Population pharmacokinetics and exposure-response analyses for efficacy and safety of upadacitinib in patients with axial spondyloarthritis.

Upadacitinib is an orally administered, selective, Janus kinase inhibitor that is approved for several auto-immune conditions, such as axial spondyloarthritis, an inflammatory rheumatic disease that includes ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (nr-axSpA). The approvals of upadacitinib for the treatment of AS and nr-axSpA were based on the safety and efficacy data for upadacitinib 15 mg once-daily compared to placebo from the SELECT-AXIS 1 and SELECT-AXIS 2 studies. Population pharmacokinetic analyses based on data from 244 patients with axSpA showed that the pharmacokinetics of upadacitinib were comparable in subjects with AS and nr-axSpA. Exposure-response relationships were characterized for key efficacy and safety end points using data from 482 patients with axSpA. The exposure-response analyses for efficacy based on Assessment of SpondyloArthritis International Society (ASAS)20 and ASAS40 responses at week 14, showed a clear differentiation from placebo with no evidence of increased responses with increasing upadacitinib plasma exposures. There were no clear exposure-response trends observed for safety end points that included serious infections, herpes zoster, pneumonia, lymphopenia (grade ≥3), neutropenia (grade ≥3), or a greater than 2 g/dL decrease in hemoglobin from baseline through week 14. The exposure-response analyses for efficacy and safety presented here supported the favorable benefit-risk profile with the use of upadacitinib 15 mg once-daily for the treatment of axSpA.

Artificial Intelligence for Quantitative Modeling in Drug Discovery and Development: An Innovation and Quality Consortium Perspective on Use Cases and Best Practices.

Recent breakthroughs in artificial intelligence (AI) and machine learning (ML) have ushered in a new era of possibilities across various scientific domains. One area where these advancements hold significant promise is model-informed drug discovery and development (MID3). To foster a wider adoption and acceptance of these advanced algorithms, the Innovation and Quality (IQ) Consortium initiated the AI/ML working group in 2021 with the aim of promoting their acceptance among the broader scientific community as well as by regulatory agencies. By drawing insights from workshops organized by the working group and attended by key stakeholders across the biopharma industry, academia, and regulatory agencies, this white paper provides a perspective from the IQ Consortium. The range of applications covered in this white paper encompass the following thematic topics: (i) AI/ML-enabled Analytics for Pharmacometrics and Quantitative Systems Pharmacology (QSP) Workflows; (ii) Explainable Artificial Intelligence and its Applications in Disease Progression Modeling; (iii) Natural Language Processing (NLP) in Quantitative Pharmacology Modeling; and (iv) AI/ML Utilization in Drug Discovery. Additionally, the paper offers a set of best practices to ensure an effective and responsible use of AI, including considering the context of use, explainability and generalizability of models, and having human-in-the-loop. We believe that embracing the transformative power of AI in quantitative modeling while adopting a set of good practices can unlock new opportunities for innovation, increase efficiency, and ultimately bring benefits to patients.

Integrating machine learning with pharmacokinetic models: Benefits of scientific machine learning in adding neural networks components to existing PK models.

Recently, the use of machine-learning (ML) models for pharmacokinetic (PK) modeling has grown significantly. Although most of the current approaches use ML techniques as black boxes, there are only a few that have proposed interpretable architectures which integrate mechanistic knowledge. In this work, we use as the test case a one-compartment PK model using a scientific machine learning (SciML) framework and consider learning an unknown absorption using neural networks, while simultaneously estimating other parameters of drug distribution and elimination. We generate simulated data with different sampling strategies to show that our model can accurately predict concentrations in extrapolation tasks, including new dosing regimens with different sparsity levels, and produce reliable forecasts even for new patients. By using a scenario of fitting PK data with complex absorption, we demonstrate that including known physiological structure into an SciML model allows us to obtain highly accurate predictions while preserving the interpretability of classical compartmental models.

Assessing the Impact of Immunogenicity and Improving Prediction of Trough Concentrations: Population Pharmacokinetic Modeling of Adalimumab in Patients with Crohn's Disease and Ulcerative Colitis.

