Psychosocial functioning and its influencing factors in patients with depression post-remission: Implications for assessment and interventions.

BACKGROUND: Enhancing psychosocial functioning is crucial for reducing relapse in depression, but methods for monitoring and recovery are unclear. METHOD: A 1-year follow-up study assessed psychosocial functioning in 182 patients with remitted depression at baseline (T0) as well as at 1, 2, 6, 9, and 12 months post-remission (T1-T5). Using generalized estimating equations (GEE) and multiple linear regression (MLR), we analyzed the impact of changes in psychosocial functioning on relapse/recurrence risk, and assessed the influence of various factors. RESULTS: An increase in psychosocial functioning significantly lowered relapse/recurrence odds by 54.2 %, averaging a risk reduction of 3.1 %. GEE analyses indicated subjective depressive symptoms (ß = -0.315) most significantly impacted psychosocial functioning, followed by social support (ß = 0.236), positive coping (ß = 0.225), and negative automatic thoughts (ß = -0.183). Negative coping and expressed emotion exhibited non-significant effects. MLR revealed that the impact of negative automatic thoughts was most significant at initial remission, but the relative importance of residual subjective depressive symptoms, positive coping, and social support on psychosocial functioning remained stable over time. LIMITATIONS: Predetermined follow-up assessments may not fully capture psychosocial functioning at relapse/recurrence, and the inclusion of factors might not be sufficiently comprehensive. CONCLUSIONS: Recovery of psychosocial functioning significantly reduces relapse risk in post-remission patients with depression more than residual subjective depressive symptoms. The degree of influence of factors on psychosocial functioning can change with the length of remission time.

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). Pharmacodynamics (PDs) were evaluated using depletion of soluble EGFR and MET. Exposure-response (E-R) analyses were performed using the primary efficacy end point of objective response rate in patients with EGFR Ex20ins. The E-R relationship for safety was explored for adverse events of clinical interest. Amivantamab exhibited linear PKs at 350-1,750 mg dose levels following administration, with no maximum tolerated dose identified. A two-compartment PopPK model with linear clearance adequately described the observed PKs. Body weight was a covariate of clearance and volume of distribution in the central compartment. PopPK modeling showed that a weight-based, 2-tier (< 80 and ≥ 80 kg) dosing strategy reduces PK variability and provides comparable exposure across 2 weight groups, with 87% of patients achieving exposures above the target threshold. The final confirmed RP2D of amivantamab was 1,050 mg for < 80 kg (1,400 mg for ≥ 80 kg) weekly in cycle 1 (28 days) and every 2 weeks thereafter. No significant exposure-efficacy or safety correlation was observed. In conclusion, the amivantamab RP2D is supported by PK, PD, safety, and efficacy analyses. E-R analyses confirmed that the current regimen provides durable efficacy with tolerable safety.

Population Pharmacokinetics and Exposure-Response with Teclistamab in Patients With Relapsed/Refractory Multiple Myeloma: Results From MajesTEC-1.

