Matilde Merino-Sanjuán

Background/Objectives: While intravitreal administration allows for increased ocular exposure to anti-TNF-α monoclonal antibodies, there is still a need for developing delivery systems able to prolong ocular drug exposure and alleviate patient compliance and safety concerns because of repeated injections. Therefore, the objective of this work was to guide the design of sustained-release formulations of anti-TNF-α monoclonal antibodies for intravitreal administration through a model-based strategy in non-infectious uveitis in the preclinical setting. Methods: Using an in-house-developed anterior uveitis disease model in rats, an intravenous reference dose reducing free TNF-α by 90% at the biophase was established. Intravitreal administrations of sustained-release formulations every 24 weeks were then simulated for adalimumab, golimumab and infliximab to evaluate TNF-α kinetics in the anterior chamber of the eye at different release rates. The selected sustained-release formulation was further evaluated for possible formulation issues causing device emptying before the next administration. Results: Intravitreal administration of sustained-release formulations releasing adalimumab, golimumab or infliximab at 1.802, 0.979 and 1.442 μg/week, respectively, met the predefined criteria of ≥90% reduction in free TNF-α at the biophase. TNF-α levels in aqueous humour were anticipated to be the most sensitive to detect possible formulation issues. Formulation emptying 10, 4 or 8 weeks for adalimumab, golimumab and infliximab, respectively, before next administration triggered TNF-α reaching pathological levels at week 24 post-dose. Conclusions: This work underscores the potential of new approach methodologies in the preclinical drug development of sustained-release formulations for intravitreal administration in ocular inflammatory disorders with less animal testing and without compromising the accuracy of model-informed predictions for human translation.

Introduction: To evaluate [18F]Fluodeoxyglucose ([18F]FDG) distribution in a murine model of myocardial infarction (MI), using Positron Emission Tomography and Computed Tomography (PET/CT) to validate this approach for use in evaluating new therapies for MI treatment. Method: MI was induced by permanent ligation of the left anterior descending coronary artery. The study included a sham group, a group with 7 days infarction (acute infarction) and another with 21 days infarction (chronic infarction). Prior to euthanasia, each group was imaged by PET/CT approximately 60 minutes after injection of [18F]FDG. Total and maximal Region of Interest and Standard Uptake Value values were obtained using CT, which enables more precise delineation of the anatomy to assess between-group differences in [18F]FDG uptake in the heart, brain and bladder. Results: Following distribution of [18F]FDG throughout the body, at 60 minutes after injection homogeneous cardiac distribution of the radiopharmaceutical was observed in the healthy group, while in the infarcted groups there was an absence of uptake in the infarct area. Using ANOVA analysis and the Kruskal-Wallis test, statistically significant differences were detected between the healthy and acute infarction groups and the acute and chronic infarction groups. There were no significant differences between the three groups in brain uptake or radiopharmaceutical clearance. Conclusions: The microPET/CT technique has the sensitivity to detect infarcted areas in the murine model. Moreover, it allows us to quantify [18F]FDG uptake and thus assess uptake by the organs in the different groups studied.

Background: Physiologically based pharmacokinetic (PBPK) modeling for biopharmaceutics applications (i.e., physiologically based biopharmaceutics modeling (PBBM)) enables mechanistic modeling from dissolution to absorption and disposition, facilitating the prediction of bioequivalence (BE) outcomes and the delimitation of the safe space. This study aims to identify the product-related parameter driving ibuprofen dissolution to upgrade an existing PBPK model, so that an in vitro safe space and virtual BE (VBE) predictions of IR ibuprofen tablets can be performed. Methods: C_max within- and between-subject variabilities of a previous PBPK model were optimized after identifying crucial physiological parameters for ibuprofen absorption and disposition. In vitro data modeling was performed to estimate the value of the parameter driving ibuprofen dissolution. A safe space was defined for this parameter and the sample size to declare BE was calculated. Finally, VBE simulations were performed to explore the effect of sample size as well as number of trial replicates and runs. Results: C_max variability was adequately predicted after changing V_ss and MRT in stomach and small intestine CV (%) to 10 and 150%, respectively. Particle surface pH was identified as the dissolution key parameter for ibuprofen. A safe space for test product surface pH values of 5.64–6.40 was defined in order to achieve a 90%CI for the C_max ratio within the 80–125% range when the reference product surface pH is 6.02. R-ibuprofen was identified as the most discriminative enantiomer. VBE studies with 24 individuals showed BE outcomes that are sensitive to the number of trial replicates and runs. Conclusions: Ibuprofen particle surface pH has been identified as the in vitro parameter governing dissolution in maleate buffer 7 mM with HCl pH 2.0 pretreatment, allowing to establish an in vitro safe space useful for calculating sample sizes and to evaluate the BE success rate through PBBM/PBPK model-informed VBE simulations.