BACKGROUND AND OBJECTIVE: Predicting adalimumab pharmacokinetics (PK) for patients impacted by anti-drug antibodies (ADA) has been challenging. The present study assessed the performance of the adalimumab immunogenicity assays in predicting which patients with Crohn's disease (CD) and ulcerative colitis (UC) have low adalimumab trough concentrations; and aimed to improve predictive performance of adalimumab population PK (popPK) model in CD and UC patients whose PK was impacted by ADA. METHODS: Adalimumab PK and immunogenicity data obtained from 1459 patients in SERENE CD (NCT02065570) and SERENE UC (NCT02065622) were analyzed. Adalimumab immunogenicity was assessed using electrochemiluminescence (ECL) and enzyme-linked immunosorbent (ELISA) assays. From these assays, three analytical approaches (ELISA concentrations, titer, and signal-to-noise [S/N] measurements) were tested as predictors for classifying patients with/without low concentrations potentially affected by immunogenicity. The performance of different thresholds for these analytical procedures was assessed using receiver operating characteristic curves and precision-recall curves. Based on the results from the most sensitive immunogenicity analytical procedure, patients were classified into PK-not-ADA-impacted and PK-ADA-impacted subpopulations. Stepwise popPK modeling was implemented to fit the PK data to an empirical adalimumab two-compartment model with linear elimination and ADA delay compartments to account for the time delay to generate ADA. Model performance was assessed by visual predictive checks and goodness-of-fit plots. RESULTS: The classical ELISA-based classification (with 20 ng/mL ADA as lower threshold) showed a good balance of precision and recall, to determine which patients had at least 30% adalimumab concentrations below 1 µg/mL. Titer-based classification with the lower limit of quantitation (LLOQ) as threshold showed higher sensitivity to classify these patients compared to the ELISA-based approach. Therefore, patients were classified as PK-ADA-impacted or PK-not-ADA impacted using the LLOQ titer threshold. In the stepwise modeling approach ADA-independent parameters were first fit using PK data from titer-PK-not-ADA-impacted population. The identified ADA-independent covariates included the effect of indication, weight, baseline fecal calprotectin, baseline C-reactive protein, baseline albumin on clearance; and sex and weight on volume of distribution of the central compartment. Pharmacokinetic-ADA-driven dynamics were characterized using PK data for the PK-ADA-impacted population. The categorical covariate based on the ELISA classification was the best at describing the additional effect of immunogenicity analytical approaches on ADA synthesis rate. The model was able to adequately describe the central tendency and variability for PK-ADA-impacted CD/UC patients. CONCLUSIONS: The ELISA assay was found to be optimal for capturing impact of ADA on PK. The developed adalimumab popPK model is robust in predicting PK profiles for CD and UC patients whose PK was impacted by ADA.

Upadacitinib Population Pharmacokinetics and Exposure-Response Relationships in Ulcerative Colitis Patients.

BACKGROUND AND OBJECTIVE: Upadacitinib, an oral selective and reversible Janus kinase (JAK) inhibitor, showed favorable efficacy and safety in patients with moderate-to-severe ulcerative colitis (UC). The objective was to characterize upadacitinib pharmacokinetics in UC patients across Phase 2b and 3 trials and evaluate the relationships between upadacitinib plasma exposures and key efficacy or safety endpoints. METHODS: Population pharmacokinetics and exposure-response analyses were performed to characterize upadacitinib pharmacokinetics in UC patients and evaluate the relationships between plasma exposures and key efficacy or safety endpoints at the end of 8-week induction and 52-week maintenance periods. Data from 1234 UC patients from Phase 2 and 3 induction trials and 449 UC patients from a Phase 3 maintenance trial were used for these analyses. Additionally, data from patients with rheumatoid arthritis, atopic dermatitis, Crohn's disease, and healthy volunteers were used in the pharmacokinetics analysis. Quartile plots and logistic regression models were used to evaluate the exposure-response relationships across upadacitinib doses of 7.5-45 mg once daily (QD) for induction and 15-30 mg QD for maintenance. RESULTS: Upadacitinib plasma exposures were dose-proportional in UC patients across the evaluated dose range. Upadacitinib pharmacokinetics in UC were consistent between the induction and maintenance periods, and with other patient populations. Upadacitinib plasma exposures associated with the 45 mg QD induction dose maximized efficacy for Week 8 clinical and endoscopic endpoints. Plasma exposures associated with upadacitinib 30 mg maintenance dose provided additional incremental benefit compared to 15 mg QD for Week 52 key clinical and endoscopic endpoints. No trends were observed in the evaluated safety events with increasing plasma exposures at the end of induction or maintenance periods. CONCLUSION: These analyses supported selection of upadacitinib UC induction and maintenance doses. TRIAL REGISTRATION: Data from studies NCT02819635 and NCT03653026 were included in these analyses.