BACKGROUND: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, is approved in patients with relapsed/refractory multiple myeloma (RRMM) who have previously received an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody. OBJECTIVE: We report the population pharmacokinetics of teclistamab administered intravenously and subcutaneously (SC) and exposure-response relationships from the phase I/II, first-in-human, open-label, multicenter MajesTEC-1 study. METHODS: Phase I of MajesTEC-1 consisted of dose escalation and expansion at the recommended phase II dose (RP2D; 1.5 mg/kg SC weekly, preceded by step-up doses of 0.06 and 0.3 mg/kg); phase II investigated the efficacy of teclistamab RP2D in patients with RRMM. Population pharmacokinetics and the impact of covariates on teclistamab systemic exposure were assessed using a 2-compartment model with first-order absorption for SC and parallel time-independent and time-dependent elimination pathways. Exposure-response analyses were conducted, including overall response rate (ORR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and the incidence of grade ≥ 3 anemia, neutropenia, lymphopenia, leukopenia, thrombocytopenia, and infection. RESULTS: In total, 4840 measurable serum concentration samples from 338 pharmacokinetics-evaluable patients who received teclistamab were analyzed. The typical population value of time-independent and time-dependent clearance were 0.449 L/day and 0.547 L/day, respectively. The time-dependent clearance decreased rapidly to < 10% after 8 weeks of teclistamab treatment. Patients who discontinue teclistamab after the 13th dose are expected to have a 50% reduction from Cmax in teclistamab concentration at a median (5th to 95th percentile) time of 15 days (7-33 days) after Tmax and a 97% reduction from Cmax in teclistamab concentration at a median time of 69 days (32-163 days) after Tmax. Body weight, multiple myeloma type (immunoglobulin G vs non-immunoglobulin G), and International Staging System (ISS) stage (II vs I and III vs I) were statistically significant covariates on teclistamab pharmacokinetics; however, these covariates had no clinically relevant effect on the efficacy of teclistamab at the RP2D. Across all doses, ORR approached a plateau at the concentration range associated with RP2D, and in patients who received the RP2D, a flat exposure-response curve was observed. No apparent relationship was observed between DoR, PFS, OS, and the incidence of grade ≥3 adverse events across the predicted exposure quartiles. CONCLUSION: Body weight, myeloma type, and ISS stage impacted systemic teclistamab exposure without any clinically relevant effect on efficacy. The exposure-response analyses for ORR showed a positive trend with increasing teclistamab systemic exposure, with a plateau at the RP2D, and there was no apparent exposure-response trend for safety or other efficacy endpoints. These analyses support the RP2D of teclistamab in patients with RRMM. CLINICAL TRIAL REGISTRATION: NCT03145181 (phase I, 09 May 2017); NCT04557098 (phase II, 21 September 2020).

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. AIM: To verify whether the BRPE scale could be used in the prescription of outdoor hiking with weight-bearing and reveal the relationship between the BRPE scale and urinary physiological measures. METHODS: Eighty-nine healthy men (average age: 22 years) were enrolled in a 40 km (6 h) hiking training exercise with a 20 kg load. After training, the BRPE scale (6-20) was completed. All participants were divided into three groups according to the rating of the BRPE scale. Urine samples were collected before and after training. Urinary myoglobin levels were measured immediately using the fluorescent immunoassay method. The remaining urine was subpacked and frozen for the subsequent detection of urinary organic acids using gas chromatography and mass spectrometry. RESULTS: The contents of organic acids and myoglobin in urine were significantly increased after participants hiked 40 km (6 h) with a 20 kg load. Only orthogonal partial least-squares discrimination analysis performed well in separating the group with a BRPE score of 6-12 from the group with a BRPE score of 13-20. Significant differences in the urine levels of several organic acids were observed between the two groups, and the heatmap also presented different metabolic profiles based on BRPE. According to the standard of a variable importance in the projection > 1, fold change > 1.5 and P < 0.05, 19 different metabolites of urinary organic acids were screened and enriched in pathways mainly including the citrate cycle (tricarboxylic acid cycle) and alanine, aspartate and glucose metabolism. CONCLUSION: The BRPE scale identified significantly different urinary organic acid profiles between the higher and lower BRPE value groups, and, thus, could be used to monitor body fatigue in individuals participating in long-distance outdoor hiking with weight bearing.

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. The effects of sex, food, and a capsule formulation were evaluated in separate cohorts. For MAD (N = 27), sequential cohorts of male and female participants received 36/100/200 mg JNJ-64264681 once daily for 10 days. JNJ-64264681 exposure (peak concentration; area under the concentration-time curve) was less than dose proportional from 4 mg to 36 mg. Dose-normalized area under the concentration-time curves following the 36 mg and 100 mg doses were generally similar. The mean terminal half-life was 1.6-13.2 hours. With multiple doses, steady state was achieved by day 2. A semimechanistic PK/PD model was developed using the first 5 SAD cohorts' data to predict %BTKO in MAD cohorts. PK/PD model guided dose-escalation, and all participants in the 200/400 mg single-dose cohorts achieved ≥90% BTKO at 4 hours after dosing (peak) with prolonged occupancy. As BTKO data became available from MAD cohorts, it was found that observed BTKO data were consistent with model predictions. JNJ-64264681 showed no safety signals of concern. Overall, safety, tolerability, PK, BTKO, and PK/PD modeling guided the rationale for dose selection for the subsequent first-in-patient lymphoma studies.

