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Model-based meta-analysis (MBMA) is a quantitative approach that leverages published summary data along with internal data and can be applied to inform key drug development decisions, including the benefit-risk assessment of a treatment under investigation. These risk-benefit assessments may involve determining an optimal dose compared against historic external comparators of a particular disease indication. MBMA can provide a flexible framework for interpreting aggregated data from historic reference studies and therefore should be a standard tool for the model-informed drug development (MIDD) framework.In addition to pairwise and network meta-analyses, MBMA provides further contributions in the quantitative approaches with its ability to incorporate longitudinal data and the pharmacologic concept of dose-response relationship, as well as to combine individual- and summary-level data and routinely incorporate covariates in the analysis.A common application of MBMA is the selection of optimal dose and dosing regimen of the internal investigational molecule to evaluate external benchmarking and to support comparator selection. Two case studies provided examples in applications of MBMA in biologics (durvalumab + tremelimumab for safety) and small molecule (fenebrutinib for efficacy) to support drug development decision-making in two different but well-studied disease areas, i.e., oncology and rheumatoid arthritis, respectively.Important to the future directions of MBMA include additional recognition and engagement from drug development stakeholders for the MBMA approach, stronger collaboration between pharmacometrics and statistics, expanded data access, and the use of machine learning for database building. Timely, cost-effective, and successful application of MBMA should be part of providing an integrated view of MIDD.
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Artrite Reumatoide , Produtos Biológicos , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Desenvolvimento de Medicamentos , Humanos , Medição de RiscoRESUMO
Since the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as an attractive target in the treatment of hypercholesterolemia, multiple anti-PCSK9 therapeutic modalities have been pursued in drug development. The objective of this research is to set the stage for the quantitative benchmarking of two anti-PCSK9 pharmacological modality classes, monoclonal antibodies (mAbs) and small interfering RNA (siRNA). To this end, we developed an integrative mathematical model of lipoprotein homeostasis describing the dynamic interplay between PCSK9, LDL-cholesterol (LDL-C), VLDL-cholesterol, HDL-cholesterol (HDL-C), apoB, lipoprotein a [Lp(a)], and triglycerides (TGs). We demonstrate that LDL-C decreased proportionally to PCSK9 reduction for both mAb and siRNA modalities. At marketed doses, however, treatment with mAbs resulted in an additional â¼20% LDL-C reduction compared with siRNA. We further used the model as an evaluation tool and determined that no quantitative differences were observed in HDL-C, Lp(a), TG, or apoB responses, suggesting that the disruption of PCSK9 synthesis would provide no additional effects on lipoprotein-related biomarkers in the patient segment investigated. Predictive model simulations further indicate that siRNA therapies may reach reductions in LDL-C levels comparable to those achieved with mAbs if the current threshold of 80% PCSK9 inhibition via siRNA could be overcome.
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Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Modelos Teóricos , Pró-Proteína Convertase 9/sangue , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais Humanizados/sangue , Apolipoproteínas B/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Humanos , Lipoproteína(a)/sangue , RNA Interferente Pequeno/genética , Triglicerídeos/sangueRESUMO
AIM: To develop a quantitative drug-disease systems model to investigate the paradox that sodium-glucose co-transporter (SGLT)2 is responsible for >80% of proximal tubule glucose reabsorption, yet SGLT2 inhibitor treatment results in only 30% to 50% less reabsorption in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: A physiologically based four-compartment model of renal glucose filtration, reabsorption and excretion via SGLT1 and SGLT2 was developed as a system of ordinary differential equations using R/IQRtools. SGLT2 inhibitor pharmacokinetics and pharmacodynamics were estimated from published concentration-time profiles in plasma and urine and from urinary glucose excretion (UGE) in healthy people and people with T2DM. RESULTS: The final model showed that higher renal glucose reabsorption in people with T2DM versus healthy people was associated with 54% and 28% greater transporter capacity for SGLT1 and SGLT2, respectively. Additionally, the analysis showed that UGE is highly dependent on mean plasma glucose and estimated glomerular filtration rate (eGFR) and that their consideration is critical for interpreting clinical UGE findings. CONCLUSIONS: Quantitative drug-disease system modelling revealed mechanistic differences in renal glucose reabsorption and UGE between healthy people and those with T2DM, and clearly showed that SGLT2 inhibition significantly increased glucose available to SGLT1 downstream in the tubule. Importantly, we found that the findings of lower than expected UGE with SGLT2 inhibition are explained by the shift to SGLT1, which recovered additional glucose (~30% of total).