Bridging Fixed Dose to Body Weight-based Regimen of Adalimumab in Paediatric Ulcerative Colitis Using a Pharmacometric Modelling Approach: Case Study with the Phase 3 ENVISION I Trial.

BACKGROUND AND AIMS: The Phase 3 study ENVISION I demonstrated efficacy and safety of adalimumab in paediatric patients with moderate to severe ulcerative colitis. The protocol-specified high-dose adalimumab regimen was numerically more efficacious than the standard-dose regimen. The objective of this work was to bridge a fixed-dosing regimen to the protocol-specified high-induction/high-maintenance, body weight-based dosing regimen studied in ENVISION I, using a pharmacometrics modelling and simulation approach. METHODS: A stepwise strategy was implemented, including developing an adalimumab paediatric population pharmacokinetic model; using this model to determine a fixed-dosing regimen in paediatric ulcerative colitis patients which achieves similar concentrations to those observed in ENVISION I patients; determining adalimumab exposure-response relationship using population pharmacokinetic/pharmacodynamic model and data from ENVISION I; simulating clinical remission rate in paediatric ulcerative colitis patients using the Markov exposure-response model and the dosing regimen determined to provide similar efficacy to that observed in ENVISION I. RESULTS: Both developed population pharmacokinetic and pharmacokinetic/pharmacodynamic models adequately described the observed data. Adalimumab exposure was identified as a significant predictor of clinical remission at Week 8 based on logistic regression [p <0.01]. Simulated efficacy suggested that the fixed-dosing regimen performs similarly to the more efficacious dosing regimen used in ENVISION I, by providing comparable clinical remission per Partial Mayo Score response rates over time. No relationship between adalimumab exposure and adverse events was identified. CONCLUSIONS: The population pharmacokinetic/pharmacodynamic model supports the appropriateness of the use of the fixed-dosing regimen in the paediatric ulcerative colitis population.

Exposure-Response Model With Time-Varying Predictors to Estimate the Effects of Veliparib in Combination With Carboplatin/Paclitaxel and as Monotherapy: Veliparib Phase 3 Study in BRCA-Mutated Advanced Breast Cancer (BROCADE3) Trial.

BRCA-Mutated Advanced Breast Cancer (BROCADE3) is a phase 3 study, evaluating veliparib in combination with carboplatin/paclitaxel with continuation as monotherapy if carboplatin/paclitaxel is discontinued in patients with germline BRCA1/2 mutation-associated, advanced human epidermal growth factor receptor 2-negative breast cancer. The objective of the current analysis was to characterize the veliparib exposure-response relationships for efficacy (progression-free survival [PFS]) and safety in this study. Exposure-efficacy analyses of PFS were conducted using Kaplan-Meier plots and cox proportional hazards (CPH) models using treatment alone or both treatment and exposure as time-dependent predictors to estimate the effect of veliparib in combination with carboplatin/paclitaxel and as monotherapy. The cox proportional hazards model with only treatment as the time-varying predictor estimated a statistically significant benefit of veliparib monotherapy compared to placebo monotherapy (hazard ratio, 0.49; 95%CI, 0.33-0.73) and a modest, non-statistically significant benefit (hazard ratio, 0.81; 95%CI, 0.62-1.05) of adding veliparib to carboplatin/paclitaxel. Inclusion of exposure as an additional time-varying predictor in the cox proportional hazards model indicated a flat exposure-response relationship between the veliparib exposure and PFS when veliparib was administered in combination with carboplatin/paclitaxel or as monotherapy. The exposure-safety analysis did not reveal any meaningful exposure-dependent trend in the incidence of adverse events of interest. These analyses support the dose regimen of veliparib (120 mg twice daily) in combination with carboplatin/paclitaxel and continuation of veliparib (300-400 mg twice daily) as monotherapy if carboplatin/paclitaxel were discontinued before disease progression in this patient population. This study is registered with ClinicalTrials.gov with a registration ID: NCT02163694.

