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Aim: Interprofessional collaboration is particularly relevant to patient safety in outpatient care with polypharmacy. The educational project "PILLE" is meant to give medical and pharmacy students an understanding of the roles and competencies needed for cooperation in the provision of healthcare and to enable interprofessional learning.Method: The curriculum is aimed at pharmacy and medical students and was developed in six steps according to the Kern cycle. It is comprised of an interprofessional seminar, a joint practical training in a simulated pharmacy, and a tandem job shadowing at a primary care practice.The project was implemented in three stages due to the pandemic: The interprofessional online seminar based on the ICAP model and the digital inverted classroom was held in the 2020 winter semester; the interprofessional practical training was added in the 2021 summer semester; and the interprofessional tandem job shadowing at a primary care practice in the 2021 winter semester.Attitudes toward interprofessional learning, among other things, was measured in the evaluation using the SPICE-2D questionnaire (Student Perceptions of Physician-Pharmacist Interprofessional Clinical Education).Results: In the first three semesters, a total of 105 students (46 pharmacy, 59 medicine) participated in the project, of which 78 participated in the evaluation (74% response rate). The students stated, in particular, that they had learned about the competencies and roles of the other profession and desired additional and more specific preparatory materials for the course sessions. The SPICE-2D questionnaire showed high values for both groups of students already in the pre-survey and these increased further as a result of the project.Conclusion: Joint case-based learning could be implemented under the conditions imposed by the pandemic. Online teaching is a low-threshold means to enable interprofessional exchange. Zielsetzung: In der ambulanten Versorgung von Patient*innen mit Polypharmazie ist interprofessionelle Zusammenarbeit für die Patientensicherheit besonders relevant. Das Lernprojekt PILLE soll Rollenverständnis und Kompetenzen für eine kooperative Versorgung an Pharmazie- und Medizinstudierende vermitteln und interprofessionelles Lernen ermöglichen.Methodik: Das Curriculum wurde nach dem Kern-Zyklus in sechs Schritten entwickelt und umfasst ein interprofessionelles Seminar, eine gemeinsame Fallbearbeitung in einer Simulationsapotheke und eine Hospitation in einer Hausarztpraxis für Pharmazie- und Medizinstudierende. Pandemiebedingt wurde das Lernprojekt in drei Stufen implementiert: im Wintersemester 2020 das Online-Seminar basierend auf dem ICAP-Modell und dem Konzept des digitalen inverted classroom, im Sommersemester 2021 ergänzend das interprofessionelle Praktikum und im Wintersemester 2021 die Hospitation in einer Hausarztpraxis. In der Evaluation wurde u.a. die Einstellung zu interprofessionellem Lernen mit dem SPICE-2D Fragebogen (Student Perceptions of Physician-Pharmacist Interprofessional Clinical Education) erhoben.Ergebnisse: In den ersten drei Semestern nahmen insgesamt 105 Studierende (46 Pharmazie, 59 Medizin) am Lernprojekt teil, davon beteiligten sich 78 an der Evaluation (74% Rücklauf). Die Studierenden geben an, besonders zu Kompetenzen und Rolle der anderen Berufsgruppe gelernt zu haben und wünschen sich weitere gezielte Vorbereitungsmaterialien für den Unterricht. Der SPICE-2D Fragebogen zeigt bereits vorab hohe Werte bei beiden Studierendengruppen, die sich durch das Lernprojekt weiter erhöhten.Schlussfolgerung: Gemeinsames fallbasiertes Lernen war unter Pandemiebedingungen umsetzbar. Online-Lehre bietet eine niedrigschwellige Möglichkeit, interprofessionellen Austausch zu ermöglichen.