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Diabetes Mellitus Tipo 2 , Glicosúria , Transportador 1 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Transportador 2 de Glucose-Sódio/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/urina , Glicosúria/metabolismo , Glicosúria/urina , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Modelos Biológicos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologiaRESUMO
This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short-acting glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA), on gastric emptying rate (GER) and the glucose rate of appearance (GluRA), and evaluate the influence of drug characteristics and food-related factors on postprandial plasma glucose (PPG) stabilization under GLP-1RA treatment. A quantitative systems pharmacology (QSP) approach was used, and the proposed model was based on data from published sources including: (1) GLP-1 and exenatide plasma concentration-time profiles; (2) GER estimates under placebo, GLP-1 or exenatide IR dosing; and (3) GluRA measurements upon food intake. According to the model's predictions, the recommended twice-daily 5- and 10-µg exenatide IR treatment is associated with GluRA flattening after morning and evening meals (48%-49%), whereas the midday GluRA peak is affected to a lesser degree (5%-30%) due to lower plasma drug concentrations. This effect was dose-dependent and influenced by food carbohydrate content, but not by the lag time between exenatide injection and meal ingestion. Hence, GER inhibition by exenatide IR represents an important additional mechanism of its effect on PPG.
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Carboidratos da Dieta/metabolismo , Exenatida/uso terapêutico , Esvaziamento Gástrico/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Incretinas/uso terapêutico , Absorção Intestinal/efeitos dos fármacos , Modelos Biológicos , Glicemia/análise , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Digestão/efeitos dos fármacos , Relação Dose-Resposta a Droga , Esquema de Medicação , Liberação Controlada de Fármacos , Exenatida/administração & dosagem , Exenatida/sangue , Exenatida/farmacocinética , Peptídeo 1 Semelhante ao Glucagon/sangue , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Hiperglicemia/prevenção & controle , Hipoglicemia/prevenção & controle , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Hipoglicemiantes/uso terapêutico , Incretinas/administração & dosagem , Incretinas/sangue , Incretinas/farmacocinética , Período Pós-Prandial , Biologia de SistemasRESUMO
Background: The thymus plays a central role in shaping human immune function. A mechanistic, quantitative description of immune cell dynamics and thymic output under homeostatic conditions and various patho-physiological scenarios are of particular interest in drug development applications, e.g., in the identification of potential therapeutic targets and selection of lead drug candidates against infectious diseases. Methods: We here developed an integrative mathematical model of thymocyte dynamics in human. It incorporates mechanistic features of thymocyte homeostasis as well as spatial constraints of the thymus and considerations of age-dependent involution. All model parameter estimates were obtained based on published physiological data of thymocyte dynamics and thymus properties in mouse and human. We performed model sensitivity analyses to reveal potential therapeutic targets through an identification of processes critically affecting thymic function; we further explored differences in thymic function across healthy subjects, multiple sclerosis patients, and patients on fingolimod treatment. Results: We found thymic function to be most impacted by the egress, proliferation, differentiation and death rates of those thymocytes which are most differentiated. Model predictions also showed that the clinically observed decrease in relapse risk with age, in multiple sclerosis patients who would have discontinued fingolimod therapy, can be explained mechanistically by decreased thymic output with age. Moreover, we quantified the effects of fingolimod treatment duration on thymic output. Conclusions: In summary, the proposed model accurately describes, in mechanistic terms, thymic output as a function of age. It may be further used to perform predictive simulations of clinically relevant scenarios which combine specific patho-physiological conditions and pharmacological interventions of interest.
