Pharmacokinetic studies in children: recommendations for practice and research

Abstract

Optimising the dosing of medicines for neonates and children remains a challenge. The importance of pharmacokinetic (PK) and pharmacodynamic (PD) research is recognised both in medicines regulation and paediatric clinical pharmacology, yet there remain barriers to undertaking high-quality PK and PD studies. While these studies are essential in understanding the dose–concentration–effect relationship and should underpin dosing recommendations, this review examines how challenges affecting the design and conduct of paediatric pharmacological studies can be overcome using targeted pharmacometric strategies. Model-based approaches confer benefits at all stages of the drug life-cycle, from identifying the first dose to be used in children, to clinical trial design, and optimising the dosing regimens of older, off-patent medications. To benefit patients, strategies to ensure that new PK, PD and trial data are incorporated into evidence-based dosing recommendations are needed. This review summarises practical strategies to address current challenges, particularly the use of model-based (pharmacometric) approaches in study design and analysis. Recommendations for practice and directions for future paediatric pharmacological research are given, based on current literature and our joint international experience. Success of PK research in children requires a robust infrastructure, with sustainable funding mechanisms at its core, supported by political and regulatory initiatives, and international collaborations. There is a unique opportunity to advance paediatric medicines research at an unprecedented pace, bringing the age of evidence-based paediatric pharmacotherapy into sight.

Population pharmacokinetics of amikacin in patients with pediatric cystic fibrosis

“…TDM of amikacin aims to minimize risks of toxicity and maximize therapeutic efficacy . Since only a limited number of blood concentrations can be ethically obtained from hospitalized pediatric patients, the PopPK approach using nonlinear mixed‐effect modeling to obtain PK parameters is an ideal tool for PK analysis in this population …”

“…20 The estimation of PK parameters through PopPK methodology allows not only for the analysis of dense data, but also for sparse and unbalanced data or a combination of both, including different types of data, such as those available from routine TDM practice. 8,[21][22][23][24] TDM of amikacin aims to minimize risks of toxicity and maximize therapeutic efficacy. 9,10,25 Since only a limited number of blood concentrations can be ethically obtained from hospitalized pediatric patients, the PopPK approach using nonlinear mixed-effect modeling to obtain PK parameters is an ideal tool for PK analysis in this population.…”

“…9,10,25 Since only a limited number of blood concentrations can be ethically obtained from hospitalized pediatric patients, the PopPK approach using nonlinear mixed-effect modeling to obtain PK parameters is an ideal tool for PK analysis in this population. [21][22][23][24] There are no clinical trials comparing once-daily dose regimen of amikacin vs twice or three times a day in patients with CF pediatric.…”

Implementation of a Physiologically Based Pharmacokinetic Modeling Approach to Guide Optimal Dosing Regimens for Imatinib and Potential Drug Interactions in Paediatrics

“…However, little is known about imatinib interactions with other potential perpetrator drugs in paediatric patients. Conducting a dedicated clinical interaction study in paediatric population remains challenging owing to the ethical and logistical constraints (Barker et al, 2018). Clearly, a feasible and systematic approach to address this gap is warranted.…”

Beyond the Randomized Clinical Trial: Innovative Data Science to Close the Pediatric Evidence Gap

“…6 These pharmacometric modeling approaches are now, despite limited data, being used with success to support neonatal and pediatric drug development as well as dosing of commonly used off-label drugs. 1,4,7 However, recent failures of RCTs in children have taught us that there is more to these studies than confirming model-based predictions. 8 These failures have been attributed to different reasons, such as an increased placebo effect in children, different disease etiology compared with adults, and inadequate dose selection.…”