CONTEXT: Optimisation of hydrocortisone replacement therapy is important to prevent under- and over dosing. Hydrocortisone pharmacokinetics is complex as circulating cortisol is protein bound mainly to corticosteroid-binding globulin (CBG) that has a circadian rhythm. OBJECTIVE: A detailed analysis of the CBG circadian rhythm and its impact on cortisol exposure after hydrocortisone administration. DESIGN AND METHODS: CBG was measured over 24 h in 14 healthy individuals and, employing a modelling and simulation approach using a semi-mechanistic hydrocortisone pharmacokinetic model, we evaluated the impact on cortisol exposure (area under concentration-time curve and maximum concentration of total cortisol) of hydrocortisone administration at different clock times and of the changing CBG concentrations. RESULTS: The circadian rhythm of CBG was well described with two cosine terms added to the baseline of CBG: baseline CBG was 21.8 μg/mL and inter-individual variability 11.9%; the amplitude for the 24 h and 12 h cosine functions were relatively small (24 h: 5.53%, 12 h: 2.87%) and highest and lowest CBG were measured at 18:00 and 02:00, respectively. In simulations, the lowest cortisol exposure was observed after administration of hydrocortisone at 23:00-02:00, whereas the highest was observed at 15:00-18:00. The differences between the highest and lowest exposure were minor (≤12.2%), also regarding the free cortisol concentration and free fraction (≤11.7%). CONCLUSIONS: CBG has a circadian rhythm but the difference in cortisol exposure is ≤12.2% between times of highest and lowest CBG concentrations; therefore hydrocortisone dose adjustment based on time of dosing to adjust for the CBG concentrations is unlikely to be of clinical benefit.

Background and objective: Optimisation of hydrocortisone replacement therapy in children is challenging as there is currently no licensed formulation and dose in Europe for children under 6 years of age. In addition, hydrocortisone has non-linear pharmacokinetics caused by saturable plasma protein binding. A paediatric hydrocortisone formulation, Infacort ® oral hydrocortisone granules with taste masking, has therefore been developed. The objective of this study was to establish a population pharmacokinetic model based on studies in healthy adult volunteers to predict hydrocortisone exposure in paediatric patients with adrenal insufficiency. Methods: Cortisol and binding protein concentrations were evaluated in the absence and presence of dexamethasone in healthy volunteers (n = 30). Dexamethasone was used to suppress endogenous cortisol concentrations prior to and after single doses of 0.5, 2, 5 and 10 mg of Infacort ® or 20 mg of Infacort ® /hydrocortisone tablet/hydrocortisone intravenously. A plasma protein binding model was established using unbound and total cortisol concentrations, and sequentially integrated into the pharmacokinetic model. Results: Both specific (non-linear) and non-specific (linear) protein binding were included in the cortisol binding model. A two-compartment disposition model with saturable absorption and constant endogenous cortisol baseline (Baseline cort ,15.5 nmol/L) described the data accurately. The predicted cortisol exposure for a given dose varied considerably within a small body weight range in individuals weighing < 20 kg. Conclusions: Our semi-mechanistic population pharmacokinetic model for hydrocortisone captures the complex pharmacokinetics of hydrocortisone in a simplified but comprehensive framework. The predicted cortisol exposure indicated the importance of defining an accurate hydrocortisone dose to mimic physiological concentrations for neonates and infants weighing < 20 kg. EudraCT number: 2013-000260-28, 2013-000259-42.

Recent work on Model Informed Drug Discovery and Development (MID3) has noted the need for clarity in model description used in quantitative disciplines such as pharmacology and statistics. 1-3 Currently, models are encoded in a variety of computer languages and are shared through publications that rarely include original code and generally lack reproducibility. The DDMoRe Model Description Language (MDL) has been developed primarily as a language standard to facilitate sharing knowledge and understanding of models.

Tesofensine is a centrally acting drug under clinical development for Alzheimer's disease, Parkinson's disease and obesity. In vitro, the major metabolite of tesofensine (M1) displayed a slightly higher activity, which however has not been determined in vivo. The aims of this investigation were (i) to simultaneously accomplish a thorough characterization of the pharmacokinetic (PK) properties of tesofensine and M1 in mice and (ii) to evaluate the potency (pharmacodynamics, PD) and concentration-time course of the active metabolite M1 relative to tesofensine and their impact in vivo using the PK/PD modelling approach.Parent compound, metabolite and vehicle were separately administered intravenously and orally over a wide dose range (0.3-20 mg kg(-1)) to 228 mice. Concentrations of tesofensine and M1 were measured; inhibition of the dopamine transporter was determined by co-administration of [(3)H]WIN35,428 as the pharmacodynamic measure.Pharmacokinetics of tesofensine and M1 were best described by one-compartment models for both compounds. Nonlinear elimination and metabolism kinetics were observed with increasing dose. The PK/PD relationship was described by an extended E(max) model. Effect compartments were used to resolve observed hysteresis. EC(50) values of M1, as an inhibitor of the dopamine transporter, were 4-5-fold higher than those for tesofensine in mice.The lower potency of M1 together with approximately 8-fold higher through steady-state concentrations suggest that M1 did contribute to the overall activity of tesofensine in mice.