How to optimise drug study design: pharmacokinetics and pharmacodynamics studies introduced to paediatricians

Abstract

ObjectivesIn children, there is often lack of sufficient information concerning the pharmacokinetics (PK) and pharmacodynamics (PD) of a study drug to support dose selection and effective evaluation of efficacy in a randomised clinical trial (RCT). Therefore, one should consider the relevance of relatively small PKPD studies, which can provide the appropriate data to optimise the design of an RCT.MethodsBased on the experience of experts collaborating in the EU‐funded Global Research in Paediatrics consortium, we aimed to inform clinician‐scientists working with children on the design of investigator‐initiated PKPD studies.Key findingsThe importance of the identification of an optimal dose for the paediatric population is explained, followed by the differences and similarities of dose‐ranging and efficacy studies. The input of clinical pharmacologists with modelling expertise is essential for an efficient dose‐finding study.ConclusionsThe emergence of new laboratory techniques and statistical tools allows for the collection and analysis of sparse and unbalanced data, enabling the implementation of (observational) PKPD studies in the paediatric clinic. Understanding of the principles and methods discussed in this study is essential to improve the quality of paediatric PKPD investigations, and to prevent the conduct of paediatric RCTs that fail because of inadequate dosing.

Melatonin pharmacokinetics and dose extrapolation after enteral infusion in neonates subjected to hypothermia

“…In a dose‐escalation study, a low dose is administered first to a group of patients. If safety issues do not arise, a new group of patients receives a higher dose …”

“…Generally, in clinical studies performed in adult subjects, a linear correlation between dose and body surface area is assumed. Dose extrapolation is more complex in neonates because the drug PK may be different due to varied rates of maturation and development of the different organs …”

“…Dose extrapolation is more complex in neonates because the drug PK may be different due to varied rates of maturation and development of the different organs. 22,24,25 Based on previous studies of the safety of melatonin administration, 15,16 we started a dose-escalation study to assess the safety and PK in neonates undergoing hypothermia (ClinicalTrials.gov Identifier: NCT02621944). We started with a melatonin dose of 0.5 mg/kg.…”

Pharmacokinetics and population pharmacokinetics in pediatric oncology

“…Additionally, the amount of blood which can be withdrawn from infants is limited . Population PK (PopPK)/PD modeling has many advantages; it allows time flexible and limited sampling (e.g., 2‐3 samples per patient), quantify variability in concentrations and identify variability sources, as well as extrapolation based on statistical models and simulations with virtual patients to expand population scenarios and further individualize dosing …”

“…6 Population PK (PopPK)/PD modeling has many advantages; it allows time flexible and limited sampling (e.g., 2-3 samples per patient), quantify variability in concentrations and identify variability sources, as well as extrapolation based on statistical models and simulations with virtual patients to expand population scenarios and further individualize dosing. 7,8 In conclusion, knowledge of PK and its variability in the pediatric oncologic population is important in the optimization of (individualized) drug dosing in this population, with the final aim of improving prognosis. However, population PK studies can be complex and difficult to interpret due to their technical nature.…”