Modelling and simulation as research tools in paediatric drug development.
OBJECTIVE
Although practical and ethical constraints impose special requirements for the evaluation of treatment safety and efficacy in children, the main issue remains the empirical basis for patient stratification and dose selection at the early stage of the development of new chemical and biological entities. The aim of this review is to highlight the advantages and limitations of modelling and simulation (M&S) in supporting decision making during paediatric drug development.


METHODS
A literature search on Pubmed's database Medical Subject Headings (MeSH) has been performed to retrieve relevant publications on the use of model-based approaches in paediatric drug development and therapeutics.


RESULTS
M&S enable the assessment of the impact of different regimens as well as of different populations on a drug's safety and efficacy profile. It has been widely used in the last two decades to support pre-clinical and early clinical drug development. In fact, M&S have been applied to drug development as decision tools, as study optimization tools and as data analysis tools. In particular, this approach can be used to support dose adjustment in specific subgroups of a population. M&S may therefore allow the individualisation of drug therapy in children, improving the risk-benefit ratio in this population.


CONCLUSIONS
The lack of consensus on how to assess the impact of developmental factors on pharmacokinetics, pharmacodynamics, efficacy and safety has so far prevented a broader use of M&S. This problem is compounded by the limited collaboration between stakeholders, which prevents data sharing in this field. In this article, we emphasise the need for a concerted effort to promote the effective use of this technology in paediatric drug development and avoid unnecessary exposure of children to clinical trials.
Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands.
Francesco
F
Bellanti
Oscar
O
Della Pasqua
D002648:Child; D002986:Clinical Trials as Topic / Q000379:methods; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D008954:Models, Biological; D010372:Pediatrics / Q000379:methods*; D018570:Risk Assessment
Fundam Clin Pharmacol. 2008 Dec;22(6):609-12
19049663
Trends Microbiol. 2007 Jan;15(1):45-50
17113776
Drug Discov Today. 2001 Aug 1;6(15):802-806
11470589
Br J Clin Pharmacol. 2010 Oct;70(4):597-603
21087295
Clin Pharmacol Ther. 2010 Mar;87(3):270-1
20160747
Nat Rev Drug Discov. 2003 Mar;2(3):192-204
12612645
Ann N Y Acad Sci. 2005 Aug;1053:505-18
16179559
J Biopharm Stat. 2009;19(3):437-55
19384687
J Clin Pharmacol. 2003 Apr;43(4):329-41
12723454
Fundam Clin Pharmacol. 2008 Dec;22(6):599-604
19049661
Br J Clin Pharmacol. 2005 Jun;59(6):663-9
15948929
Cephalalgia. 2009 Jul;29(7):772-80
19281474
J Am Coll Cardiol. 2005 Oct 4;46(7):1322-30
16198851
Rheumatology (Oxford). 2005 Jul;44(7):846-59
15855183
Br J Clin Pharmacol. 2008 Dec;66(6):846-53
19032726
Diabetes. 2001 Jan;50(1):150-8
11147781
Eur J Anaesthesiol. 2009 Feb;26(2):105-10
19156973
Eur J Clin Pharmacol. 2009 Aug;65(8):849-50; author reply 851-2
19396437
Metabolism. 2008 Apr;57(4):445-7
18328342
J Clin Pharm Ther. 2007 Feb;32(1):57-79
17286790
Br J Clin Pharmacol. 2002 Oct;54(4):415-22
12392590
Mol Biosyst. 2006 Jun;2(6-7):288-91
16880946
Birth Defects Res B Dev Reprod Toxicol. 2004 Oct;71(5):303-20
15505806
Clin Pharmacol Ther. 2010 Mar;87(3):294-302
20107435
Basic Clin Pharmacol Toxicol. 2005 Mar;96(3):228-34
15733219
Trends Pharmacol Sci. 2008 Apr;29(4):186-91
18353445
Drug Discov Today. 2009 Mar;14(5-6):316-20
19059496
Clin Pharmacol Ther. 2010 Sep;88(3):375-82
20686477
J Clin Pharmacol. 2009 Aug;49(8):889-904
19531673
Clin Pharmacol Ther. 2007 Jul;82(1):21-32
17522597
Clin Pharmacol Ther. 2009 Sep;86(3):248-54
19657333
Fundam Clin Pharmacol. 2008 Dec;22(6):575-8
19049657
AAPS J. 2009 Mar;11(1):155-66
19280352
Br J Clin Pharmacol. 2009 Oct;68(4):493-501
19843052
J Clin Pharmacol. 2005 Mar;45(3):246-56
15703360
Fundam Clin Pharmacol. 2008 Dec;22(6):589-94
19049659
Pharmacoepidemiol Drug Saf. 2007 Jul;16 Suppl 1:S2-S15
17546573
Annu Rev Pharmacol Toxicol. 2009;49:291-301
18851702
Drug Discov Today. 2008 Apr;13(7-8):341-6
18405847
Eur J Pediatr. 2006 Nov;165(11):741-6
16807730
Oncology (Williston Park). 2002 Oct;16(10 Suppl 11):37-44
12435172
Fundam Clin Pharmacol. 2008 Dec;22(6):579-87
19049658
Pediatrics. 2008 Mar;121(3):530-9
18310202
Biochem Soc Trans. 2010 Oct;38(5):1294-301
20863302
Stud Health Technol Inform. 2005;111:37-42
15718695
Drug Discov Today. 2002 Oct 15;7(20 Suppl):S192-6
12546905
Eur J Pharm Sci. 2001 May;13(2):115-22
11297895
Br J Clin Pharmacol. 2008 Apr;65(4):511-22
17995971
Toxicol Lett. 2003 Feb 18;138(1-2):29-49
12559691