nlme

Background: ORIN1001, a first-in-class oral IRE1-α endoribonuclease inhibitor to block the activation of XBP1, is currently in clinical development for inhibiting tumor growth and enhancing the effect of chemical or targeted therapy. Early establishment of a population pharmacokinetic (PopPK) model could characterize the pharmacokinetics (PK) of ORIN1001 and evaluate the effects of individual-specific factors on PK, which will facilitate the future development of this investigational drug. Methods: Non-linear mixed effect model was constructed by Phoenix NLME software, utilizing the information from Chinese patients with advanced solid tumors in a phase I clinical trial (Register No...

Tamoxifen is widely used in patients with hormone receptor-positive breast cancer. The polymorphic enzyme CYP2D6 is primarily responsible for metabolic activation of tamoxifen, resulting in substantial interindividual variability of plasma concentrations of its most important metabolite, Z-endoxifen. The Z-endoxifen concentration thresholds below which tamoxifen treatment is less efficacious have been proposed but not validated, and prospective trials of individualized tamoxifen treatment to achieve Z-endoxifen concentration thresholds are considered infeasible...

The aim of this study was to investigate the accuracy of single-time-point (STP) renal dosimetry imaging using SPECT/CT data, a nonlinear mixed-effects (NLME) model, and a population-based model selection (PBMS) in a large population for 177 Lu-labeled prostate-specific membrane antigen therapy. Methods: Biokinetic data (mean ± SD) of [177 Lu]Lu-PSMA-617 in kidneys at time points 1 (1.8 ± 0.8 h), 2 (18.7 ± 0.9 h), 3 (42.6 ± 1.0 h), 4 (66...

INTRODUCTION: Pseudomyxoma peritonei (PMP) is a disease characterized by progressive accumulation of intraperitoneal mucinous ascites produced by neoplasms in the abdominal cavity. Since the prognosis of patients with PMP remain unsatisfactory, the development of effective therapeutic drug(s) is a matter of pressing concern. Genetic analyses of PMP have clarified the frequent activation of GNAS and/or KRAS. However, the involvement of global epigenetic alterations in PMPs has not been reported...

Diarrhea and respiratory diseases pose significant challenges in the rearing of pre-weaned calves, motivating the investigation of tools to improve gastrointestinal tract development, health, and overall performance in young calves. Consequently, the primary objective of this study was to assess the effectiveness of an additive incorporated into milk replacer to promote the development and health of the animals. Forty-six dairy calves were randomly assigned into two treatments: control (CON, n = 23; with 15 females and 8 males), and sodium butyrate (SB, n = 23; with 15 females and 8 males)...

Pharmacokinetic data for injectable azithromycin in children remain limited. This study aims to develop and validate a population pharmacokinetic model of azithromycin for injection in children under 6 years old and optimize its dosage regimen in this population. We prospectively enrolled patients under 6 years old who received azithromycin for injection at Beijing Friendship Hospital, Capital Medical University. Demographic information, clinical characteristics, and venous blood samples were collected in accordance with the research protocol...

BACKGROUND AND PURPOSE: Rotigotine extended-release microspheres is a weekly intramuscular injection formulation to treat Parkinson's Disease. This study aimed to develop a population pharmacokinetics (PK) model for rotigotine extended-release microspheres to investigate its PK ethnic differences. EXPERIMENTAL APPROACH: Data for the study were obtained from three studies in China, Japan, and the US. The population PK model was developed using the Phoenix NLME 8...

This analysis aimed to quantify tumor dynamics in patients receiving either bintrafusp alfa (BA) or pembrolizumab, by population pharmacokinetic (PK)-pharmacodynamic modeling, and investigate clinical and molecular covariates describing the variability in tumor dynamics by pharmacometric and machine-learning (ML) approaches. Data originated from two clinical trials in patients with biliary tract cancer (BTC; NCT03833661) receiving BA and non-small cell lung cancer (NSCLC; NCT03631706) receiving BA or pembrolizumab...

BACKGROUND: Synthetic biologists use and combine diverse biological parts to build systems such as genetic circuits that perform desirable functions in, for example, biomedical or industrial applications. Computer-aided design methods have been developed to help choose appropriate network structures and biological parts for a given design objective. However, they almost always model the behavior of the network in an average cell, despite pervasive cell-to-cell variability. RESULTS: Here, we present a computational framework and an efficient algorithm to guide the design of synthetic biological circuits while accounting for cell-to-cell variability explicitly...

PURPOSE: We aimed to describe the performance and evaluate the educational value of justifications provided by artificial intelligence chatbots, including GPT-3.5, GPT-4, Bard, Claude, and Bing, on the Peruvian National Medical Licensing Examination (P-NLME). METHODS: This was a cross-sectional analytical study. On July 25, 2023, each multiple-choice question (MCQ) from the P-NLME was entered into each chatbot (GPT-3, GPT-4, Bing, Bard, and Claude) 3 times. Then, 4 medical educators categorized the MCQs in terms of medical area, item type, and whether the MCQ required Peru-specific knowledge...

