Impact of a reduced metabolizable protein supply during the transition period on the immune and metabolic status of dairy cows.

During the transition period, the incidence of diseases increases due to a negative energy balance that affects metabolic and immune status. Limiting milk production at the beginning of lactation by milking once a day or by incompletely milking twice a day improves the metabolic and immune status of cows. Previous studies have shown that milk production is highly responsive to additional MP.

Applications of pharmacometrics in drug development.

The last two decades have witnessed profound changes in how advanced computational tools can help leverage tons of data to improve our knowledge, and ultimately reduce cost and increase productivity in drug development. Pharmacometrics has demonstrated its impact through model-informed drug development (MIDD) approaches. It is now an indispensable component throughout the whole continuum of drug discovery, development, regulatory review, and approval.

Evaluation of National Academies of Sciences, Engineering, and Medicine (NASEM, 2021) feed evaluation model on predictions of milk protein yield on Québec commercial dairy farms.

A recent study assessed the ability of 4 feed evaluation models to predict milk protein yield (MPY) in a commercial context, with data of 541 cows from 23 dairy herds in the province of Québec, Canada. However, the recently published Nutrient Requirements of Dairy Cattle from the National Academies of Sciences, Engineering, and Medicine (NASEM, 2021) was not released at that time. Thus, the current study evaluated NASEM using the same dataset.

Effects of protein and forage source on performance and splanchnic and mammary net fluxes of nutrients in lactating dairy cows.

This study was conducted to determine if the decreased MP supply predicted by the NRC (2001) when canola meal (CM) substitutes soybean meal (SBM) was supported by direct measurement of net portal absorption of AA or energy-yielding nutrients, plus the effect of the type of forage in CM-based rations. Nine Holstein cows with indwelling catheters in splanchnic blood vessels, 8 also with a ruminal cannula, were used to examine the effects of protein source in corn silage-based diets, comparing SBM versus CM, and forage source in CM-based diets, comparing corn versus grass silage. The cows were allocated to a triple 3 × 3 Latin square design with 21-d periods.

Evaluating drug interaction potential from cytokine release syndrome using a physiologically based pharmacokinetic model: A case study of teclistamab.

Cytokine release syndrome (CRS) was associated with teclistamab treatment in the phase I/II MajesTEC-1 study. Cytokines, especially interleukin (IL)-6, are known suppressors of cytochrome P450 (CYP) enzymes' activity. A physiologically based pharmacokinetic model evaluated the impact of IL-6 serum levels on exposure of substrates of various CYP enzymes (1A2, 2C9, 2C19, 3A4, 3A5).

Telehealth-Delivered Program and Accompanying Patients to Enhance the Clinical Condition of Patients Throughout a Liver Transplant: Protocol for a Mixed Methods Study.

Background: Liver transplantation (LT) is indicated in patients with severe acute or chronic liver failure for which no other therapy is available. With the increasing number of LTs in recent years, liver centers worldwide must manage their patients according to their clinical situation and the expected waiting time for transplantation. The LT clinic at the Centre hospitalier de l'Université de Montréal (CHUM) is developing a new health care model across the entire continuum of pre-, peri-, and posttransplant care that features patient monitoring by an interdisciplinary team, including an accompanying patient; a digital platform to host a clinical plan; a learning program; and data collection from connected objects.

Demonstrating Bioequivalence for Two Dose Strengths of Niraparib and Abiraterone Acetate Dual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.

Background And Objective: The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs.

Teclistamab: Mechanism of action, clinical, and translational science.

Multiple myeloma (MM) remains incurable despite improvements in treatment options. B-cell maturation antigen (BCMA) is predominantly expressed in B-lineage cells and represents a promising new target for MM. Teclistamab (TECVAYLI ) is the first T-cell redirecting bispecific antibody approved for patients with MM.

Ability of three dairy feed evaluation systems to predict postruminal outflows of amino acids in dairy cows: A meta-analysis.

Adequate prediction of postruminal outflows of essential AA (EAA) is the starting point of balancing rations for EAA in dairy cows. The objective of this meta-analysis was to compare the performance of 3 dairy feed evaluation systems (National Research Council [NRC], Cornell Net Protein and Carbohydrate System version 6.5.

Challenging the Norm: A Multidisciplinary Perspective on Intravenous to Subcutaneous Bridging Strategies for Biologics.

The transition from intravenous (i.v.) to subcutaneous (s.

Artificial Intelligence: From Buzzword to Useful Tool in Clinical Pharmacology.

The advent of artificial intelligence (AI) in clinical pharmacology and drug development is akin to the dawning of a new era. Previously dismissed as merely technological hype, these approaches have emerged as promising tools in different domains, including health care, demonstrating their potential to empower clinical pharmacology decision making, revolutionize the drug development landscape, and advance patient care. Although challenges remain, the remarkable progress already made signals that the leap from hype to reality is well underway, and AI promises to offer clinical pharmacology new tools and possibilities for optimizing patient care is gradually coming to fruition.

Mechanism-based pharmacokinetic and pharmacodynamic modeling for bispecific antibodies: challenges and opportunities.

Introduction: Unlike conventional antibodies, bispecific antibodies (bsAbs) are engineered antibody- or antibody fragment-based molecules that can simultaneously recognize two different epitopes or antigens. Over the past decade, there has been an explosion of bsAbs being developed across therapeutic areas. Development of bsAbs presents unique challenges and mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) modeling has served as a powerful tool to optimize their development and realize their clinical utility.