Background/Objectives: Patient care and control of inflammatory disorders, such as psoriasis, can be improved by model-informed precision dosing (MIPD) techniques based on population pharmacokinetic/pharmacodynamic (PK/PD) models. Clinical dose selection decisions based on MIPD strategies need to take account of the uncertainty associated with the individual PK/PD model parameters, which is determined by the quantity of individual observational data collected in clinical practice. Methods: The aim of this study was to propose an approach for personalized dosage regimens of secukinumab (SCK) in 22 Spanish patients with plaque psoriasis, whose severity level was considered moderate to severe, taking into account the uncertainty associated with individual parameters in a population-based PK/PD model. Results: The link between SCK serum concentrations and Psoriasis Area and Severity Index (PASI) scores was explained using an indirect response model. A maximum inhibition (I_max) drug effect model was applied to limit the progression of psoriatic skin lesions within the turnover PD mechanism, which explains the changes in PASI scores during treatment. A first-order remission rate constant for psoriatic lesions (k_out = 0.11 day⁻¹) was estimated. Conclusions: According to the MIPD strategy, 50% of patients would require an optimized regimen and 14% would require an intensified dosage regimen in comparison to current clinical treatment. This research has shown its usefulness as a tool for choosing individualized SCK dosage regimens in patients with long-lasting plaque psoriasis to improve the probability of achieving satisfactory response levels.

Background/Objectives: Implementing model-informed precision dosing (MIPD) strategies guided by population pharmacokinetic/pharmacodynamic (PK/PD) models could enhance the management of inflammatory diseases such as psoriasis. However, the extent of individual experimental data gathered during MIPD significantly influences the uncertainty in estimating individual PK/PD parameters, affecting clinical dose selection decisions. Methods: This study proposes a methodology to individualize ustekinumab (UTK) dosing strategies for 23 Spanish patients with moderate to severe chronic plaque psoriasis., considering the uncertainty of individual parameters within a population PK/PD model. Results: An indirect response model from previous research was used to describe the PK/PD relationship between UTK serum concentrations and the Psoriasis Area and Severity Index (PASI) score. A maximum inhibition drug effect (I_max) model was selected, and a first-order remission constant rate of psoriatic skin lesion (k_out = 0.016 d⁻¹) was estimated. Conclusions: The MIPD approach predicted that 35% and 26% of the patients would need an optimized and intensified dosage regimen, respectively, compared to the regimen typically used in clinical practice. This analysis demonstrated its utility as a tool for selecting personalized UTK dosing regimens in clinical practice in order to optimize the probability of achieving targeted clinical outcomes in patients with psoriasis.

La Farmacia Hospitalaria es una de las salidas profesionales más demandada por los titulados en Grado en Farmacia o en doble grado en Farmacia y Nutrición y Dietética Humana. que requiere, entre otras actuaciones, participar de forma continuada en la toma de decisiones relacionadas con la farmacoterapia que reciben los pacientes con la finalidad de minimizar los riesgos asociados con la utilización de medicamentos. Con el objetivo de entrenar en estas actuaciones a los estudiantes matriculados en la asignatura de Farmacia Clínica y Atención Farmacéutica, se han planteado en el contexto de las clases prácticas de la asignatura tres actividades, que recrean situaciones similares a las que se presentan en el ejercicio profesional. Estas actividades se han desarrollado en el Centro de Simulación Interdisciplinar en Salud de la Universitat de València (CESIS-UV) y se han resuelto utilizando el método de enseñanza basado en la simulación clínica. Con ello, los estudiantes han tomado conciencia del grado de responsabilidad professional en diversos aspectos relacionados con la utilización de medicamentós y la importancia de seleccionar adecuadamente la información y la educación al paciente (o cuidador) de manera integrada y corresponsable con el resto de profesionales sanitarios que le atienden. La valoración de las actividades por parte del alumnado puede considerarse positiva

The demonstration of bioequivalence proposed in the European Medicines Agency’s (EMA’s) draft guideline for topical products with the same qualitative and quantitative composition requires the confirmation of the internal structure equivalence. The impact of the shelf-life on the parameters proposed for internal structure comparison has not been studied. The objectives of this work were: (1) to quantify the effect of the time since manufacturing on the mean value and variability of the parameters proposed by the EMA to characterize the internal structure and performance of topical formulations of a complex topical formulation, and (2) to evaluate the impact of these changes on the assessment of the microstructure equivalence. A total of 5 batches of a topical emulgel containing 1% diclofenac diethylamine were evaluated 5, 14, and 23 months after manufacture. The zero-shear viscosity (η₀), viscosity at 100 s⁻¹ (η₁₀₀), yield stress (σ₀), elastic (G′) and viscous (G″) moduli, internal phase droplet size and in vitro release of the active ingredient were characterized. While no change in variability over time was detected, the mean value of all the parameters changed, especially the droplet size and in vitro release. Thus, combining data from batches of different manufacturing dates may compromise the determination of bioequivalence. The results confirm that to assess the microstructural similarity of complex formulations (such as emulgel), the 90% confidence interval limit for the mean difference in rheological and in vitro release parameters should be 20% and 25%, respectively.