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Esclerose Múltipla , Timócitos , Humanos , Camundongos , Animais , Timócitos/metabolismo , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Cloridrato de Fingolimode/metabolismo , Timo , Diferenciação Celular , Esclerose Múltipla/metabolismoRESUMO
Introduction: In vivo T cell migration has been of interest to scientists for the past 60 years. T cell kinetics are important in the understanding of the immune response to infectious agents. More recently, adoptive T cell therapies have proven to be a most promising approach to treating a wide range of diseases, including autoimmune and cancer diseases, whereby the characterization of cellular kinetics represents an important step towards the prediction of therapeutic efficacy. Methods: Here, we developed a physiologically-based pharmacokinetic (PBPK) model that describes endogenous T cell homeostasis and the kinetics of exogenously administered T cells in mouse. Parameter calibration was performed using a nonlinear fixed-effects modeling approach based on published data on T cell kinetics and steady-state levels in different tissues of mice. The Partial Rank Correlation Coefficient (PRCC) method was used to perform a global sensitivity assessment. To estimate the impact of kinetic parameters on exogenously administered T cell dynamics, a local sensitivity analysis was conducted. Results: We simulated the model to analyze cellular kinetics following various T cell doses and frequencies of CCR7+ T cells in the population of infused lymphocytes. The model predicted the effects of T cell numbers and of population composition of infused T cells on the resultant concentration of T cells in various organs. For example, a higher percentage of CCR7+ T cells among exogenously administered T lymphocytes led to an augmented accumulation of T cells in the spleen. The model predicted a linear dependence of T cell dynamics on the dose of adoptively transferred T cells. Discussion: The mathematical model of T cell migration presented here can be integrated into a multi-scale model of the immune system and be used in a preclinical setting for predicting the distribution of genetically modified T lymphocytes in various organs, following adoptive T cell therapies.
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Linfócitos T , Animais , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Movimento Celular , Imunoterapia Adotiva/métodos , Modelos Teóricos , Terapia Baseada em Transplante de Células e Tecidos/métodosRESUMO
Assessment of drug-induced effects on the cardiovascular (CV) system remains a critical component of the drug discovery process enabling refinement of the therapeutic index. Predicting potential drug-related unintended CV effects in the preclinical stage is necessary for first-in-human dose selection and preclusion of adverse CV effects in the clinical stage. According to the current guidelines for small molecules, nonclinical CV safety assessment conducted via telemetry analyses should be included in the safety pharmacology core battery studies. However, the manual for quantitative evaluation of the CV safety signals in animals is available only for electrocardiogram parameters (i.e., QT interval assessment), not for hemodynamic parameters (i.e., heart rate, blood pressure, etc.). Various model-based approaches, including empirical pharmacokinetic-toxicodynamic analyses and systems pharmacology modeling could be used in the framework of telemetry data evaluation. In this tutorial, we provide a comprehensive workflow for the analysis of nonclinical CV safety on hemodynamic parameters with a sequential approach, highlight the challenges associated with the data, and propose respective solutions, complemented with a reproducible example. The work is aimed at helping researchers conduct model-based analyses of the CV safety in animals with subsequent translation of the effect to humans seamlessly and efficiently.
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Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Animais , Humanos , Avaliação Pré-Clínica de Medicamentos , Pressão Sanguínea , Hemodinâmica , Frequência CardíacaRESUMO
The research & development (R&D) of novel therapeutic agents for the treatment of autoimmune diseases is challenged by highly complex pathogenesis and multiple etiologies of these conditions. The number of targeted therapies available on the market is limited, whereas the prevalence of autoimmune conditions in the global population continues to rise. Mathematical modeling of biological systems is an essential tool which may be applied in support of decision-making across R&D drug programs to improve the probability of success in the development of novel medicines. Over the past decades, multiple models of autoimmune diseases have been developed. Models differ in the spectra of quantitative data used in their development and mathematical methods, as well as in the level of "mechanistic granularity" chosen to describe the underlying biology. Yet, all models strive towards the same goal: to quantitatively describe various aspects of the immune response. The aim of this review was to conduct a systematic review and analysis of mathematical models of autoimmune diseases focused on the mechanistic description of the immune system, to consolidate existing quantitative knowledge on autoimmune processes, and to outline potential directions of interest for future model-based analyses. Following a systematic literature review, 38 models describing the onset, progression, and/or the effect of treatment in 13 systemic and organ-specific autoimmune conditions were identified, most models developed for inflammatory bowel disease, multiple sclerosis, and lupus (5 models each). ≥70% of the models were developed as nonlinear systems of ordinary differential equations, others - as partial differential equations, integro-differential equations, Boolean networks, or probabilistic models. Despite covering a relatively wide range of diseases, most models described the same components of the immune system, such as T-cell response, cytokine influence, or the involvement of macrophages in autoimmune processes. All models were thoroughly analyzed with an emphasis on assumptions, limitations, and their potential applications in the development of novel medicines.
