Drug Delivery Formulations and Devices Tailored for Paediatric and Older Patients

Abstract

“Drugs don’t work in patients who don’t take them,” C. Everett Coop, US Surgeon General (1985). This is a quote widely used in discussions of poor compliance with drug dosing regimens. It is particularly apt in relation to the non-adherence to medications by children and older persons, where ascertaining correct doses in the context of physiological differences according to age profiles is a key consideration in making acceptable formulations and devices for delivery. The concept of the average patient is a myth—there is no average child or older person, hence one formulation will not necessarily be safe and effective for all patients. When a new medicine is submitted to regulatory agencies for approval, clinical trials are generally carried out on patients over the age of 18 and under the age of 65. Trials in “average” patients aim to determine if a medicine will be safe and efficacious, but drugs are also required for patients that lie outside of the average, including paediatrics and older persons. Few drugs have undergone clinical trials in paediatric patients, so in the absence of specific formulations, physicians can opt to use such drugs off-label and/or in an unlicensed fashion (Chen et al., 2021). Off-label use is one when a licenced product is used outside the specifics of the license or label granted by the national regulator. For use in paediatrics and older persons, this might include the age range, the dose level, or its use in other clinical indications. A common mantra in the field of paediatrics is that “children are not small adults”. Childhood spans pre-term infants, full term infants (0–28 days), infants and toddlers (28 days–23 months), children from 2–11 years old, and adolescents from 12 to 16/18 years old. In the absence of a licenced drug, physicians tend to adjust the dose of a drug licenced in adults on a mg/kg basis, use a lower dose strength, or opt for a compounded formulation where preparation errors can be made. In many cases there will be no difference between how a dosage form performs in adults and children and safety and efficacy will not be compromised. The differences between adults and children relevant to dosing include weight, height, body water content, metabolism, gastric pH, gastric emptying, sensitivity to drugs and excipients, and hepatic clearance. Pharmacokinetic (PK) changes may arise in paediatric patients due to differences in body water content that can influence distribution. There may also be altered expression of transporters, enzymes, and carriers that in turn impact absorption, distribution, metabolism, and excretion. Altered expression of metabolising enzymes in paediatric patients can have a profound effect on PK parameters leading to compromised drug and excipient safety. Similarly, the expression of drug targets may be reduced, and this may potentially affect the pharmacodynamic (PD) outcome. When it comes to the formulation, manipulating a dosage form to aide swallowing or to reduce the dose in paediatrics can lead to product instability and lack of bioequivalence with the adult formulation, which adds further to the unpredictable drug behaviour in this patient population. In recent years the European Medicines Agency (2017) has drafted Guidances to promote paediatric medicine development and to create clearer pathways for the paediatric clinical testing of therapeutics (EMA, 2020). It also requires applicants to agree a Paediatric Implementation Plan (PIP) with it if Edited and reviewed by: Maria A. Deli, Biological Research Centre, Hungary