Scaling pharmacodynamics in children: Lessons from immunology, infectious diseases and critical care
Joseph F Standing (1,2,3)
(1) Infection, Immunity, Inflammation Programme, UCL Great Ormond Street Institute of Child Health, London, UK; (2) Department of Pharmacy, Great Ormond Street Hospital for Children, London, UK; (3) Paediatric Infectious Diseases Group, St George’s, University of London, UK.
Objectives: With changes to medicines regulation in recent years, under 18 year olds are no longer “therapeutic orphans” but a group of patients that all drug developers need to consider. Using examples, this presentation will consider pharmacodynamic scaling to help answer: Can we assume equal effect with equal PK exposure? How can modelling support extrapolation of PD?
Overview: The paradigm in much of paediatric PK research once centred on the philosophy “children are not small adults” and hence all possible should be known about the physiological differences with potential impact [1-4]. More useful perhaps than merely listing differences, is to know how PK scales with size and age, and this has been addressed as early as 1950 [5], then refined to account for maturation [6,7] and now explained using PBPK scaling [8]. Whilst it has been suggested that matching PK exposure in children maybe sufficient to understand PD, in practice regulatory approval requires an indication of PD equivalence [9]. Some examples of our recently published and ongoing work in PD scaling from immunology [10], infectious diseases and critical care/anaesthesia [11] will be discussed.
Conclusions: PD scaling requires a heterogeneous range of data sources and can be complicated by differing PD measures with age, but whether and how to scale will be necessary for rational paediatric drug development and dosing guidelines.
References:
[1] Kearns GL et al. NEJM, 2003;349:1157-67.
[2] de Zwart LL et al. Reg Tox Pharmacol., 2004;39:282-309.
[3] Morselli PL et al. Clin PK, 1980;5:485-527.
[4] Gilman JT. Clin. PK, 1990;19:1-10.
[5] Crawford JD et al. Pediatrics, 1950;5:783-90.
[6] Tod M et al. Clin Pharmacokinet., 2008;47: 231-243
[7] Holford NH et al. J Pharm Sci, 2013;102:2941-2952.
[8] Calvier EA et al., Clin Pharmacokinet. 2017;56:273-285
[9] Mehrotra N et al. Drug Metab Dispos., 2016;44:924-33.
[10] Hoare RL et al. Clin Pharmacol Ther. 2017;Jan 11[Epub ahead of print]
[11] Sciusco A et al. Paediatr Anaesth. 2017;27 :399-408