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Doenças Autoimunes , Humanos , Doenças Autoimunes/imunologia , Modelos Teóricos , Animais , Modelos Imunológicos , AutoimunidadeRESUMO
BACKGROUND: Cardio-ankle vascular index (CAVI) and its modified version (CAVI0) are promising non-invasive markers of arterial stiffness, extensively evaluated primarily in the Japanese population. In this work, we performed a model-based analysis of the association between different population characteristics and CAVI or CAVI0 values in healthy Russian subjects and propose a tool for calculating the range of reference values for both types of indices. METHODS: The analysis was based on the data from 742 healthy volunteers (mean age 30.4 years; 73.45% men) collected from a multicenter observational study. Basic statistical analysis [analysis of variance, Pearson's correlation (r), significance tests] and multivariable linear regression were performed in R software (version 4.0.2). Tested covariates included age, sex, BMI, blood pressure, and heart rate (HR). RESULTS: No statistically significant difference between healthy men and women were observed for CAVI and CAVI0. In contrast, both indices were positively associated with age (râ =â 0.49 and râ =â 0.43, Pâ <â 0.001), however, with no clear distinction between subjects of 20-30 and 30-40 years old. Heart rate and blood pressure were also identified as statistically significant predictors following multiple linear regression modeling, but with marginal clinical significance. Finally, the algorithm for the calculation of the expected ranges of CAVI in healthy population was proposed, for a given age category, HR and pulse pressure (PP) values. CONCLUSIONS: We have evaluated the quantitative association between various population characteristics, CAVI, and CAVI0 values and established a method for estimating the subject-level reference CAVI and CAVI0 measurements.
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Benchmarking , Rigidez Vascular , Masculino , Humanos , Feminino , Adulto , Valores de Referência , Pressão Sanguínea/fisiologia , Índice Vascular Coração-Tornozelo , Rigidez Vascular/fisiologia , Federação RussaRESUMO
GP40141 is a romiplostim biosimilar. A Phase 1 clinical trial was previously conducted in healthy volunteers to evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety of GP40141 compared to the reference romiplostim (NCT05652595). Using noncompartmental analysis, the biosimilarity of PD end points was determined according to the classical criterion (0.8-1.25). PK end points were also in good agreement between GP40141 and the reference romiplostim; however, the confidence interval for the area under concentration-time curve from time 0 to the time of last measurement was slightly out of the bioequivalence range (0.91-1.29). Population PK/PD was used in the present study to characterize the individual PK and PD data of 56 healthy subjects in 2 cross-over periods of the Phase 1 clinical trial. Body weight and neutralizing antibodies to romiplostim were found to be important predictors of apparent volume of distribution and linear elimination constant, respectively. Within the framework of the conducted modeling, population estimates of PK/PD parameters were obtained, which were in agreement with literature data for the reference romiplostim. Additionally, values of intersubject variability, previously unreported for romiplostim in a healthy subject population, were derived. Covariate analysis, conducted during model development, as well as visual diagnostics and model-based simulations, demonstrated the absence of significant differences in PK and PD between GP40141 and romiplostim-ref.
