Sutimlimab Pharmacokinetics and Pharmacodynamics in Patients with Cold Agglutinin Disease.

Sutimlimab, a humanized monoclonal antibody targeting the classic complement pathway, is approved in the United States, Japan, and the European Union for the treatment of hemolytic anemia in adults with cold agglutinin disease. The objectives of this study were to support dose selection for phase 3 studies, assess dose recommendations, and establish the relationship between sutimlimab exposure and clinical outcome [hemoglobin (Hb) levels]. Clinically meaningful biomarkers were graphically analyzed and the exposure-response relationship was proposed.

LaTeX tutorial for the standardization and automation of population analysis reports.

Writing population analysis reports that fulfilling the specifications of submission readiness is a time-consuming process and prone to human error. Thus, there is a need to streamline the creation of these reports through elements of standardization and automation. LaTeX is considered a suitable program package capable of creating long, modular, structured documents, and, because of its typographic quality, includes formula typesetting.

Pediatric Extrapolation in Type 2 Diabetes: Future Implications of a Workshop.

Extrapolation from adults to youth with type 2 diabetes (T2D) is challenged by differences in disease progression and manifestation. This manuscript presents the results of a mock-team workshop focused on examining the typical team-based decision process used to propose a pediatric development plan for T2D addressing the viability of extrapolation. The workshop was held at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) in Orlando, Florida on March 21, 2018.

Challenges and Opportunities in the Development of Medical Therapies for Pediatric Populations and the Role of Extrapolation.

Extrapolation can be used to address challenges in pediatric drug development. This review describes how these challenges could be addressed by further evolution of quantitative frameworks (i.e.

Predicting the "First dose in children" of CYP3A-metabolized drugs: Evaluation of scaling approaches and insights into the CYP3A7-CYP3A4 switch at young ages.

First-dose-in-children relies on the prediction of clearance from adults for which little information is available on the accuracy of the scaling-approaches applied. For CYP3A-metabolized compounds, scaling of clearance is further challenged by different isoforms and by the CYP3A7 to CYP3A4 switch at young ages. This investigation aimed to evaluate the accuracy of two frequently used scaling approaches and to gain insights into the ontogeny of CYP3A.

Guidelines for the quality control of population pharmacokinetic-pharmacodynamic analyses: an industry perspective.

Quality population modeling and simulation analyses and reports are something every modeler desires. However, little attention in the literature has been paid to what constitutes quality regarding population analyses. Very rarely do published manuscripts contain any statement about quality assurance of the modeling results contained therein.

First dose in children: physiological insights into pharmacokinetic scaling approaches and their implications in paediatric drug development.

Dose selection for "first in children" trials often relies on scaling of the pharmacokinetics from adults to children. Commonly used approaches are physiologically-based pharmacokinetic modeling (PBPK) and allometric scaling (AS) in combination with maturation of clearance for early life. In this investigation, a comparison of the two approaches was performed to provide insight into the physiological meaning of AS maturation functions and their interchangeability.

A semiphysiological population model for prediction of the pharmacokinetics of drugs under liver and renal disease conditions.

The application of model-based drug development in special populations becomes increasingly important for clinical trial optimization, mostly by providing a rationale for dose selection and thereby aiding risk-benefit assessment. In this article, a semiphysiological approach is presented, enabling the extrapolation of the pharmacokinetics from healthy subjects to patients with different disease conditions. This semiphysiological approach was applied to solifenacin, using clinical data on total and free plasma and urine concentrations in healthy subjects.

Pharmacokinetic-pharmacodynamic model for the reversal of neuromuscular blockade by sugammadex.

Background: Sugammadex selectively binds steroidal neuromuscular blocking drugs, leading to reversal of neuromuscular blockade. The authors developed a pharmacokinetic-pharmacodynamic model for reversal of neuromuscular blockade by sugammadex, assuming that reversal results from a decrease of free drug in plasma and/or neuromuscular junction. The model was applied for predicting the interaction between sugammadex and rocuronium or vecuronium.

Modelling of the concentration--effect relationship of THC on central nervous system parameters and heart rate -- insight into its mechanisms of action and a tool for clinical research and development of cannabinoids.

Pharmacokinetics after pulmonary administration of delta-9-tetrahydrocannabinol (THC) and its major metabolites 11-OH-THC and 11-nor-9-COOH-THC was quantified. Additionally, the relationship between THC and its effects on heart rate, body sway and several visual analogue scales was investigated using pharmacokinetic-pharmacodynamic (PK-PD) modelling. This provided insights useful for the research and development of novel cannabinoids and the physiology and pharmacology of cannabinoid systems.

Population pharmacokinetic modelling of the enterohepatic recirculation of diclofenac and rofecoxib in rats.

Background And Purpose: Enterohepatic recirculation (EHC) is a common pharmacokinetic phenomenon that has been poorly modelled in animals. The presence of EHC leads to the appearance of multiple peaks in the concentration-time profile and increased exposure, which may have implications for drug effect and extrapolation across species. The aim of this investigation was to develop a population pharmacokinetic model for diclofenac and rofecoxib that describes EHC and to assess its consequence for the pharmacodynamics of both drugs.