Patient-specific in vitro drug release testing coupled with in silico PBPK modeling to forecast the in vivo performance of oral extended-release levodopa formulations in Parkinson's disease patients.

Biorelevant in vitro release models are valuable analytical tools for oral drug development but often tailored to gastrointestinal conditions in 'average' healthy adults. However, predicting in vivo performance in individual patients whose gastrointestinal conditions do not match those of healthy adults would be of great value for optimizing oral drug therapy for such patients. This study focused on establishing patient-specific in vitro and in silico models to predict the in vivo performance of levodopa extended-release products in Parkinson's disease patients. Current knowledge on gastrointestinal conditions in these patients was incorporated into model development. Relevant in vivo pharmacokinetic data and patient-specific in vitro release data from a novel in vitro test setup were integrated into patient-specific physiologically-based pharmacokinetic models. AUC, cmax and tmax of the computed plasma profiles were calculated using PK-Sim®. For the products studied, levodopa plasma concentration-time profiles modeled using this novel approach compared far better with published average plasma profiles in Parkinson's disease patients than those derived from in vitro release data obtained from the 'average' healthy adult setup. Although further work is needed, results of this study highlight the importance of addressing patient-specific gastrointestinal conditions when aiming to predict drug release in such specific patient groups.

Obtención y evaluación del semen de capibara Hydrochoerus hydrochaeris / Collection and evaluation of semen from the Capybara Hydrochoerus hydrochaeris

Objetivo. Determinar las características del semen y la morfometría de los espermatozoides del Capibara (Hydrochoerus hydrochaeris). Materiales y métodos. Se utilizaron 10 machos con peso entre 21-45 kg, los cuales fueron restringidos y anestesiados. El semen se obtuvo mediante electroeyaculación y se determinó el color, volumen, pH, motilidad en masa, motilidad individual, viabilidad, concentración y morfología. Se realizaron además mediciones de la cabeza y la cola de los espermatozoides. Resultados. Se obtuvo semen en el 100% (10/10) de los animales. El mayor número de eyaculaciones (80%; 8/10), se obtuvo con un voltaje máximo de 6V. El color fue blanco, de aspecto lechoso, los valores promedio fueron volumen 135.5±93.56 µl, pH 8.14±0.38, motilidad masal 32.60±13.46%, motilidad individual 34±19.81%, viabilidad 51.3±19.42%, concentración espermática 127±59.01x106 espermatozoides/mL y morfología 51.3±19.42 espermatozoides normales. La longitud de la cabeza fue 5.41±0.7 µm, el ancho de la cabeza 3.77±0.5 µm y área de la cabeza 75.66±20.6 µm². La longitud de la cola fue 27.9±11.3 µm. Conclusiones. La obtención del semen fue satisfactoria mediante electroeyaculación, sin presentar notables diferencias en las características del semen y morfología de los espermatozoides con otros roedores silvestres de menor tamaño, aunque se observó una alta variabilidad de estas características entre los animales muestreados posiblemente por la heterogeneidad de los animales experimentales.

Objective. Determine the characteristics of semen and morphometry of the Capybara (Hydrochoerus hydrochaeris) spermatozoid. Materials and methods. 10 males, weighing between 21-45 kg, which were restrained and anesthetized, were used in the study. The semen sample was obtained by electroejaculation and the color, volume, pH, mass motility, individual motility, viability, concentration and morphology were determined. Measurements of the head and tail of spermatozoids were also conducted. Results. Semen was obtained from 100% (10/10) of the animals. The highest number of ejaculations (80%; 8/10) was obtained with a maximum voltage of 6V. The color was white, of a milky appearance, average values were volume 135.5 ± 93.56 µl, pH 8.14 ± 0.38, mass motility 32.60 ± 13.46%, individual motility 34 ± 19.81%, viability 19.42 ± 51.3%, sperm concentration 127 ± 59.01x106 spermatozoids / mL and morphology 51.3 ± 19.42 normal spermatozoids. The head length was 5.41 ± 0.7µm, the width of head 3.77 ± 0.5 and head area 75.66 ± 20.6 µm². The tail length was of 27.9 ± 11.3 µm. Conclusions. Semen collection by electro ejaculation was successful, without presenting significant differences in semen characteristics and spermatozoid morphology with other smaller wild rodents, although there was a high variability of these characteristics observed between the animals sampled, possibly due to the heterogeneity of the experimental animals.