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. To inform further drug development, population pharmacokinetic (PopPK) modeling and exposure-response (E-R) analyses were planned and performed. A 1-compartment PopPK model with first-order absorption and parallel linear and nonlinear elimination pathways was established for tesnatilimab in patients with CD. No clinically significant covariates were identified, and overall consistent pharmacokinetics were observed between part I and part II patients. Receptor occupancy data suggested full occupancy of the peripheral blood natural killer group 2 member D receptors and target engagement at all tested dose levels. Pooled part I and part II data showed a positive efficacy E-R relationship; however, this was driven by data from part I. Part II-only analysis did not show an apparent efficacy E-R relationship. No important covariates were identified in efficacy E-R analyses, overall, and in various subpopulations. No apparent E-R relationships were observed for the investigated safety end points. The PopPK and E-R analyses indicated that the inadequate efficacy of tesnatilimab in CD was unlikely due to insufficient drug exposure and target engagement.

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. As the models become more complex, the question of structural and parameter identifiability arises. To address this question, we work through a trastuzumab case example to guide the modeler's choice for model and parameter optimization in light of the context of use. We leave the readers of this tutorial with a brief summary of the advantages and limitations of each model expansion, as well as the model source codes for further self-guided exploration and hands-on analysis.

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]). Analyses were conducted to explore exposure-response (E-R) relationships for efficacy and select treatment-emergent adverse events (TEAEs). METHODS: The PPK analysis included pooled data from the D-Pd cohorts of the phase 3 APOLLO and phase 1b EQUULEUS studies. Covariates were evaluated in the PPK model. Model-predicted exposures to daratumumab were compared between covariate subgroups of interest and used to investigate relationships between daratumumab exposure and efficacy and safety in APOLLO. RESULTS: The PPK analysis included 1146 daratumumab PK samples from 239 patients (APOLLO, n = 140; EQUULEUS, n = 99). Observed concentration-time data of daratumumab were well described by a two-compartment PPK model with first-order absorption and parallel linear and nonlinear elimination pathways. Treatment with D-Pd provided similar daratumumab PK characteristics versus historical daratumumab monotherapy. The E-R dataset contained data from 290 APOLLO patients (D-Pd, n = 140; Pd, n = 150). The PK-efficacy relationship of daratumumab supported improved progression-free survival for patients in the D-Pd group vs. the Pd group. Additionally, TEAEs did not increase with increasing PK exposure in the D-Pd group. CONCLUSIONS: The PPK and E-R analyses support the daratumumab subcutaneous 1800 mg dosing regimen in combination with Pd for treatment of patients with RRMM. No dose adjustment is recommended in this indication for any of the investigated factors, none of which had clinically relevant effects on daratumumab PK.

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 × 106 (range 0.5-1.0 × 106 ) CAR positive viable T-cells per kg body weight. The population PK model development was primarily guided by the current mechanistic understanding of CAR-T kinetics and the principles of building a parsimonious model. Cilta-cel PK was adequately described by a two-compartment model (with a fast and a slow apparent decline rate from each compartment, respectively) and a chain of four transit compartments with a lag time empirically representing the process from infused CAR-T cell to measurable CAR transgene. No apparent relationship was observed between cilta-cel dose (i.e., the actual number of CAR positive viable T-cells infused), given the narrow dose range, and the observed transgene level. Based on covariate search and subgroup analysis of maximum systemic CAR transgene level (Cmax ) and area under curve from the first dose to day 28 (AUC0-28d ), none of the investigated subjects' demographics, baseline characteristics, and manufactured product characteristics had significant effects on cilta-cel PK. The developed model is deemed robust and adequate for enabling subsequent exposure-safety and exposure-efficacy analyses.

