No abstract

3D printing of pediatric-centered drug formulations can provide suitable alternatives to current treatment options, though further research is still warranted for successful clinical implementation of these innovative drug products. Extensive research has been conducted on the compliance of 3D-printed drug products to a pediatric quality target product profile. The 3D-printed tablets were of particular interest in providing superior dosing and release profile similarity compared to conventional drug manipulation and compounding methods, such as oral liquids. In the future, acceptance of 3D-printed tablets in the pediatric patient population might be better than current treatments due to improved palatability. Further research should focus on expanding clinical knowledge, providing regulatory guidance and expansion of the product range, including dosage form possibilities. Moreover, it should enable the use of diverse good manufacturing practice (GMP)-ready 3D printing techniques for the production of various drug products for the pediatric patient population.

Personalized medicine is currently hampered by the lack of flexible drug formulations. Especially for pediatric patients, manual compounding of personalized drug formulations by pharmacists is required. Three‐Dimensional (3D) printing of medicines, which enables small‐scale manufacturing at the point‐of‐care, can fulfill this unmet clinical need. This study investigates the feasibility of developing a 3D‐printed tablet formulation at the point‐of‐care which complies to quality requirements for clinical practice, including bioequivalence. Development, manufacturing, and quality control of the 3D‐printed tablets was performed at the manufacturing facility and laboratory of the department of Clinical Pharmacy and Toxicology at Leiden University Medical Center. Sildenafil was used as a model drug for the tablet formulation. Along with the 3D‐printed tablets a randomized, an open‐label, 2‐period, crossover, single‐dose clinical trial to assess bioequivalence was performed in healthy adults. Bioequivalence was established if areas under the plasma concentration curve from administration to the time of the last quantifiable concentration (AUC0‐t) and maximum plasma concentration (Cmax) ratios were within the limits of 80.00–125.00%. The manufacturing process provided reproducible 3D‐printed tablets that adhered to quality control requirements and were consequently used in the clinical trial. The clinical trial was conducted in 12 healthy volunteers. The 90% confidence intervals (CIs) of both AUC0‐t and Cmax ratios were within bioequivalence limits (AUC0‐t 90% CI: 87.28–104.14; Cmax 90% CI: 80.23–109.58). For the first time, we demonstrate the development of a 3D‐printed tablet formulation at the point‐of‐care that is bioequivalent to its marketed originator. The 3D printing of personalized formulations is a disruptive technology for compounding, bridging the gap toward personalized medicine.

Background and importance Many medications have been implicated in prolonging the QT interval, and additional agents continue to be identified. Concomitant use of QT prolonging agents increases the risk of adverse events. Our hospital uses electronic medication records with a built-in drugdrug interaction (DDI) database that enables different analyses in prespecified populations. DDI analyses are part of a hospital/clinical pharmacist's work in our hospital. Aim and objectives The aim of the study was to characterise QT prolonging DDIs in patients admitted to the cardiovascular department in the university hospital. Another objective was to compare DDI risk ratings in our built-in DDI database with two distinct DDI databases, to find possible differences and to further determine clinical significance. Material and methods The study population consisted of patients hospitalised in the cardiovascular department who experienced at least one QT DDI during hospitalisation. Only DDIs with overall significance ratings of 5 or 6 on the 0-6 scale, with a QT prolonging mechanism, were included in the analysis. The cardiovascular department has 50 standard beds and 12 ICU beds. The study period was January to December 2019. DDI data were retrospectively extracted from electronic medication records. The respective electronic medical records were manually reviewed for additional information. The analyses were performed using descriptive statistics methods. Results 3.7% of the patients admitted to the cardiovascular department (230/6250) experienced at least one QT DDI (study population). Single and multiple QT DDIs were more common in ICU patients than in standard unit patients. The most frequently involved agents were amiodarone, melperone, tiapride, citalopram, ciprofloxacin, tramadol, escitalopram, clarithromycin and sertraline. A maximum number of nine QT DDIs was found in one patient. Seven patients experienced drug associated long QT syndrome. DDI risk rating in our built-in database was considerably more stringent than in the comparator database (Lexi-Interact). Conclusion and relevance The analysis revealed that QT DDIs were frequent among patients hospitalised in the cardiovascular department. The DDI database should be viewed as a guide, not an algorithm. Some QT DDIs rated as highly significant by our built-in DDI database seemed to have a low clinical impact in real world settings. It is useful to consult more sources or seek expert opinion, if in doubt. The role of the hospital/clinical pharmacist as a consultant seems essential.