Iztok Grabnar (1), Štefan Grosek (2,3,4), Barbara Ostanek (1), Mojca Kerec Kos (1)
(1) University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia, (2) University Medical Centre Ljubljana, Department of Perinatology, Ljubljana, Slovenia, (3) Department of Pediatric Surgery and Intensive Therapy, Ljubljana, Slovenia, (4) University of Ljubljana, Medical Faculty, Ljubljana, Slovenia
Objectives: Children with severe acute bronchiolitis often require mechanical ventilation with sedation to decrease anxiety and discomfort of the intubation. Opioid agonist fentanyl is used as a first-line treatment, mostly in combination with midazolam [1, 2]. Drug dosing in this patient group is challenging due to complex pharmacokinetics (PKs) and pharmacodynamics (PDs) changing rapidly during the first year of life. Furthermore, long-term treatment with fentanyl is associated with tolerance development. We aimed to develop a population PK-PD model of fentanyl sedation in critically ill children younger than 2 years to optimise the long-term treatment. Additionally, we aimed to explore the influence of common polymorphisms of the catechol O-methyltransferase, opioid receptor m1, and ABCB1 genes.
Methods: We included 49 children (median age 2.2 months, median body weight 5.3 kg) on intravenous infusion with fentanyl for at least 3 days. Five blood samples were taken for PK analysis (5 min, 15 min, 60 min, 12 h after the start of the infusion, and just before stopping the infusion). Sedation and anaesthesia were monitored by COMFORT-B scale and bispectral index score (BIS). COMT Val158Met, ABCB1 C3435T and OPRM1 A118G genetic polymorphisms were determined. Population PK-PD model was developed using NONMEM 7.4. The PK-PD model was built sequentially. One and two compartment PK models were fitted to fentanyl plasma concentration data. Sigmoid Emax, Emax and log-linear concentration-effect models using direct-link and effect compartment model were tested to assess PD relationships with BIS and COMFORT-B. Tolerance was modelled using the approach originally proposed by Porchet et al [3] by modelling net pharmacological effect of the interaction of fentanyl and accumulation of the hypothetical inhibitor in its effect compartment. Various types of interaction derived from receptor theory, including reverse agonist, competitive agonist, non-competitive agonist and partial agonist were evaluated.
Results: The final PK model of fentanyl was a two compartment model with the estimated volume of central compartment 109 L/70 kg, volume of peripheral compartment 39.9 L/70 kg, clearance 36.6 L/h/70 kg, and distribution clearance 87.1 L/h/70 kg. Theoretic allometric relationship of PK parameters with body weight was used. Maturation of clearance with postmenstrual age (PMA) was assessed with a sigmoidal maturation function. The estimated value of PMA50 was 43.5 weeks. PK-PD relationships with COMFORT-B and BIS were adequately described by a direct-link sigmoidal Emax model and tolerance was modelled as an interaction with partial agonist. COMT genotype was associated with the fentanyl effect on COMFORT-B. The potency of fentanyl was higher (80% lower C50) in carriers of variant allele compared to patients who were homozygous wild-type. Additionally, C50 increased with PMA. In the model for BIS, efficacy of fentanyl was higher in patients homozygous for variant ABCB1 allele (15% higher Emax), while older children had higher C50 and Emax.
Conclusion: In the developed PK-PD models bodyweight, PMA, COMT and ABCB1 gene polymorphisms influenced the levels of sedation achieved by continuous infusion of fentanyl. The model can be used for fentanyl dosing regimen design to optimize sedation in critically ill children with acute bronchiolitis.
References:
[[1] Vet NJ et al. Sedation in Critically Ill Children with Respiratory Failure. Front Pediatr 2016, 24 (4): 89.
[2] Lamas A, Lopez – Herce J. Monitoring sedation in the critically ill child. Anaesth 2010, 65: 516–524.
[3] Porchet HC, Benowitz NL, Sheiner LB. Pharmacodynamic Model of Tolerance: Application to Nicotine. J Pharmacol Exp Ther 1988, 244 (1), 231-236.
Reference: PAGE 30 (2022) Abstr 10126 [www.page-meeting.org/?abstract=10126]
Poster: Drug/Disease Modelling - CNS