Kirill Peskov - Academia.edu (original) (raw)

Papers by Kirill Peskov

Frontiers in Cardiovascular Medicine, Jan 7, 2024

Cancer Research, Apr 4, 2023

AZD5305 is a potent and selective PARP1 inhibitor and trapper which is hypothesized to improve th... more AZD5305 is a potent and selective PARP1 inhibitor and trapper which is hypothesized to improve therapeutic index over first generation nonselective PARP inhibitors. AZD5305 demonstrated significant and sustained antitumor activity in multiple BRCA1/2 mutant xenograft models. Here we present a mechanistic Quantitative Systems Pharmacology (QSP) model to analyze dose-dependent antitumor activity of AZD5305 (0.01-10 mg/kg) across a selection of xenograft models with different homologous recombination repair (HRR) status (Capan-1, DLD-1 BRCA2 KO, HBCx-9, HBCx-17, MDA-MB-436 and SUM149PT). A QSP model was developed based on a system of ordinary differential equations (ODEs) to address formation and repair of trapped PARP-DNA fragments and longitudinal changes in tumor size as a function of pharmacokinetic (PK) profiles in individual animals. Tumor growth data as well as intratumoral PARylation inhibition from xenograft models were utilized for model development and qualification. Model parameters characterizing intrinsic tumor growth and cancer cell sensitivity to accumulated DNA damage, were set to be different across xenograft models, to provide unbiased data reproduction. Sensitivity analyses were performed to identify model parameters which have the most impact on differential antitumor activity observed across various xenograft models. Maximal antitumor efficacy was seen at 0.1 to 1 mg/kg AZD5305, depending on the tumor model. Exposures at 1 mg/kg were similar to those causing peak PARP1 trapping in vitro. The QSP model adequately captures antitumor activity across different xenograft models. Simulations indicate antitumor activity of AZD5305 was driven mainly by differences in the HRR status-related model parameter (khrr). Xenograft models with HRR deficiency such as HBCx-17, DLD-1 BRCA2 KO and MDA-MB-436 (with a very low khrr) were the most sensitive to AZD5305 and treatment led to tumor regressions. In contrast, tumor models with partial sensitivity, such as HBCx-9, Capan-1, SUM149PT (with khrr up to 1000-fold higher than in the sensitive tumors), AZD5305 only achieved tumor growth inhibition. Dosing AZD5305 at 0.03 mg/kg daily was associated with tumor regression in HBCx-17 and MDA-MB-436 xenografts, whereas 1 mg/kg daily dosing was required to achieve tumor regression in the DLD-1 BRCA2 KO model, and maximal tumor growth inhibition in less sensitive models. Further biomarker analyses to assess functional HRR status (e.g. via RAD51 foci score) in these xenograft models is ongoing to validate model estimated khrr parameters. The calibrated model was used to predict antitumor activity of AZD5305 at clinically relevant exposures observed in the phase I clinical study PETRA. Model-based simulations indicated near maximal efficacy at clinical doses equivalent to 1 mg/kg AZD5305 exposure in xenograft models. Citation Format: Ganesh Moorthy, Veronika Voronova, Cesar Pichardo, Kirill Peskov, Giuditta Illuzzi, Anna Staniszewska, Mark Albertella, Holly Kimko. A Quantitative Systems Pharmacology (QSP) model to characterize dose-dependent antitumor activity of AZD5305, PARP1 selective inhibitor, across multiple xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2794.

Российский медицинский журнал, Jun 25, 2020

Introduction and objectives. The combination of radiotherapy and immune checkpoint inhibitors has... more Introduction and objectives. The combination of radiotherapy and immune checkpoint inhibitors has demonstrated antitumor activity in numerous preclinical studies and is currently being investigated in the clinical setting. This study aims to compare the efficacy of radiotherapy alone (RT) vs. the combination of radio- and immunotherapy (IT-RT) and identify the treatment regimen associated with maximal efficacy by using a meta-analysis. Materials and methods. A systematic literature search was performed using the PubMed database and materials of the key oncology congresses. Studies reporting 1-year overall survival (OS) of patients with brain metastases undergoing IT-RT treatment were included in the analysis. Information about 1-year OS, individual patients characteristics, and treatment regimens for both IT-RT and control RT arms was extracted. Identification of the optimal treatment regimen was performed using a mixed meta-regression modeling approach. Analysis was performed using the R statistical environment (metafoR package). Results. In total, 30 studies were identified, of which 13 reported outcomes for the control RT groups. The analysis revealed that IT inclusion into RT is associated with a significant increase in 1-year OS; given simultaneously, IT and RT demonstrated the highest efficacy with a 1-year OS of 68% (95% confidence interval (CI): 60%75%), followed by a sequential regimen: 1-year OS = 54% (95% CI: 47%61%) and RT alone: 1-year OS = 32% (95% CI: 2539%). Conclusion. The current study demonstrates the superiority of combined IT-RT over RT alone; simultaneous IT and RT treatment is associated with the highest efficacy.

