Determination and Confirmation of Recommended Ph2 Dose of Amivantamab in Epidermal Growth Factor Receptor Exon 20 Insertion Non-Small Cell Lung Cancer.

Amivantamab has demonstrated durable responses with a tolerable safety profile in non-small cell lung cancer with EGFR exon 20 insertions (Ex20ins) who progressed after prior platinum chemotherapy. Data supporting the amivantamab recommended phase II dose (RP2D) in this patient population are presented. Pharmacokinetic (PK) analysis and population PK (PopPK) modeling were conducted using serum concentration data obtained following amivantamab intravenous administration (140-1,750 mg).

Associations between Borg's rating of perceived exertion and changes in urinary organic acid metabolites after outdoor weight-bearing hiking.

Background: Developing methods to monitor exercise load and evaluate body fatigue and muscle injury over time in hiking training remains a key problem to be solved. A widely used psycho-physical tool to assess the subjective perception of effort during exercise is Borg's rating of perceived exertion (BRPE) scale. Data on the relationships and validity of the BRPE compared to objectively assessed metabolic criteria are still lacking, especially urinary organic acid concentrations.

A Phase 1 First-in-Human Pharmacokinetic and Pharmacodynamic Study of JNJ-64264681, a Covalent Inhibitor of Bruton's Tyrosine Kinase.

JNJ-64264681 is an irreversible covalent inhibitor of Bruton's tyrosine kinase. This phase 1, first-in-human, 2-part (single-ascending dose [SAD]; multiple-ascending dose [MAD]) study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD; Bruton's tyrosine kinase occupancy [BTKO]) of JNJ-64264681 oral solution in healthy participants. For SAD (N = 78), 6 increasing doses of JNJ-64264681 (4-400 mg) or placebo were evaluated in fasted males.

Model-Based Investigation of Inadequate Efficacy of Tesnatilimab, an Anti-Natural Killer Group 2 Member D Monoclonal Antibody, in Moderately to Severely Active Crohn Disease.

Tesnatilimab is a human immunoglobulin G4 isotype monoclonal antibody that blocks the natural killer group 2 member D (NKG2D) receptor and prevents the downstream signaling of proinflammatory cytokines and cytotoxic mediators. Subcutaneous tesnatilimab was investigated in a phase 2 randomized, double-blind, placebo-controlled trial in patients with moderately to severely active Crohn disease (CD). While the proof-of-concept part I of the study demonstrated significant treatment effects, part II (dose-ranging) revealed an unexpected lack of dose-response and a modest degree of clinical benefit for treatment groups.

The quest for balance between capturing data and model complexity: A quantitative clinical pharmacology approach applied to monoclonal antibodies.

The main objective of this tutorial is to provide the readers with a roadmap of how to establish increasingly complex target-mediated drug disposition (TMDD) models for monoclonal antibodies. To this end, we built mathematical models, each with a detailed visualization, starting from the basic TMDD model by Mager and Jusko to the well-established, physiologically based model by Li et al. in a step-wise fashion to highlight the relative importance of key physiological processes that impact mAb kinetics and system dynamics.

Population pharmacokinetics and exposure-response analyses of daratumumab plus pomalidomide/dexamethasone in relapsed or refractory multiple myeloma.

Aim: A population pharmacokinetic (PPK) model was developed to characterize pharmacokinetics (PK) of subcutaneous or intravenous daratumumab administration in a new indication (i.e., combination with pomalidomide and dexamethasone [D-Pd] in patients with relapsed or refractory multiple myeloma [RRMM]).

Population-based cellular kinetic characterization of ciltacabtagene autoleucel in subjects with relapsed or refractory multiple myeloma.

The aims of this work were to develop a population pharmacokinetic (PK) model for chimeric antigen receptor (CAR) transgene after single intravenous infusion administration of ciltacabtagene autoleucel in adult patients with relapsed or refractory multiple myeloma. CAR transgene level in blood were measured by quantitative polymerase chain reaction (qPCR) from 97 subjects in a phase Ib/II CARTITUDE-1 study (NCT03548207), with a targeted cilta-cel dose of 0.75 × 10 (range 0.

Intravenous Golimumab in Patients with Polyarticular Juvenile Idiopathic Arthritis and Juvenile Psoriatic Arthritis and Subcutaneous Ustekinumab in Patients with Juvenile Psoriatic Arthritis: Extrapolation of Data from Studies in Adults and Adjacent Pediatric Populations.

Objectives: To describe the extrapolation approaches used to support intravenous (IV) golimumab for polyarticular juvenile idiopathic arthritis (pJIA) and juvenile psoriatic arthritis (jPsA) and subcutaneous (SC) ustekinumab for jPsA.