This study aimed to develop a population pharmacokinetic (PPK) model for rivaroxaban and establish a model-based dosing guideline tailored to Chinese patients with deep vein thrombosis (DVT). A nonlinear mixed-effects modeling approach was employed using Phoenix NLME 7.0 software to construct the PPK model for rivaroxaban. The PK of rivaroxaban was adequately characterized through a one-compartment model. Monte Carlo simulations were employed to formulate dosing guidelines applicable to different patient subgroups...

OBJECTIVE: The conventional approach to the analysis of dynamic PET data can be described as a two-stage approach. In Stage 1, each individual's kinetic parameter estimates are obtained by modeling their PET data. Then in Stage 2, those parameter estimates are treated as though they are the observed data and compared across subjects and groups using standard statistical analyses. In this context, we explore the application of nonlinear mixed-effects (NLME) model under the assumptions of simplified reference tissue model...

INTRODUCTION: Mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), is widely used in the treatment of systemic lupus erythematosus (SLE). It has been shown that its therapeutic drug monitoring based on the area under the curve (AUC) improves treatment efficacy. MPA exhibits a complex bimodal absorption, and a double gamma distribution model has been already proposed in the past to accurately describe this phenomenon. These previous population pharmacokinetics models (POPPK) have been developed using iterative two stage Bayesian (IT2B) or non-parametric adaptive grid (NPAG) methods...

The nature of nonlinear magnetoelectric (NLME) effect has been investigated at room-temperature in a single-crystal Zn substituted nickel ferrite. Tuning of the frequency of magnetostatic surface wave (MSSW) modes under an applied pulsed DC electric field/current has been utilized to probe the effect. The frequencies of the modes at 8-20 GHz were found to decrease by ~ 400 MHz for an applied DC power P of ~ 100 mW and the frequency shift was the same for all of the MSSW modes and linearly proportional to P...

BACKGROUND: Pimobendan is an important therapy for dogs with myxomatous mitral valve disease (MMVD). The pharmacokinetics are reported in healthy dogs but not in dogs with heart disease. HYPOTHESIS/OBJECTIVES: To determine if dog characteristics such as age, breed, body condition score, ACVIM stage of heart disease or biochemical laboratory value alter the pharmacokinetics of orally administered pimobendan and its metabolite in a cohort of dogs with naturally occurring MMVD...

AIMS: Dasatinib, a second-generation tyrosine kinase inhibitor of BCR-ABL 1, used for first-line treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML), exhibits high pharmacokinetic (PK) variability. However, its PK data in Chinese patients with CML remains rarely reported to date. Thus, we developed a population pharmacokinetic (PPK) model of dasatinib in Chinese patients and identified the covariate that could explain the individual variability of PK for optimal individual administration...

BACKGROUND: Imatinib is presently the first-line choice for the treatment of chronic myeloid leukemia. However, there are limited real-world data on Chinese patients to support individualized medicine. This work aims to characterize population pharmacokinetics in Chinese patients with chronic myeloid leukemia, investigate the effects of several covariates on imatinib exposure, and provide support for personalized medicine and dose reduction. METHODS: A total of 230 patients with chronic myeloid leukemia were enrolled, and 424 steady-state concentration measurements were taken to perform the population pharmacokinetic analysis and Monte Carlo simulations with Phoenix NLME software...

Cannabidiol (CBD) products gain increasing popularity amongst animal owners and veterinarians as an alternative remedy for treatment of stress, inflammation or pain in horses. Whilst the use of cannabinoids is banned in equine sports, there is limited information available concerning CBD detection times in blood or urine. The aim of this study was to determine the pharmacokinetic properties of CBD following oral administration in the horse to assist doping control laboratories with interpreting CBD analytical results...

BACKGROUND AND OBJECTIVES: Model-informed precision dosing (MIPD) frequently uses nonlinear mixed-effects (NLME) models to predict and optimize therapy outcomes based on patient characteristics and therapeutic drug monitoring data. MIPD is indicated for compounds with narrow therapeutic range and complex pharmacokinetics (PK), such as voriconazole, a broad-spectrum antifungal drug for prevention and treatment of invasive fungal infections. To provide guidance and recommendations for evidence-based application of MIPD for voriconazole, this work aimed to (i) externally evaluate and compare the predictive performance of a published so-called 'hybrid' model for MIPD (an aggregate model comprising features and prior information from six previously published NLME models) versus two 'standard' NLME models of voriconazole, and (ii) investigate strategies and illustrate the clinical impact of Bayesian forecasting for voriconazole...

In pharmacogenomic studies, the use of human liver microsomes as a model system to evaluate the impact of complex genomic traits (i.e., linkage-disequilibrium patterns, coding, and non-coding variation, etc.) on efficiency of drug metabolism is challenging. To accurately predict the true effect size of genomic traits requires large richly sampled datasets representative of the study population. Moreover, the acquisition of this data can be labor-intensive if the study design or bioanalytical methods are not high throughput, and it is potentially unfeasible if the abundance of sample needed for experiments is limited...