aged 2 to 6 years undergoing elective comprehensive surgery. One of the healthy adults’ studies included both intravenous (IV) and nasal spray administration data while the 3 other studies included nasal spray administration data only. The covariates significantly affecting the PK were analyzed via a stepwise covariate method (SCM), while the model qualification was performed using bootstrap approach and prediction-corrected visual predictive checks (pcVPC). Logistic regression modeling was used to analyze the relationship between the Cmax within 45 min and the proportion of subjects who achieved Ramsay scale=3 within 45 minutes of intranasal administration. Results: A total of 1,294 PK concentration data points from 231 subjects were included in the PopPK analysis, comprising 35 pediatric patients and 196 adult subjects. The final model was best described by a two-compartment model with first-order absorption and linear elimination, with an estimated bioavailability of 70.8%. Body weight was retained as a significant covariate on distribution and elimination parameters via allometric scaling, as previously reported6,7. In addition, the central volume of distribution was impacted by the population (i.e. 85.9L in patients versus 28L for healthy subjects). The remaining parameters of the final model included a clearance (CL) of 35.8 L/h, intercompartmental distribution clearance (Q) of 104 L/h, peripheral volume of distribution of 86.3 L, absorption rate constant (KA) of 1.29 h?¹, and an absorption lag time (ALAG) of 0.0618 h. The between-subject variability was estimated on CL and V2. Logistic regression analysis showed a significant exposure-response relationship between Cmax within 45 min and the proportion of Ramsay scale=3 in both pediatric and adult groups. The concentration slope was very similar between pediatric and adult subjects (i.e. ~0.01), while the intercept was 0.069 for pediatric patients versus 0.31 for adults. Conclusion: This analysis reports the PopPK model built for dexmedetomidine nasal spray in both Chinese adults and children. The body weight was identified as a covariate influencing drug distribution and clearance. Once body weight-dose adjustment was applied, the pediatric population had similar PK exposure and efficacy to adults. Current dosing guidelines (i.e. 30 µg nasal spray for children weighing 10.7 to less than 19.4 kg and 50 µg for those weighing 19.4 to 28.0 kg) are deemed effective and well-tolerated. These findings not only enhance our understanding of dexmedetomidine’s pharmacokinetics but also provide practical recommendations for optimizing therapeutic outcomes in clinical practice. Key word: Dexmedetomidine; Nasal Spray; PopPK; Pediatric; Exposure-efficacy.
1. Carollo, D. S., Nossaman, B. D. & Ramadhyani, U. Dexmedetomidine: A review of clinical applications. Curr Opin Anaesthesiol 21, 457–461 (2008). 2. Nelson, L. E. et al. The 2-Adrenoceptor Agonist Dexmedetomidine Converges on an Endogenous Sleep-promoting Pathway to Exert Its Sedative Effects. Anesthesiology 98, (2003). 3. Weerink, M. A. S. et al. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clin Pharmacokinet 56, 893–913 (2017). 4. Filho, E. M., Robinson, F., Carvalho, W. B. De, Gilio, A. E. & Mason, K. P. Intranasal dexmedetomidine for sedation for pediatric computed tomography imaging. Journal of Pediatrics 166, 1313-1315.e1 (2015). 5. McClean, C. H., Alsabri, M. H., Tahir, S., Song, R. & Chin, C. Intranasal drug delivery in pediatric emergency departments: brief review and future outlook. Pediatric Emergency Medicine Journal 10, 109–117 (2023). 6. James, N. T. et al. Population pharmacokinetic analysis of dexmedetomidine in children using real-world data from electronic health records and remnant specimens. Br J Clin Pharmacol 88, 2885–2898 (2022). 7. Song, I. K. et al. A population pharmacokinetic model of intravenous dexmedetomidine for mechanically ventilated children after neurosurgery. J Clin Med 8, (2019).
Reference: PAGE 33 (2025) Abstr 11410 [www.page-meeting.org/?abstract=11410]
Poster: Drug/Disease Modelling - Paediatrics