Foslevodopa/foscarbidopa subcutaneous infusion maintains equivalent levodopa exposure to levodopa-carbidopa intestinal gel delivered to the jejunum.

INTRODUCTION: The objective of this study was to compare the pharmacokinetics (PK) of levodopa (LD) from 24-h continuous subcutaneous infusion of foslevodopa/foscarbidopa to the LD pharmacokinetics from 16-h levodopa-carbidopa intestinal gel (LCIG) followed by night-time oral LD/carbidopa (CD) doses. METHODS: This was a Phase 1, open-label, randomized, 2-period crossover study conducted in 25 male and female healthy volunteers. RESULTS: The LD exposures (Cmax0-16, AUC0-16 and AUC∞) following subcutaneous infusion of 700/35 mg foslevodopa/foscarbidopa over 24 h were similar (<8% difference) to those of LCIG 350/87.5 mg LD/CD administered over 16 h followed by two 100/25 mg LD/CD oral doses at 18 and 21 h after the start of LCIG delivery. CONCLUSION: Foslevodopa/foscarbidopa subcutaneous infusion provides levodopa exposures comparable to LCIG throughout the day. GOV IDENTIFIER: Not Applicable.

Validation of a quantitative systems pharmacology model of calcium homeostasis using elagolix Phase 3 clinical trial data in women with endometriosis.

Elagolix is a novel, oral gonadotropin-releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and heavy menstrual bleeding associated with uterine fibroids. Consistent with its mechanism of action, elagolix exhibited dose-dependent suppression of estradiol (E2) in clinical studies. A dose-response model that describes the relationship between elagolix dosages and average E2 levels was combined with a previously published quantitative systems pharmacology (QSP) model of calcium homeostasis to predict bone mineral density (BMD) changes during and following elagolix treatment. In the QSP model, changes in E2 levels were linked to downstream changes in markers of bone resorption (carboxyterminal cross-linked telopeptide of type 1 collagen [CTX]), formation (N-terminal propeptide of type 1 procollagen [P1NP]) and BMD. The BMD, CTX, and P1NP predictions by the QSP model were validated against observed data from four phase III clinical trials of elagolix in premenopausal women with endometriosis. BMD, CTX, and P1NP were successfully described by the QSP model, without any model fitting, suggesting that the model was validated for further predictions of elagolix effects on BMD. Simulations using the validated QSP model demonstrated that elagolix 150 mg once daily dosing for 24 months is predicted to result in -0.91% change from baseline in lumbar spine BMD. The QSP model simulation results were part of the totality of evidence to support the approved duration of therapy for elagolix 150 mg once daily in patients with endometriosis.

A Population Pharmacokinetic Meta-Analysis of Veliparib, a PARP Inhibitor, Across Phase 1/2/3 Trials in Cancer Patients.

Veliparib (ABT-888) is a poly(ADP-ribose) polymerase inhibitor in development for the treatment of high-grade ovarian cancer or BRCA-mutated breast cancer in combination with carboplatin and paclitaxel. The population pharmacokinetics of veliparib were characterized using combined data from 1470 adult subjects with ovarian cancer, breast cancer, or other solid tumors enrolled in 6 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies of veliparib oral doses of 10 to 400 mg twice daily as monotherapy or in combination with chemotherapy. A 1-compartment model with linear clearance and first-order absorption best characterized veliparib pharmacokinetics. The predicted apparent oral clearance (CL/F) and volume of distribution (Vc /F) were 479 L/day and 152 L, respectively. The significant covariates in the final model included albumin, creatinine clearance, strong inhibitors of cytochrome P450 (CYP) 2D6, and sex on CL/F and albumin, body weight, and sex on Vc /F. Mild and moderate renal impairment increased veliparib median (95%CI) steady-state AUC (AUCss ) by 27.3% (23.7%-30.9%) and 65.4% (56.0%-75.5%), respectively, compared with normal renal function. Male subjects had 16.5% (7.53%-23.9%) lower AUCss compared with female subjects and coadministration with strong CYP2D6 inhibitors increased AUCss by 13.0% (6.11%-20.8%). Race, age, region, cancer type, or enzyme (CYP3A4, CYP2C19) or transporter (P-glycoprotein, multidrug and toxin extrusion protein 1/2, organic cation transporter 2) inhibiting/inducing comedications were not found to significantly impact veliparib pharmacokinetics. Other than baseline creatinine clearance and hence renal impairment effect on veliparib clearance, no other covariates had a clinically meaningful effect on veliparib exposure warranting dose adjustment.