Ability of three dairy feed evaluation systems to predict postruminal outflows of nitrogenous compounds in dairy cows: A meta-analysis.

Adequate prediction of postruminal outflow of protein fractions is the starting point for the determination of metabolizable protein supply in dairy cows. The objective of this meta-analysis was to compare the performance of 3 dairy feed evaluation systems (National Research Council [NRC], Cornell Net Protein and Carbohydrate System [CNCPS], and National Academies of Sciences, Engineering and Medicine [NASEM]) to predict outflows (g/d) of nonammonia nitrogren (NAN), microbial N (MiN), and nonammonia nonmicrobial N (NANMN). Predictions of rumen degradabilities (% of nutrient) of protein (RDP), NDF, and starch were also evaluated.

Training the next generation of pharmacometric modelers: a multisector perspective.

The current demand for pharmacometricians outmatches the supply provided by academic institutions and considerable investments are made to develop the competencies of these scientists on-the-job. Even with the observed increase in academic programs related to pharmacometrics, this need is unlikely to change in the foreseeable future, as the demand and scope of pharmacometrics applications keep expanding. Further, the field of pharmacometrics is changing.

Review: How the efficiency of utilization of essential amino acids can be applied in dairy cow nutrition.

How the efficiency of utilization of essential amino acids (EffU) can be applied in dairy cow nutrition is presented in this review. The concept of EffU proposed by the National Academies of Sciences, Engineering and Medicine (NASEM, 2021) is first detailed. It represents the proportion of the metabolisable essential amino acids (mEAA) supply used to support protein secretions and accretions (scurf, metabolic fecal, milk and growth).

Effect of Metabolizable Protein Supply on Milk Performance, Ruminal Fermentation, Apparent Total-Tract Digestibility, Energy and Nitrogen Utilization, and Enteric Methane Production of Ayrshire and Holstein Cows.

In North America, the nutrient requirements of dairy cattle are predicted using the Cornell Net Carbohydrate and Protein System (CNCPS) or the National Research Council (NRC). As Holstein is the most predominant dairy cattle breed, these models were developed based on the phenotypic, physiological, and genetic characteristics of this breed. However, these models may not be appropriate to predict the nutrient requirements of other breeds, such as Ayrshire, that are phenotypically and genetically different from Holstein.

Latent variable indirect response modeling of clinical efficacy endpoints with combination therapy: application to guselkumab and golimumab in patients with ulcerative colitis.

Accurate characterization of longitudinal exposure-response of clinical trial endpoints is important in optimizing dose and dosing regimens in drug development. Clinical endpoints are often categorical, for which much progress has been made recently in latent variable indirect response (IDR) modeling with single drugs. However, such applications have not yet been used for trials employing multiple drugs administered concurrently.

Development of Therapeutic Proteins for a New Subcutaneous Route of Administration After the Establishment of Intravenous Dosages: A Systematic Review.

Therapeutic proteins may first be developed as intravenous (i.v.) therapies with new subcutaneous (s.

Comparison of feed evaluation models on predictions of milk protein yield on Québec commercial dairy farms.

Feed evaluation models (FEM) are a core part in dairy cow feeding. As these models are developed using different biological and mathematical approaches mainly tested in a research context, their abilities to predict production in commercial farms need to be validated, even more so when they are used outside the context of their development. Four FEM-National Research Council, 2001 (NRC_2001); Cornell Net Carbohydrate and Protein System, 2015 (CNCPS); NorFor, 2011; and INRA, 2018 (INRA_2018)-were evaluated on their abilities to predict daily milk protein yield (MPY) of 541 cows from 23 dairy herds in the province of Québec, Canada.

Exposure-response analyses of erdafitinib in patients with locally advanced or metastatic urothelial carcinoma.

Background: Exposure-response analyses were conducted to explore the relationship between selected efficacy and safety endpoints and serum phosphate (PO4) concentrations, a potential biomarker of efficacy and safety, in locally advanced or metastatic urothelial carcinoma patients with FGFR alterations treated with erdafitinib.

Methods: Data from two dosing regimens of erdafitinib in a phase 2 study (NCT02365597), 6 and 8-mg/day with provision for pharmacodynamically guided titration per serum PO4 levels, were analyzed using Cox proportional hazard or logistic regression models. Efficacy endpoints were overall survival (OS), progression-free survival (PFS), and objective response rate (ORR).

Erdafitinib's effect on serum phosphate justifies its pharmacodynamically guided dosing in patients with cancer.

A population pharmacokinetic (PK)-pharmacodynamic (PD) model was developed using data from 345 patients with cancer. The population PK-PD model evaluated the effect of erdafitinib total and free plasma concentrations on serum phosphate concentrations after once-daily oral continuous (0.5-12 mg) and intermittent (10-12 mg for 7 days on/7 days off) dosing, and investigated the potential covariates affecting erdafitinib-related changes in serum phosphate levels.

Milk production and efficiency of utilization of nitrogen, metabolizable protein, and amino acids are affected by protein and energy supplies in dairy cows fed alfalfa-based diets.

Alfalfa has a lower fiber digestibility and a greater concentration of degradable protein than grasses. Dairy cows could benefit from an increased digestibility of alfalfa fibers, or from a better match between nitrogen and energy supplies in the rumen. Alfalfa cultivars with improved fiber digestibility represent an opportunity to increase milk production, but no independent studies have tested these cultivars under the agroclimatic conditions of Canada.