Microbiology spectrum, Apr 27, 2022

The SARS-CoV-2 coronavirus, which causes COVID-19, uses a viral surface spike protein for host ce... more 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. KEYWORDS COVID-19, antiviral pharmacology, camostat T he coronavirus disease 2019 (COVID-19) pandemic has reinforced the need for early oral treatment to prevent disease progression (1). Currently such drugs are not available. Drug repurposing, based on a relevant mechanism of action as driving

Frontiers in Applied Mathematics and Statistics, Oct 26, 2022

Annals of Oncology, Oct 1, 2019

Background While urine biomarkers are widely used to diagnose bladder cancer (BLC), little is kno... more Background While urine biomarkers are widely used to diagnose bladder cancer (BLC), little is known about plasma protein levels in patients with BLC. The current research is aimed to evaluate diagnostic potential of 13 plasma markers including tumor antigens, inflammatory markers and apolipoproteins (Apo) as well as combinations of thereof. Methods In total 203 healthy volunteers (HV) and 59 patients with BLC were enrolled into the study. Concentrations of alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (СА 19-9), prostate-specific antigen (PSA), beta 2 microglobulin (B2M), human-specific C-reactive protein (hsCRP), D-dimer, сytokeratin 19-fragments (CYFRA 21-1), ApoA1, ApoA2, ApoВ, transthyretin (TTR), and soluble vascular cell adhesion molecule-1 (sVCAM-1) in plasma were measured via ELISA. t-test after log-transformation was used to identify between-group differences in biomarker levels. Diagnostic accuracy of the single biomarkers as well as trained random forest (RF), linear discriminant analysis (LDA) and support vector machine (SVM) classifiers was assessed by ROC analysis. Results Plasma levels of ApoB, B2M, CA 19-9, CYFRA 21-1, D-dimer, hsCRP, sVCAM-1 and TTR were significantly higher (p-value&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.001) whereas ApoA1 and ApoA2 levels were significantly lower (p-value&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0005) in patients with BLC vs HV. No differences in AFP, CEA and PSA was found between the groups. The highest discriminative power was shown for sVCAM-1 and ApoA1 with area under ROC curve (AUROC) 0.92 and 0.90, respectively, whereas AUROC for several classifiers based on measurements of 2-12 biomarkers was higher than 0.95. Conclusions Numerous abnormalities in plasma biomarker levels were detected in patients with BLC, hence, blood-based tests represent a promising strategy to improve performance of urinary-based tests and cystoscopy in BLC detection and prognosis. Combining several biomarkers allows to increase diagnostic test accuracy. Legal entity responsible for the study I.M. Sechenov First Moscow State Medical University. Funding I.M. Sechenov First Moscow State Medical University. Disclosure All authors have declared no conflicts of interest.

Journal of Clinical Oncology, Feb 10, 2020

83 Background: Immune checkpoint inhibitors (ICIs) are associated with immune-mediated adverse ev... more 83 Background: Immune checkpoint inhibitors (ICIs) are associated with immune-mediated adverse events (imAEs). The objective of this study was to use a Bayesian model-based meta-analysis to quantify dose dependence and compare imAE frequencies for PD-1, PD-L1 and CTLA-4 inhibitor monotherapies and their combinations. Methods: We searched PubMed, TrialTrove, ASCO and ESMO databases and retrieved relevant ICI safety data. In order to quantitatively compare safety across doses and drugs against a given target, we converted the various dose regimens used into drug exposures derived from pharmacokinetic models; we also normalized exposures by the corresponding drug potency. We performed a Bayesian meta-analysis for Grades 3&4 of treatment related (trAE) and immune-mediated (imAE) adverse events. Results: A total of 149 articles were identified, covering 35,559 patients in 197 dosing cohorts treated with ICI therapies. For PD-1 and PD-L1 inhibitor monotherapies, no dose dependence of AEs was found; Grades 3&4 trAE rates for anti PD-L1 vs. anti PD-1 were, respectively, 12% and 15%. The AE rates for the different ICI drugs and organ classes were estimated. Dose dependence was found for anti CTLA-4 monotherapies, for total trAEs of Grades 3/4, gastrointestinal and hepatic imAEs. Dose dependence was found and quantified for anti CTLA-4 in combination with anti PD-1 with respect to total trAEs of Grades 3/4 trAEs and imAEs per gastrointestinal and hepatic organ groups. We found that combination of anti PD-L1 agents with anti CTLA-4 exhibited lower AE rates, as compared to anti PD-1 combined with anti CTLA-4. Conclusions: We introduced a novel meta-analysis methodology and used it to quantify and compare AE rates across ICI agents. Significant AE rate dose dependencies were observed for CTLA-4 inhibitors, either as monotherapy or used in combinations. Patients naive to anti-cancer therapies exhibited higher AE rates vs. previously treated patients. AE rates for CTLA-4 + PD-1 inhibitor combination regimens were supra-additive vs. the respective monotherapies. AE rates for anti PD-L1 agents were lower vs. anti PD-1, both in monotherapy and combinations with CTLA-4.