Methods: Pharmacokinetic, clinical response, and safety data from trials of IV golimumab and SC ustekinumab in polyarticular-course JIA (pc-JIA) (GO-VIVA) or pediatric psoriasis (PsO) (CADMUS and CADMUS Jr) and data from pivotal, phase 3 trials of these agents in adults with similar diseases were used to support extrapolation in pJIA and jPsA. In the phase 3 GO-VIVA trial, patients with pc-JIA aged 2 to < 18 years received IV golimumab 80 mg/m at weeks 0, 4, then every 8 weeks (Q8W).

Study on Emission Characteristics and Emission Reduction Effect for Construction Machinery under Actual Operating Conditions Using a Portable Emission Measurement System (Pems).

With the acceleration of urban construction, the pollutant emission of non-road mobile machinery such as construction machinery is becoming more and more prominent. In this paper, a portable emissions measurement system (PEMS) tested the emissions of eight different types of construction machinery under actual operating conditions and was used for idling, walking, and working under the different emission reduction techniques. The results showed that the pollutant emission of construction machinery is affected by the pollutant contribution of working conditions.

Feasibility Analysis of Mutual Benefit Cooperation between Environment-Embedded Art Design Education and Local SMEs Development Based on Improved Grey Analysis.

With the continuous progress of the economic era, both art and design education and local small and medium-sized enterprises are facing the crisis of survival and the pressure of competition, forcing the two to join hands to resist this crisis. The protection of the ecological environment will not only affect people's lives, but also affect the design and creation of art. This paper adopts the methods of correlation degree and correlation coefficient to construct a feasibility analysis model of mutual benefit cooperation between environment-embedded art and design education and local SMEs development based on improved grey analysis.

Population Pharmacokinetic and Exposure-Response Model Simulations: Predicted Exposure and Efficacy for Maintenance Doses of Intravenous Golimumab Every 6 or 8 Weeks in Patients With Moderately to Severely Active Rheumatoid Arthritis.

Purpose: Golimumab is approved to treat moderate-to-severe active rheumatoid arthritis when given intravenously at weeks 0 and 4, then every 8 weeks (Q8W) with concomitant methotrexate. These analyses assessed whether a shorter dosing interval could ameliorate diminished efficacy experienced by a small proportion of patients toward the end of the dosing interval.

Methods: Population pharmacokinetic and exposure-response modeling simulations were performed for intravenous golimumab 2 mg/kg at weeks 0 and 4, then Q8W or every 6 weeks (Q6W) through 1 year.

Population pharmacokinetics and exposure-response modeling analyses of guselkumab in patients with psoriatic arthritis.

Guselkumab is an anti-interleukin-23 human monoclonal antibody effective in treating psoriatic arthritis (PsA). To characterize the pharmacokinetics (PKs) and exposure-response relationship of guselkumab in PsA, population PKs, and exposure-response modeling, analyses were conducted using data from pivotal phase III studies of subcutaneous guselkumab in patients with PsA. The observed serum concentration-time data of guselkumab were adequately described by a one-compartment linear PK model with first-order absorption and elimination.

Improving categorical endpoint longitudinal exposure-response modeling through the joint modeling with a related endpoint.

Exposure-response modeling is important to optimize dose and dosing regimens in clinical drug development. While primary clinical trial endpoints often have few categories and thus provide only limited information, sometimes there may be additional, more informative endpoints. Benefits of fully incorporating relevant information in longitudinal exposure-response modeling through joint modeling have recently been shown.

Population Pharmacokinetics and Exposure-Response Modeling of Daratumumab Subcutaneous Administration in Patients With Light-Chain Amyloidosis.

The purpose of this study is to characterize the population pharmacokinetics (popPK) of subcutaneous (SC) daratumumab in combination with bortezomib, cyclophosphamide, and dexamethasone and explore the relationship between daratumumab systemic exposure and selected efficacy and safety end points in patients with newly diagnosed systemic amyloid light-chain amyloidosis. The popPK analysis included pharmacokinetic and immunogenicity data from patients receiving daratumumab SC in combination with bortezomib, cyclophosphamide, and dexamethasone in the ANDROMEDA study (AMY3001; safety run-in, n = 28; randomized phase, n = 183). Nonlinear mixed-effects modeling was used to characterize the popPK and quantify the impact of potential covariates.

Application of expanded noninvasive prenatal test in prenatal diagnosis of fetuses with increased nuchal translucency.

Objectives: To investigate the efficiency of the upgraded noninvasive prenatal test (NIPT-Plus) in fetuses with increased nuchal translucency (NT).

