Physiologically based pharmacokinetic models for systemic disposition of protein therapeutics in rabbits.

Physiologically based pharmacokinetic (PBPK) modelling is an important tool to predict drug disposition in the body. Rabbits play a pivotal role as a highly valued small animal model, particularly in the field of ocular therapeutics, where they serve as a crucial link between preclinical research and clinical applications. In this context, we have developed PBPK models designed specifically for rabbits, with a focus on accurately predicting the pharmacokinetic profiles of protein therapeutics following intravenous administration. Our goal was to comprehend the influence of key physiological factors on systemic disposition of antibodies and their functional derivatives. For the development of the systemic PBPK models, rabbit physiological factors such as gene expression, body weight, neonatal fragment crystallizable receptor (FcRn) binding, target binding, target concentrations, and target turnover rate were meticulously considered. Additionally, key protein parameters, encompassing hydrodynamic radius, binding kinetic constants (KD, koff), internal degradation of the protein-target complex, and renal clearance, were represented in the models. Our final rabbit models demonstrated a robust correlation between predicted and observed serum concentration-time profiles after single intravenous administration in rabbits, covering IgG, Fab, F(ab)2, Fc, and Fc fusion proteins from various publications. These pharmacokinetic simulations offer a promising platform for translating preclinical findings to clinical settings. The presented rabbit intravenous PBPK models lay an important foundation for more specific applications of protein therapeutics in ocular drug development.

Association of clinical parameters and polygenic risk scores for body mass index, schizophrenia, and diabetes with antipsychotic-induced weight gain.

Antipsychotic-induced weight gain (AIWG) is a common adverse event in schizophrenia. Genome-wide association studies (GWAS) and polygenic risk scores (PRS) for other diseases or traits are recent approaches to disentangling the genetic architecture of AIWG. 200 patients with schizophrenia treated monotherapeutically with antipsychotics were included in this study. A multiple linear regression analysis with ten-fold crossvalidation was performed to predict the percentage weight change after five weeks of treatment. Independent variables were sex, age, body mass index (BMI) at baseline, medication-associated risk, and PRSs (BMI, schizophrenia, diabetes, and metabolic syndrome). An explorative GWAS analysis was performed on the same subjects and traits. PRSs for BMI (ß = 3.78; p = 0.0041), schizophrenia (ß = 5.38; p = 0.021) and diabetes type 2 (ß = 13.4; p = 0.046) were significantly associated with AIWG. Other significant factors were sex, baseline BMI and medication. Compared to the model without genetic factors, the addition of PRSs for BMI, schizophrenia, and diabetes type 2 increased the goodness of fit by 6.5 %. The GWAS identified the association of three variants (rs10668573, rs10249381 and rs1988834) with AIWG at a genome-wide level of p < 1 · 10-6. Using PRS for schizophrenia, BMI, and diabetes type 2 increased the explained variation of predicted weight gain, compared to a model without PRSs. For more precise results, PRSs derived from other traits (ideally AIWG) should be investigated. Potential risk variants identified in our GWAS need to be further investigated and replicated in independent samples.

Investigation of Helix-Pultruded CFRP Rebar Geometry Variants for Carbon-Reinforced Concrete Structures.

Carbon concrete is a new, promising class of materials in the construction industry. This corrosion-resistant reinforcement material leads to a reduction in the concrete cover required for medial shielding. This enables lean construction and the conservation of concrete and energy-intensive cement manufacturing. Bar-type reinforcement is essential for heavily loaded structures. The newly developed helix pultrusion is the first process capable of producing carbon fiber-reinforced polymer (CFRP) reinforcement bars with a topological surface in a single pultrusion process step, with fiber orientation tailored to the specific loads. The manufacturing feasibility and load-bearing capacity were thoroughly tested and compared with other design and process variants. Approaches to increase stiffness and strength while maintaining good concrete anchorage have been presented and fabricated. Tensile testing of the helical rebar variants with a 7.2 mm lead-bearing cross-section was conducted using adapted wedge grips with a 300 mm restraint length. The new helix geometry variants achieved, on average, 40% higher strengths and almost reached the values of the base material. Concrete pull-out tests were carried out to evaluate the bond properties. The helix contour design caused the bar to twist out of the concrete test specimen. Utilizing the Rilem beam test setup, the helical contour bars could also be tested. Compared with the original helix variant, the pull-out forces could be increased from 8.5 kN to up to 22.4 kN, i.e., by a factor of 2.5. It was thus possible to derive a preferred solution that is optimally suited for use in carbon concrete.