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Medicamentos Biossimilares , Proteínas Recombinantes de Fusão , Humanos , Voluntários Saudáveis , Medicamentos Biossimilares/farmacocinética , Trombopoetina , Receptores FcRESUMO
Aims: To develop a model-informed methodology for the optimization of the Major Adverse Cardiac Events (MACE) composite endpoint, based on a model-based meta-analysis across anti-hypercholesterolemia trials of statin and anti-PCSK9 drugs. Methods and results: Mixed-effects meta-regression modeling of stand-alone MACE outcomes was performed, with therapy type, population demographics, baseline and change over time in lipid biomarkers as predictors. Randomized clinical trials up to June 28, 2022, of either statins or anti-PCSK9 therapies were identified through a systematic review process in PubMed and ClinicalTrials.gov databases. In total, 54 studies (270,471 patients) were collected, reporting 15 different single cardiovascular events. Treatment-mediated decrease in low density lipoprotein cholesterol, baseline levels of remnant and high-density lipoprotein cholesterol as well as non-lipid population characteristics and type of therapy were identified as significant covariates for 10 of the 15 outcomes. The required sample size per composite 3- and 4-point MACE endpoint was calculated based on the estimated treatment effects in a population and frequencies of the incorporated events in the control group, trial duration, and uncertainty in model parameters. Conclusion: A quantitative tool was developed and used to benchmark different compositions of 3- and 4-point MACE for statins and anti-PCSK9 therapies, based on the minimum population size required to achieve statistical significance in relative risk reduction, following meta-regression modeling of the single MACE components. The approach we developed may be applied towards the optimization of the design of future trials in dyslipidemia disorders as well as in other therapeutic areas.
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The SARS-CoV-2 coronavirus, which causes COVID-19, uses a viral surface spike protein for host cell entry and the human cell-surface transmembrane serine protease, TMPRSS2, to process the spike protein. Camostat mesylate, an orally available and clinically used serine protease inhibitor, inhibits TMPRSS2, supporting clinical trials to investigate its use in COVID-19. A one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) model for camostat and the active metabolite FOY-251 was developed, incorporating TMPRSS2 reversible covalent inhibition by FOY-251, and empirical equations linking TMPRSS2 inhibition of SARS-CoV-2 cell entry. The model predicts that 95% inhibition of TMPRSS2 is required for 50% inhibition of viral entry efficiency. For camostat 200 mg dosed four times daily, 90% inhibition of TMPRSS2 is predicted to occur but with only about 40% viral entry inhibition. For 3-fold higher camostat dosing, marginal improvement of viral entry rate inhibition, up to 54%, is predicted. Because respiratory tract viral load may be associated with negative outcome, even modestly reducing viral entry and respiratory tract viral load may reduce disease progression. This modeling also supports medicinal chemistry approaches to enhancing PK/PD and potency of the camostat molecule. IMPORTANCE Strategies to repurpose already-approved drugs for the treatment of COVID-19 has been attractive since the beginning of the pandemic. Camostat mesylate, a serine protease inhibitor approved in Japan for the treatment of acute exacerbations of chronic pancreatitis, inhibits TMPRSS1, a host cell surface serine protease essential for SARS-CoV-2 viral entry. In vitro experiments provided data suggesting that camostat might be effective in the treatment of COVID-19. Multiple clinical trials were planned to test the hypothesis that camostat would be beneficial for treating COVID-19 (for example, clinicaltrials.gov, NCT04353284). The present work used a one-compartment pharmacokinetic (PK)/pharmacodynamic (PD) mathematical model for camostat and the active metabolite FOY-251, incorporating TMPRSS2 reversible covalent inhibition by FOY-251, and empirical equations linking TMPRSS2 inhibition of SARS-CoV-2 cell entry. This work is valuable to guide further development of camostat mesylate and possible medicinal chemistry derivatives for the treatment of COVID-19.