Pharmacokinetics of Upadacitinib in Healthy Subjects and Subjects With Rheumatoid Arthritis, Crohn's Disease, Ulcerative Colitis, or Atopic Dermatitis: Population Analyses of Phase 1 and 2 Clinical Trials.

Upadacitinib (ABT-494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment of several inflammatory disorders. A population pharmacokinetic model was developed for upadacitinib using 11,658 plasma concentrations from 1145 subjects from 4 phase 1 and 5 phase 2 studies in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis. A 2-compartment model with first-order absorption and lag time for the immediate-release formulation and mixed zero- and first-order absorption with lag time for the extended-release formulation, and linear elimination adequately described upadacitinib plasma concentration-time profiles. The oral bioavailability of upadacitinib extended-release formulation was estimated to be approximately 80% relative to the immediate-release formulation. Covariates included in the final model were creatinine clearance, subject population (healthy subjects vs subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease vs subjects with rheumatoid arthritis) and sex on apparent oral clearance and sex and body weight on apparent volume of distribution of the central compartment. Female subjects had 21% higher upadacitinib steady-state area under the plasma concentration-time curve (AUC) compared to male subjects. Compared to healthy subjects, subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease had 21% higher upadacitinib steady-state AUC, while subjects with rheumatoid arthritis had 35% higher steady-state AUC. Subjects with mild or moderate renal impairment were estimated to have 10% or 22% higher AUC, respectively, compared to subjects with normal renal function. Based on final model parameter estimates, effects of the tested covariates are not expected to result in clinically relevant changes in upadacitinib steady-state exposures.

Exposure-response analysis to inform the optimal dose of veliparib in combination with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer patients.

PURPOSE: Veliparib, a poly(ADP-ribose)-polymerase (PARP) 1 and 2 enzyme inhibitor, was administered at 120 mg twice daily (BID) for 7 days in a 21-day cycle with carboplatin/paclitaxel in the Phase 2 BROCADE study in patients with BRCA-deficient recurrent or metastatic breast cancer, a dose based on Phase 1 results. Population pharmacokinetic (PK) and exposure-response analyses were undertaken to retrospectively evaluate whether an optimal dose was used in BROCADE. METHODS: A population PK analysis was performed using data from 168 patients in BROCADE along with data from 288 subjects in another 5 studies. The relationship between veliparib exposure and efficacy variables (including progression-free survival [PFS] and objective response rate [ORR]) and safety variables (selected grade 3 or greater hematological adverse events) were analyzed. RESULTS: Veliparib PK parameters in BROCADE were comparable to the previous studies. Creatinine clearance on veliparib apparent clearance and lean body weight on veliparib apparent volume of distribution were identified as covariates. A trend of better efficacy (PFS and ORR) in the veliparib arm compared to placebo was observed. However, veliparib exposure-efficacy response was relatively flat with higher veliparib exposures not showing better efficacy. No exposure-response relationship was observed in grade 3 or greater hematological toxicities (anemia, neutropenia, leukopenia, and thrombocytopenia). CONCLUSIONS: The exposure-response analysis suggested that intermittent 7-day veliparib 120 mg BID dosing in a 21-day cycle provided additional efficacy without meaningfully impacting the safety and tolerability when co-administered with carboplatin and paclitaxel in patients with BRCA-deficient breast cancer. A higher dose of veliparib is unlikely to provide greater benefit in this combination in patients with BRCA-deficient recurrent or metastatic breast cancer.

An Integrated Population Pharmacokinetic Model Versus Individual Models of Depatuxizumab Mafodotin, an Anti-EGFR Antibody Drug Conjugate, in Patients With Solid Tumors Likely to Overexpress EGFR.