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/m2 at weeks 0, 4, then every 8 weeks (Q8W). In the phase 3, randomized, placebo-controlled CADMUS trial, patients with PsO aged ≥ 12 to < 18 years received ustekinumab at weeks 0, 4, then Q12W. In the phase 3 CADMUS Jr trial, patients with PsO aged ≥ 6 to < 12 years received ustekinumab at weeks 0, 4, then Q12W. The ustekinumab analyses used data only from patients who received the standard ustekinumab dosing regimen (≤ 60 kg: 0.75 mg/kg; > 60 to ≤ 100 kg: 45 mg; > 100 kg: 90 mg). RESULTS: In the 127 patients with pc-JIA treated with IV golimumab (GO-VIVA), pharmacokinetic and exposure-response results were similar to those in adults with rheumatoid arthritis treated with IV golimumab. Additionally, pharmacokinetic and clinical response data from five patients with jPsA in GO-VIVA were comparable to those in adults with PsA treated with IV golimumab. No new safety signals were observed in GO-VIVA. Pharmacokinetic and clinical response data observed in the four pediatric patients with PsO and jPsA treated with ustekinumab in CADMUS and CADMUS Jr were similar to those in the 91 pediatric patients with PsO without jPsA in these trials and to those in adults with PsA treated with ustekinumab. Safety was extrapolated from CADMUS or CADMUS Jr; no new signals were observed. CONCLUSIONS: These three sets of analyses corroborate similar exposure and efficacy of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in patients with jPsA to support extrapolation of established adult efficacy. The overall safety profiles of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in pediatric patients with PsO with or without jPsA were consistent with the safety profiles of these agents in the context of their clinical programs and cumulative use. Based on these analyses, the US Food and Drug Administration approved IV golimumab for polyarticular JIA and active PsA in patients 2 years and older and SC ustekinumab for pediatric PsA in patients 6 years and older, highlighting how use of an extrapolation approach can help streamline drug development for pediatric patient populations in whom larger clinical trials are not feasible. CLINICAL TRIAL REGISTRATION: GO-VIVA (NCT02277444) was registered at clinicaltrials.gov on 29 October 2014; CADMUS (NCT01090427) was registered on 22 March 2010; and CADMUS Jr (NCT02698475) was registered on 3 March 2016.

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. According to different emission reduction techniques, the diesel oxidation catalyst (DOC) can reduce carbon monoxide (CO) by 41.6-94.8% and hydrocarbon (HC) by 92.7-95.1%, catalytic diesel particulate filter (CDPF) can reduce particulate matter (PM) by 87.1-99.5%, and selective catalytic reduction (SCR) using urea as a reducing agent can reduce nitrogen oxides (NOx) by 60.3% to 80.5%. Copper-based SCR is better than vanadium-based SCR in NOx reduction. In addition, the study found that when the enhanced 3DOC + CDPF emission reduction technique is used on forklifts, DOC has a "low-temperature saturation effect", which will reduce the emission reduction effect of CO and THC. The use of Burner + DOC + CDPF emission reduction techniques and fuel injection heating process will increase CO's emission factors by 3.2-3.5 and 4.4-6.7 times compared with the actual operating 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. It is to help art and design education and local small and medium-sized enterprises to continue to develop. The research results of this paper show that: (1) The accuracy of the model in this paper is on the rise as a whole, with the highest accuracy rate of 96.2%; the highest accuracy rate of the improved neural network model is 87.1%; the highest accuracy rate of the random forest algorithm is 86.3%; and the traditional model is the highest. The accuracy rate is 80.3%. (2) The recall rate of the traditional model is between 0.0816 and 0.0984; the recall rate of the random forest algorithm is between 0.726 and 0.983; the recall rate of the improved neural network is between 0.752 and 0.961; the recall rate of the model in this paper is between 0.615 and 0.815. (3) The overall static payback period is decreasing year by year, and the overall rate of return is also increasing year by year, which shows that the cooperation between art and design education and enterprises can bring higher benefits to enterprises. (4) After the cooperation between the two companies in 2016, various indicators have risen significantly. The highest net present value is 92.55 million yuan; the highest profit index is 1.98; the highest net present value rate is 35.8%, and the highest internal rate of return is 79.2%. (5) After school 2 cooperates with the enterprises, the employment rate has increased year by year, with the highest employment rate of 88.3%. In contrast, the annual employment rate of school 1, which does not cooperate with enterprises, is irregular. (6) The percentages of environmental indicators such as total emission reduction, environmental quality, and pollution control have all increased, and resource consumption has decreased by 28%; the public's satisfaction with the results of environmental protection has also reached 90%. (7) The average evaluation of each index is above 8 points, the highest score for completeness is 8.5, the highest score for feasibility is 8.9, the highest score for recognition is 9.2, and the highest score for practicality is 8.7.

