M. Bardol (1), V. Fellman (2,3), E. Norman (3), A. Rane (4) J. Standing (1)
(1) Infection, Inflammation and Rheumatology Section, UCL Great Ormond Street Institute of Child Heath, University College London, London, UK(2) Children´s Hospital, University of Helsinki, Helsinki, Finland(3) Department of Clinical Sciences, Pediatrics, Lund, Lund University and Skåne University Hospital, Lund, Sweden(4) Karolinska University Hospital and Karolinska Institutet, Division of Clinical Pharmacology, Stockholm, Sweden
Objectives: The aim of this work was to develop a population pharmacokinetic model for a new formulation of fentanyl 5 μg/mL in preterm infants.
Methods: This PK study is part of a PK/PD/PG study designed to optimize fentanyl dosage for procedural pain in newborn preterm infants. 25 infants born with gestational age between 23.3 and 30.7 weeks were included. They received 0.5 μg/kg before skin-breaking procedures or 2 μg/kg before tracheal intubation. Physiologic parameters were monitored. The median gestational age and weight were 27 weeks and 0.85 kg, respectively. Population pharmacokinetic modelling was undertaken with NONMEM 7.4. One-, two- and three-compartment structural models were tested to define the basic structural model and size and age were tested as covariates. Body weight and postmenstrual age (PMA) were included in the model using an allometric weight scaling and a sigmoidal maturation function, respectively [1]. The value below the limit of quantification (12%) were included using the M3 method. The final model was validated using prediction corrected visual predictive check (PC-VPC).
Results: A two compartment model with allometric scaling and fixed maturation function adequately described fentanyl concentration in this specific population. The estimates of the PK parameters (standardized to 70 kg) were: Clearance (CL) = 55.7 L/h (CV 18%), central volume of distribution (V1)= 179 L (CV 15%) with an interindividual variability of 31% (CV 54%), peripheral volume of distribution (V2)= 83.9 L/h (CV 23%), and inter-compartmental clearance (Q)= 17.5 L/h (CV 19%). Allometric weight exponent fixed to 0.75 for clearances and 1 for volumes of distribution provided a good fit of the model and clearance was best described fixing parameters of the maturation function to values estimated from a previous study [2]. Global PK parameters CL and steady state volume of distribution (Vss) calculated for the studied population were 0.10 L/h and 3.2 L, respectively.
Conclusions: A semi-mechanistic population PK model has been developed that can adequately describe the fentanyl plasma concentration in preterm infants. CL in this population is affected by both PMA and weight. To our knowledge, this study is the first one to include change in organ maturation in a mechanistic model to describe the fentanyl clearance in a neonate cohort. Further analysis will be done to investigate the influence of the genotype on the PK, and the relationship between PK and analgesic effect evaluated using pain scales (PK/PD modelling).
References:
[1] Germovsek, E., C. I. Barker, M. Sharland, and J. F. Standing. 2017. “Scaling clearance in paediatric pharmacokinetics: All models are wrong, which are useful?” Br J Clin Pharmacol 83 (4): 777–90
[2] Anderson, B. J., and P. Larsson. 2011. “A maturation model for midazolam clearance.” Paediatr Anaesth 21 (3): 302–8
Reference: PAGE 28 (2019) Abstr 9163 [www.page-meeting.org/?abstract=9163]
Poster: Drug/Disease Modelling - Paediatrics