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Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , Estudos Clínicos como Assunto , Ésteres , Guanidinas , Humanos , Serina Proteases , Inibidores de Serina Proteinase/farmacologia , Inibidores de Serina Proteinase/uso terapêutico , Glicoproteína da Espícula de CoronavírusRESUMO
Clinical trials investigate treatment endpoints that usually include measurements of pharmacodynamic and efficacy biomarkers in early-phase studies and patient-reported outcomes as well as event risks or rates in late-phase studies. In recent years, a systematic trend in clinical trial data analytics and modeling has been observed, where retrospective data are integrated into a quantitative framework to prospectively support analyses of interim data and design of ongoing and future studies of novel therapeutics. Joint modeling is an advanced statistical methodology that allows for the investigation of clinical trial outcomes by quantifying the association between baseline and/or longitudinal biomarkers and event risk. Using an exemplar data set from non-small cell lung cancer studies, we propose and test a workflow for joint modeling. It allows a modeling scientist to comprehensively explore the data, build survival models, investigate goodness-of-fit, and subsequently perform outcome predictions using interim biomarker data from an ongoing study. The workflow illustrates a full process, from data exploration to predictive simulations, for selected multivariate linear and nonlinear mixed-effects models and software tools in an integrative and exhaustive manner.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Biomarcadores/análise , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Estudos Longitudinais , Modelos Estatísticos , Estudos Retrospectivos , Fluxo de TrabalhoRESUMO
Immuno-oncology is an emerging field in the treatment of oncological diseases, that is based on recruitment of the host immune system to attack the tumor. Radiation exposure may help to unlock the potential of the immune activating agents by enhancing the antigen release and presentation, attraction of immunocompetent cells to the inflammation site, and eliminating the tumor cells by phagocytosis, thereby leading to an overall enhancement of the immune response. Numerous preclinical studies in mouse models of glioma, murine melanoma, extracranial cancer, or colorectal cancer have contributed to determination of the optimal radiotherapy fractionation, as well as the radio- and immunotherapy sequencing strategies for maximizing the antitumor activity of the treatment regimen. At the same time, efficacy of combined radio- and immunotherapy has been actively investigated in clinical trials of metastatic melanoma, non-small-cell lung cancer and renal cell carcinoma. The present review summarizes the current advancements and challenges related to the aforementioned treatment approach.
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Background: Abnormal branched-chained amino acids (BCAA) accumulation in cardiomyocytes is associated with cardiac remodeling in heart failure. Administration of branched-chain α-keto acid dehydrogenase (BCKD) kinase inhibitor BT2 has been shown to reduce cardiac BCAA levels and demonstrated positive effects on cardiac function in a preclinical setting. The current study is focused on evaluating the impact of BT2 on the systemic and cardiac levels of BCAA and their metabolites as well as activities of BCAA catabolic enzymes using a quantitative systems pharmacology model. Methods: The model is composed of an ordinary differential equation system characterizing BCAA consumption with food, disposal in the proteins, reversible branched-chain-amino-acid aminotransferase (BCAT)-mediated transamination to branched-chain keto-acids (BCKA), followed by BCKD-mediated oxidation. Activity of BCKD is regulated by the balance of BCKDK and protein phosphatase 2Cm (PP2Cm) activities, affected by BT2 treatment. Cardiac BCAA levels are assumed to directly affect left ventricular ejection fraction (LVEF). Biochemical characteristics of the enzymes are taken from the public domains, while plasma and cardiac BCAA and BCKA levels in BT2 treated mice are used to inform the model parameters. Results: The model provides adequate reproduction of the experimental data and predicts synchronous BCAA responses in the systemic and cardiac space, dictated by rapid BCAA equilibration between the tissues. The model-based simulations indicate maximum possible effect of BT2 treatment on BCAA reduction to be 40% corresponding to 12% increase in LVEF. Model sensitivity analysis demonstrates strong impact of BCKDK and PP2Cm activities as well as total BCKD and co-substrate levels (glutamate, ketoglutarate and ATP) on BCAA and BCKA levels. Conclusion: Model based simulations confirms using of plasma measurements as a marker of cardiac BCAA changes under BCKDK inhibition. The proposed model can be used for optimization of preclinical study design for novel compounds targeting BCAA catabolism.