Depatuxizumab mafodotin (depatux-m) is an antibody-drug conjugate (ADC) designed for the treatment of tumors expressing epidermal growth factor receptor (EGFR), consisting of a veneered "humanized" recombinant IgG1κ antibody that has binding properties specific to a unique epitope of human EGFR with noncleavable maleimido-caproyl linkers each attached to a potent antimitotic cytotoxin, monomethyl auristatin F. We aimed to describe the development and comparison of 2 population pharmacokinetic modeling approaches. Data from 2 phase 1 studies enrolling patients with glioblastoma multiforme or advanced solid tumors were included in the analysis. Patients in these studies received doses of depatux-m ranging from 0.5 to 4.0 mg/kg as monotherapy, in combination with temozolomide, or radiation plus temozolomide depending on the study and/or arm. First, an integrated ADC model to simultaneously describe the concentration-time data for ADC, total antibody, and cys-mafodotin was built using a 2-compartment model for ADC for each drug-to-antibody ratio. Then, 3 individual models were developed for ADC, total antibody, and cys-mafodotin separately using 2-compartment models for ADC and total antibody and a 1-compartment model for cys-mafodotin. Visual predictive checks suggested accurate model fitting across a range of concentrations. The analysis showed that both an integrated complex ADC model and the individual models that have shorter computational time would result in similar outcomes.

Effect of veliparib (ABT-888) on cardiac repolarization in patients with advanced solid tumors: a randomized, placebo-controlled crossover study.

PURPOSE: Veliparib (ABT-888) is an orally bioavailable potent inhibitor of poly(ADP-ribose) polymerase (PARP)-1 and PARP-2. This phase 1 study evaluated the effect of veliparib on corrected QT interval using Fridericia's formula (QTcF). METHODS: Eligible patients with advanced solid tumors received single-dose oral veliparib (200 mg or 400 mg) or placebo in a 6-sequence, 3-period crossover design. The primary endpoint was the difference in the mean baseline-adjusted QTcF between 400 mg veliparib and placebo (∆∆QTcF) at six post-dose time points. Absence of clinically relevant QTcF effect was shown if the 95 % upper confidence bound (UCB) for the mean ∆∆QTcF was <10 ms for all time points. An exposure-response analysis was also performed. RESULTS: Forty-seven patients were enrolled. Maximum mean ∆∆QTcF of veliparib 400 mg was 6.4 ms, with a 95 % UCB of 8.9 ms; for veliparib 200 mg, the maximum mean ∆∆QTcF was 3.6 ms, with a 95 % UCB of 6.1 ms. No patient had a QTcF value >480 ms or change from baseline in QTcF interval >30 ms. Treatment-emergent adverse events (TEAEs) were experienced by 36.2, 48.9, and 47.8 % of patients while receiving veliparib 200 mg, veliparib 400 mg, and placebo, respectively. Most common TEAEs were nausea (12.8 %) and myalgia (8.5 %) after veliparib 200 mg, nausea (8.5 %) and vomiting (8.5 %) after veliparib 400 mg, and nausea (6.5 %) after placebo. CONCLUSIONS: Single-dose veliparib (200 mg or 400 mg) did not result in clinically significant QTc prolongation and was well tolerated in patients with advanced solid tumors.

Parameter-free continuous drift-diffusion models of amorphous organic semiconductors.

Continuous drift-diffusion models are routinely used to optimize organic semiconducting devices. Material properties are incorporated into these models via dependencies of diffusion constants, mobilities, and injection barriers on temperature, charge density, and external field. The respective expressions are often provided by the generic Gaussian disorder models, parametrized on experimental data. We show that this approach is limited by the fixed range of applicability of analytic expressions as well as approximations inherent to lattice models. To overcome these limitations we propose a scheme which first tabulates simulation results performed on small-scale off-lattice models, corrects for finite size effects, and then uses the tabulated mobility values to solve the drift-diffusion equations. The scheme is tested on DPBIC, a state of the art hole conductor for organic light emitting diodes. We find a good agreement between simulated and experimentally measured current-voltage characteristics for different film thicknesses and temperatures.