Soumya Perinparajah1, Sophie Rhodes1, Yin Edwards1, Anna Largajolli1, Li Qin1, Elke H.J. Krekels1,2, Yu-Wei Lin1, Justin Hay1, Piet van der Graaf1,2, S.Y. Amy Cheung1,3
1Certara, 2Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, 3University of Warwick
Introduction: The pediatric population spans from 0 to < 18 years of age, and appropriate parameter scaling across this age range to account for changes in size and maturation is necessary to determine the optimal drug dose for different pediatric age groups. While the extrapolation of adult doses to pediatric doses via exposure matching is sometimes a useful approach, it is not always viable for the pediatric population due to age-dependent differences in PK, PD and/or disease mechanism, present in the therapeutic area of pain [1]. To date, multiple pediatric population PK (popPK) and/or PKPD models have been developed for commonly administered drugs for pain, including analgesics and antipyretics, with various model structures reported for the same drug and different scaling methods implemented based for example on allometry. As such, there is an unmet need to harmonize the PK and/or PKPD scaling for pain medications across the pediatric age ranges [2]. Objectives: •Undertake a literature search to identify previously published pediatric popPK/PKPD models in pain with individual-level data focusing on paracetamol, morphine, and fentanyl •Review identified pain models focusing on parameter scaling methods used Methods: A literature search protocol was first developed to identify previously published pediatric studies reporting popPK and/or PKPD models for paracetamol, morphine, and fentanyl in PubMed. The key inclusion criteria were; any study in subjects < 18 years of age for any pain indication, where paracetamol, morphine, or fentanyl were administered in at least one arm of the study, and the study contained individual-level data for either PK, efficacy, or PKPD endpoints. A literature search was then undertaken according to the protocol. Relevant information pertaining to drug administration, pain indication, and modelling were extracted from the identified models, with a particular focus on the parameter scaling methods used. Results: A total of 28 previously published pediatric studies reporting popPK and/or PKPD models were identified and reviewed for paracetamol (n=8), morphine (n=15), and fentanyl (n=5). Of these, PKPD models were reported in 5 studies (paracetamol, n=1; morphine, n=4) while the remaining studies reported popPK models. The most common pain indication was pre- or post-operative analgesia. The ages of participants across the identified studies spanned the entire pediatric age range (n=3), neonates only (n=7), infants only (n=4), children only (n=3), neonates and infants (n=1), infants and children (n=5), and children and adolescents (n=3). The number of participants (median (range)) in the studies were; 39 (9-144) for paracetamol, 34 (15-875) for morphine, and 72 (14-164) for fentanyl. In terms of scaling, 13 models fixed the allometric exponents, 2 models estimated the exponents and 1 model both fixed and estimated the exponent for clearance. For the models with fixed exponents, these were fixed to 0.75 for clearance and 1 for volume of distribution for the age range of neonates to adolescents. For the models with estimated components (n=2), both conducted in neonates, the range of the estimated weight exponent on clearance was 1.1-1.44, and the value of the estimated weight exponent on volume of distribution was 0.8. In terms of PD, reported endpoints for paracetamol included the pain relief and pain intensity difference score (PRID) and temperature reduction. For, while for morphine, the COMFORT and COMFORT-B scores, and heart rate changes or Premature Infant Pain Profile (PIPP) scores recorded with endotracheal tube suctioning were reported. Conclusion: Fixing allometric exponents was observed as a common parameter scaling method in previously published pediatric popPK/PKPD models for pain medications. Future work will focus on expanding the literature search to include additional drug classes and more PD endpoints across the pediatric age range towards developing a harmonizing framework for PK and/or PKPD scaling for pain medications in the pediatric population.
[1] Bardol M, Pan S, Walker SM, Standing JF, Dawes JM. Pharmacokinetic pharmacodynamic modeling of analgesics and sedatives in children. Paediatr Anaesth. 2023 Oct;33(10):781-792. doi: 10.1111/pan.14712. Epub 2023 Jun 21. PMID: 37341161; PMCID: PMC10947261. [2] Krekels EH, van Hasselt JG, Tibboel D, Danhof M, Knibbe CA. Systematic evaluation of the descriptive and predictive performance of paediatric morphine population models. Pharm Res. 2011 Apr;28(4):797-811. doi: 10.1007/s11095-010-0333-1. Epub 2010 Dec 14. PMID: 21153913; PMCID: PMC3063866.
Reference: PAGE 33 (2025) Abstr 11624 [www.page-meeting.org/?abstract=11624]
Poster: Drug/Disease Modelling - Paediatrics