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Therapy optimization remains an important challenge in the treatment of advanced non-small cell lung cancer (NSCLC). We investigated tumor size (sum of the longest diameters (SLD) of target lesions) and neutrophil-to-lymphocyte ratio (NLR) as longitudinal biomarkers for survival prediction. Data sets from 335 patients with NSCLC from study NCT02087423 and 202 patients with NSCLC from study NCT01693562 of durvalumab were used for model qualification and validation, respectively. Nonlinear Bayesian joint models were designed to assess the impact of longitudinal measurements of SLD and NLR on patient subgrouping (by Response Evaluation Criteria in Solid Tumors 1.1 criteria at 3 months after therapy start), long-term survival, and precision of survival predictions. Various validation scenarios were investigated. We determined a more distinct patient subgrouping and a substantial increase in the precision of survival estimates after the incorporation of longitudinal measurements. The highest performance was achieved using a multivariate SLD and NLR model, which enabled predictions of NSCLC clinical outcomes.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Linfócitos/efeitos dos fármacos , Modelos Biológicos , Neutrófilos/efeitos dos fármacos , Carga Tumoral/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Teorema de Bayes , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Lung function, measured as forced expiratory volume in one second (FEV1), and exacerbations are two endpoints evaluated in chronic obstructive pulmonary disease (COPD) clinical trials. Joint analysis of these endpoints could potentially increase statistical power and enable assessment of efficacy in shorter and smaller clinical trials. OBJECTIVE: To evaluate joint modelling as a tool for analyzing treatment effects in COPD clinical trials by quantifying the association between longitudinal improvements in FEV1 and exacerbation risk reduction. METHODS: A joint model of longitudinal FEV1 and exacerbation risk was developed based on patient-level data from a Phase III clinical study in moderate-to-severe COPD (1740 patients), evaluating efficacy of fixed-dose combinations of a long-acting bronchodilator, formoterol, and an inhaled corticosteroid, budesonide. Two additional studies (1604 and 1042 patients) were used for external model validation and parameter re-estimation. RESULTS: A significant (p<0.0001) association between FEV1 and exacerbation risk was estimated, with an approximate 10% reduction in exacerbation risk per 100 mL improvement in FEV1, consistent across trials and treatment arms. The risk reduction associated with improvements in FEV1 was relatively small compared to the overall exacerbation risk reduction for treatment arms including budesonide (10-15% per 160 µg budesonide). High baseline breathlessness score and previous history of exacerbations also influenced the risk of exacerbation. CONCLUSION: Joint modelling can be used to co-analyze longitudinal FEV1 and exacerbation data in COPD clinical trials. The association between the endpoints was consistent and appeared unrelated to treatment mechanism, suggesting that improved lung function is indicative of an exacerbation risk reduction. The risk reduction associated with improved FEV1 was, however, generally small and no major impact on exacerbation trial design can be expected based on FEV1 alone. Further exploration with other longitudinal endpoints should be considered to further evaluate the use of joint modelling in analyzing COPD clinical trials.
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Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Broncodilatadores/efeitos adversos , Budesonida/uso terapêutico , Combinação de Medicamentos , Volume Expiratório Forçado , Fumarato de Formoterol/uso terapêutico , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Testes de Função RespiratóriaRESUMO
Background: Adenosine receptor type 2 (A2AR) inhibitor, AZD4635, has been shown to reduce immunosuppressive adenosine effects within the tumor microenvironment (TME) and to enhance the efficacy of checkpoint inhibitors across various syngeneic models. This study aims at investigating anti-tumor activity of AZD4635 alone and in combination with an anti-PD-L1-specific antibody (anti-PD-L1 mAb) across various TME conditions and at identifying, via mathematical quantitative modeling, a therapeutic combination strategy to further improve treatment efficacy. Methods: The model is represented by a set of ordinary differential equations capturing: 1) antigen-dependent T cell migration into the tumor, with subsequent proliferation and differentiation into effector T cells (Teff), leading to tumor cell lysis; 2) downregulation of processes mediated by A2AR or PD-L1, as well as other immunosuppressive mechanisms; 3) A2AR and PD-L1 inhibition by, respectively, AZD4635 and anti-PD-L1 mAb. Tumor size dynamics data from CT26, MC38, and MCA205 syngeneic mice treated with vehicle, anti-PD-L1 mAb, AZD4635, or their combination were used to inform model parameters. Between-animal and between-study variabilities (BAV, BSV) in treatment efficacy were quantified using a non-linear mixed-effects methodology. Results: The model reproduced individual and cohort trends in tumor size dynamics for all considered treatment regimens and experiments. BSV and BAV were explained by variability in T cell-to-immunosuppressive cell (ISC) ratio; BSV was additionally driven by differences in intratumoral adenosine content across the syngeneic models. Model sensitivity analysis and model-based preclinical study simulations revealed therapeutic options enabling a potential increase in AZD4635-driven efficacy; e.g., adoptive cell transfer or treatments affecting adenosine-independent immunosuppressive pathways. Conclusions: The proposed integrative modeling framework quantitatively characterized the mechanistic activity of AZD4635 and its potential added efficacy in therapy combinations, across various immune conditions prevailing in the TME. Such a model may enable further investigations, via simulations, of mechanisms of tumor resistance to treatment and of AZD4635 combination optimization strategies.