Methods: Fetuses with an increased NT at or above 2.5 mm were selected for prenatal diagnosis.

Utilization of physiologically-based pharmacokinetic model to assess disease-mediated therapeutic protein-disease-drug interaction in immune-mediated inflammatory diseases.

It is known that interleukin-6 (IL-6) can significantly modulate some key drug-metabolizing enzymes, such as phase I cytochrome P450s (CYPs). In this study, a physiologically-based pharmacokinetic (PBPK) model was developed to assess CYPs mediated therapeutic protein drug interactions (TP-DIs) in patients with immune-mediated inflammatory diseases (IMIDs) with elevated systemic IL-6 levels when treated by anti-IL-6 therapies. Literature data of IL-6 levels in various diseases were incorporated in SimCYP to construct respective virtual patient populations.

Combined exome sequencing and deep phenotyping in highly selected fetuses with skeletal dysplasia during the first and second trimesters improves diagnostic yield.

Objective: To investigate the genetic etiology of skeletal dysplasia in highly selected fetuses during the first and second trimesters using deep phenotyping and exome sequencing (ES).

Method: Fetuses with short femurs were identified using the established prenatal diagnostic approach. A multidisciplinary team reviewed fetal phenotypic information (prenatal ultrasound findings, fetal postmortem, and radiographs) in a cohort of highly selected fetuses with skeletal dysplasia during the first and second trimesters.

[Trends in Vehicle Emissions in Sichuan Province, 2010-2017].

Vehicle pollution in Sichuan Province is becoming increasingly serious. Here, based on specific inventory calculation methods and multi-caliber activity level data, this study calculated vehicle exhaust emissions from 2010 to 2017 in Sichuan Province. The results show that the average growth rate of vehicle ownership in Sichuan is higher than the national trend.

Exposure-Response and Population Pharmacokinetic Analyses of a Novel Subcutaneous Formulation of Daratumumab Administered to Multiple Myeloma Patients.

We report the population pharmacokinetic (PK) and exposure-response analyses of a novel subcutaneous formulation of daratumumab (DARA) using data from 3 DARA subcutaneous monotherapy studies (PAVO Part 2, MMY1008, COLUMBA) and 1 combination therapy study (PLEIADES). Results were based on 5159 PK samples from 742 patients (DARA 1800 mg subcutaneously, n = 487 [monotherapy, n = 288; combination therapy, n = 199]; DARA 16 mg/kg intravenously, n = 255 [all monotherapy, in COLUMBA]; age, 33-92 years; weight, 28.6-147.

Whole-exome sequencing identified two novel mutations of DYNC2LI1 in fetal skeletal ciliopathy.

Background: Skeletal ciliopathies are a group of clinically and genetically heterogeneous disorders with the spectrum of severity spanning from relatively mild to prenatally lethal. The aim of our study was to identify pathogenic mutations in a Chinese family with two siblings presenting a Short-rib polydactyly syndrome (SRPS)-like phenotype.

Method: Karyotyping and NGS-based CNVseq were performed.

A minimal physiologically based pharmacokinetic model to characterize colon TNF suppression and treatment effects of an anti-TNF monoclonal antibody in a mouse inflammatory bowel disease model.

Biotherapeutic drugs against tumor necrosis factor (TNF) are effective treatments for moderate to severe inflammatory bowel disease (IBD). Here, we evaluated CNTO 5048, an antimurine TNF surrogate monoclonal antibody (mAb), in a CD45RB adoptive T cell transfer mouse colitis model, which allows examination of the early immunological events associated with gut inflammation and the therapeutic effects. The study was designed to quantitatively understand the effects of IBD on CNTO 5048 disposition, the ability of CNTO 5048 to neutralize pathogenic TNF at the colon under disease conditions, and the impact of dosing regimen on CNTO 5048 treatment effect.

Extrapolating Pharmacodynamic Effects From Adults to Pediatrics: A Case Study of Ustekinumab in Pediatric Patients With Moderate to Severe Plaque Psoriasis.

Ustekinumab (STELARA) is a human monoclonal antibody against interleukins-12 and -23 for the treatment of adult and adolescent (≥ 12 to < 18 years of age) patients with moderate-to-severe plaque psoriasis. A phase III study was recently completed in pediatric patients (≥ 6 to < 12 years of age) with psoriasis. The objectives of the current analysis were to develop a population pharmacokinetic (PK) model and a joint longitudinal exposure-response model using ordered categorial end points derived from Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA) scores (namely a joint PASI response criteria (PRC) and PGA model) to characterize the PK and exposure-response relationship of ustekinumab in pediatric patients with psoriasis.