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. A 2-compartment pharmacokinetic model with linear clearance developed based on GO-FURTHER (A Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Golimumab, an Anti-TNFα Monoclonal Antibody, Administered Intravenously, in Patients With Active Rheumatoid Arthritis Despite Methotrexate Therapy) study data was used for pharmacokinetic simulations. A latent-variable indirect exposure-response model developed based on GO-FURTHER American College of Rheumatology (ACR) 20%/50%/70% improvement (ACR20, ACR50, and ACR70, respectively) data was used to predict clinical endpoints of ACR20/ACR50/ACR70 response rates. FINDINGS: For Q6W and Q8W dosing, respectively, predicted median golimumab steady-state trough (Ctrough,ss) concentrations were 0.57 and 0.24 µg/mL, and Cmax at steady state values were 33.1 and 32.9 µg/mL. Predicted peak median ACR20 steady-state response rates were 76.7% (Q6W) and 75.6% (Q8W). Predicted median ACR20 response rates at Ctrough,ss increased by 4.7 percentage points with Q6W (73.7%) versus Q8W (69.0%) dosing. Greater improvement in ACR20 response rates at trough time points was predicted in patients with lower golimumab trough serum concentrations. Consistent findings were observed for ACR50/ACR70 response rates. IMPLICATIONS: These simulations suggest that intravenous golimumab Q6W dosing increases golimumab Ctrough,ss, which may improve clinical response in the small proportion of patients with rheumatoid arthritis with waning efficacy at the end of the standard dosing interval. CLINICALTRIALS: gov identifier: NCT00973479. Clinicaltrialsregister.eu: EudraCT 2008-006064-11.

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. Covariates identified as contributing to the observed guselkumab PK variability were body weight and diabetes comorbidity; however, the magnitude of the effects of these covariates was not considered clinically relevant, and dose adjustment was not warranted for the patient population investigated. Positive exposure-response relationships were demonstrated with landmark and longitudinal exposure-response analyses between guselkumab exposure and clinical efficacy end points (American College of Rheumatology [ACR] 20%, 50%, and 70% improvement criteria and Investigator's Global Assessment [IGA] of psoriasis) at weeks 20 and/or 24, with no clinically relevant differences observed in improvement of PsA signs and symptoms between the two guselkumab treatment regimens evaluated (100 mg every 4 weeks or 100 mg at weeks 0 and 4, then every 8 weeks). Baseline Disease Activity Score in 28 joints (DAS28), Psoriasis Area and Severity Index (PASI) score, and/or C-reactive protein level were identified as influencing covariates on guselkumab exposure-response model parameters. These results provide a comprehensive evaluation of subcutaneous guselkumab PKs and exposure-response relationship that supports the dose regimen of 100 mg at weeks 0 and 4, then every 8 weeks in patients with PsA.

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. This manuscript aims to further investigate the benefit of joint modeling of an ordered categorical primary endpoint with a related near-continuous endpoint, through the sharing of model parameters in the latent variable indirect response (IDR) modeling framework. This is illustrated by analyzing the data collected through up to 116 weeks from a phase 3b response-adaptive trial of ustekinumab in patients with psoriasis. The primary endpoint was based on the 6-point physician's global assessment (PGA) score. The Psoriasis area and severity Index (PASI) data, ranging from 0 to 72 with 0.1 increments, were also available. Separate and joint latent variable Type I IDR models of PGA and PASI scores were developed and compared. The results showed that the separate PGA model had a substantial structural bias, which was corrected by the joint modeling of PGA and PASI scores.