Assuntos
Antagonistas do Receptor A2 de Adenosina/farmacologia , Antineoplásicos/farmacologia , Modelos Biológicos , Receptor A2A de Adenosina/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Algoritmos , Animais , Antineoplásicos Imunológicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Linhagem Celular Tumoral , Suscetibilidade a Doenças , Resistencia a Medicamentos Antineoplásicos , Quimioterapia Combinada , Isoenxertos , Camundongos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was developed to investigate its complex network kinetics and non-steroidal anti-inflammatory drugs (NSAIDs) efficacy in different in vitro and in vivo conditions. To correctly describe the complex mechanism of PGHS-1 catalysis, we developed a microscopic approach to modelling of intricate network dynamics of 35 intraenzyme reactions among 24 intermediate states of the enzyme. The developed model quantitatively describes interconnection between cyclooxygenase and peroxidase enzyme activities; substrate (arachidonic acid, AA) and reducing cosubstrate competitive consumption; enzyme self-inactivation; autocatalytic role of AA; enzyme activation threshold; and synthesis of intermediate prostaglandin G2 (PGG2) and final prostaglandin H2 (PGH2) products under wide experimental conditions. In the paper, we provide a detailed description of the enzyme catalytic cycle, model calibration based on a series of in vitro kinetic data, and model validation using experimental data on the regulatory properties of PGHS-1. The validated model of PGHS-1 with a unified set of kinetic parameters is applicable for in silico screening and prediction of the inhibition effects of NSAIDs and their combination on the balance of pro-thrombotic (thromboxane) and anti-thrombotic (prostacyclin) prostaglandin biosynthesis in platelets and endothelial cells expressing PGHS-1.
RESUMO
Objectives: The goal of this quantitative research was to evaluate the impact of various factors (e.g., scheduling or radiotherapy (RT) type) on outcomes for RT vs. RT in combination with immune checkpoint inhibitors (ICI), in the treatment of brain metastases, via a meta-analysis. Methods: Clinical studies with at least one ICI+RT treatment combination arm with brain metastasis patients were identified via a systematic literature search. Data on 1-year overall survival (OS), 1-year local control (LC) and radionecrosis rate (RNR) were extracted; for combination studies which included an RT monotherapy arm, odds ratios (OR) for the aforementioned endpoints were additionally calculated and analyzed. Mixed-effects meta-analysis models were tested to evaluate impact on outcome, for different factors such as combination treatment scheduling and the type of ICI or RT used. Results: 40 studies representing a total of 4,359 patients were identified. Higher 1-year OS was observed in ICI and RT combination vs. RT alone, with corresponding incidence rates of 59% [95% CI: 54-63%] vs. 32% [95% CI: 25-39%] (P < 0.001). Concurrent ICI and RT treatment was associated with significantly higher 1-year OS vs. sequential combinations: 68% [95% CI: 60-75%] vs. 54% [95% CI: 47-61%]. No statistically significant differences were observed in 1-year LC and RNR, when comparing combinations vs. RT monotherapies, with 1-year LC rates of 68% [95% CI: 40-90%] vs. 72% [95% CI: 63-80%] (P = 0.73) and RNR rates of 6% [95% CI: 2-13%] vs. 9% [95% CI: 5-14%] (P = 0.37). Conclusions: A comprehensive, study-level meta-analysis of brain metastasis disease treatments suggest that combinations of RT and ICI result in higher OS, yet comparable neurotoxicity profiles vs. RT alone, with a superiority of concurrent vs. sequential combination regimens. A similar meta-analysis using patient-level data from past trials, as well as future prospective randomized trials would help confirming these findings.