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. The exposure-response (E-R) analysis included data from all patients in the randomized phase of ANDROMEDA (n = 388). Logistic regression and survival analysis were used to evaluate the relationships between daratumumab systemic exposure and efficacy end points. The E-R analysis on safety was conducted using quartile comparison and logistic regression analysis. The observed concentration-time data of daratumumab SC were well described by a 1-compartment popPK model with first-order absorption and parallel linear and nonlinear Michaelis-Menten elimination pathways. None of the investigated covariates were determined to be clinically meaningful. Daratumumab systemic exposure was generally similar across subgroups that achieved different levels of hematologic response, and there was no apparent relationship between daratumumab systemic exposure and the investigated safety end points. In conclusion, the popPK and E-R analyses supported the selected 1800-mg flat dose of daratumumab SC in combination with the bortezomib, cyclophosphamide, and dexamethasone regimen for the treatment of light-chain amyloidosis. No dose adjustment was recommended for investigated 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. Amniotic fluid was collected from all cases for karyotype analysis and copy number variation sequencing (CNV-seq), and cell-free fetal DNA (cfDNA) in maternal blood was tested using Noninvasive Prenatal Test (NIPT-Plus) before amniocentesis in some cases. The results of amniocentesis with different NT thicknesses were analyzed and compared with those of NIPT-Plus. RESULTS: A total of 125 eligible patients were divided into group A (2.5 mm ≤ NT < 3.0 mm) and group B (NT ≥ 3.0 mm). In group A, the detection rate of chromosomal aneuploidy and pathogenic copy number variation (CNV) was 10.6% and 6.4%, respectively. The total chromosome abnormality rate in group B (34.7%) was significantly higher than that in group A (17%). In 72 patients who underwent NIPT-Plus and amniocentesis, chromosomal aneuploidy accounted for 80.8% of the total chromosomal abnormalities. Among 21 cases of chromosomal aneuploidy, NIPT-Plus detected 20 cases. The sensitivity and specificity of NIPT-Plus toward aneuploidy detection were 95.2% and 100%, respectively. Among the five cases of pathogenic CNV, only two were detected using NIPT-Plus. CONCLUSION: NIPT-plus is recommended as the first choice for fetal diagnosis in pregnant women with 2.5 mm ≤ NT < 3.0 mm who do not accept invasive prenatal diagnosis. When NT ≥ 3.0 mm and NIPT-Plus detects chromosomal aneuploidy, a rapid prenatal diagnosis can be performed through amniocentesis. In cases where NIPT-Plus yields negative results, amniocentesis still needs to be performed to detect chromosome microdeletions/duplications in order to avoid a missed 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. The modulation effects of systemic IL-6 level and local IL-6 level in the gastrointestinal tract (GI) on CYPs activities were assessed. Upon blockade of the IL-6 signaling pathway by an anti-IL-6 treatment, the area under plasma concentration versus time curves (AUCs) of S-warfarin, omeprazole, and midazolam were predicted to decrease by up to 40%, 42%, and 46%, respectively. In patients with Crohn's disease and ulcerative colitis treated with an anti-IL-6 therapy, the lowering of the elevated IL-6 levels in the local GI tissue were predicted to result in further decreases in AUCs of those CYP substrates. The propensity of TP-DIs under comorbidity conditions, such as in patients with cancer with IMID, were also explored. With further validation with relevant clinical data, this PBPK model may provide an in silico way to quantify the magnitude of potential TP-DI in patients with elevated IL-6 levels when an anti-IL-6 therapeutic is used with concomitant small-molecule drugs. This model may be further adapted to evaluate the CYP modulation effect by other therapeutic modalities, which would significantly alter levels of proinflammatory cytokines during the treatment period.

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. The affected families underwent multiplatform genetic tests. RESULTS: Of the 27 affected fetuses, 21 (77.8%) had pathogenic or potential pathogenic variations in the following genes: COL1A1, FGFR3, COL2A1, COL1A2, FLNB, DYNC2LI1, and TRIP11. Two fetuses had compound heterozygous mutations in DYNC2LI1 and TRIP11, respectively, and the other 19 carried de novo autosomal dominant variants. Novel variants were identified in COL1A1, COL2A1, COL1A2, DYNC2LI1, and TRIP11 in 11 fetuses. We also included the first description of the phenotype of odontochondrodysplasia in a prenatal setting. CONCLUSIONS: ES or panel sequencing offers a high diagnostic yield for fetal skeletal dysplasia during the first and second trimesters. Comprehensive and complete phenotypic information is indispensable for genetic analysis and the expansion of genotype-phenotype correlations in fetal skeletal abnormalities.