Frontiers in Oncology, Dec 5, 2022

The article tells about problems in development and launch of innovative products, including cris... more The article tells about problems in development and launch of innovative products, including crisis of productivity in the pharmaceutical industry and search for new approaches in drug development. Special attention is paid to application of mathematical modeling in phar-maceutics. The basic concepts of pharmacometrics, biological, pharmacological and statistical models and interaction with regulating authorities are described.

Russian Journal of Cardiology

Aim. To compare the cardio-ankle vascular index (CAVI) and the novel START vascular stiffness ind... more Aim. To compare the cardio-ankle vascular index (CAVI) and the novel START vascular stiffness index and assess their values and correlations with clinical parameters.Material and methods. This multicenter study included 928 (403 men and 525 women) randomly selected patients, aged 18 to 89 years (mean age, 41±15,8 years). Inclusion criteria were age over 18 years. There were following exclusion criteria: mental disorder, severe somatic diseases and cancer, contraindications for volume sphygmography using the Fukuda Denshi VS-1500 VaSera system, no patient consent, ankle-brachial index <1,0 and >1,3. Further, according to the main parameters obtained using volum sphygmography, a novel START index was calculated. Comparison of index values and analysis of their correlation with clinical indicators, such as age, systolic blood pressure, diastolic blood pressure, pulse pressure (PP), body mass index and heart rate (HR), were carried out using simple and multiple linear regression, ...

Frontiers in Pharmacology

Background: Abnormal branched-chained amino acids (BCAA) accumulation in cardiomyocytes is associ... more 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 BT...

Cancer Immunology Research

There has been significant interest in combining anti-PD-1/PD-L1 agents with other clinically act... more There has been significant interest in combining anti-PD-1/PD-L1 agents with other clinically active anticancer agents. Gefitinib, a first-generation inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is approved for non-small cell lung cancer (NSCLC) patients with sensitizing EGFR mutations. Durvalumab has demonstrated clinical activity in NSCLC and is approved for Stage III, unresectable NSCLC that has not progressed following platinum-based chemotherapy and radiotherapy. A phase I trial (NCT02088112) combining gefitinib and durvalumab was initiated to establish the safety profile of this combination in tyrosine-kinase inhibitor (TKI)-naive patients with NSCLC containing EGFR-positive sensitizing mutations. As part of this trial, paired tumor biopsies and multiple blood samples were collected for biomarker evaluation. Peripheral blood samples were analyzed for gene expression, cytokine production, immunophenotyping, and circulating DNA (ctDNA). Paired tumor ...

Further information on model development and testing can be found in Additional file 1: the biolo... more Further information on model development and testing can be found in Additional file 1: the biological rationale for the proposed mathematical model structure; the structure of the mathematical model; population model development to describe inter-animal variability in tumor growth; model parameter estimations; model diagnostics; experimental data used for model development; model diagnostics; model validation against newly, independently generated sets of experimental tumor size data; design of efficacy simulations; a model sensitivity analysis. Additional file 1 also contains supplemental figures and references. (ZIP 6120 kb)

Radiotherapy and Oncology, 2020

Frontiers in Oncology, 2020

The goal of this quantitative research was to evaluate the impact of various factors (e.g., sched... more 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.

Diabetes, Obesity and Metabolism, 2018

This study aimed to quantify the effect of the immediate release (IR) of exenatide, a short‐actin... more 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.

Tumor Biology, 2019

Objectives: PI3Kγ inhibition re-polarizes macrophages to an immuno-stimulatory phenotype, thereby... more Objectives: PI3Kγ inhibition re-polarizes macrophages to an immuno-stimulatory phenotype, thereby activating a T-cell mediated tumor immune response. AZD3458 is a highly selective PI3Kγ inhibitor. Administration of AZD3458 in combination with checkpoint inhibitors such as α-PD-(L)1 antibodies had greater anti-tumor effects (TGI 26-86%) than checkpoint inhibitor alone in 4T1, LLC, CT-26 and MC-38 syngeneic mouse models. In these, AZD3458 remodeled the tumor microenvironment (TME), reducing immunosuppressive markers (e.g in 4T1 model there was a 20% decrease in total macrophages and 50% decrease in markers of immune suppression like CD206 by flow cytometry) and promoting cytotoxic T-cell activation (e.g. in CT-26 model there was a 2-fold increase in gzmB mRNA). We developed a predictive quantitative systems pharmacology (QSP) model, to quantitatively simulate TME effects and delineate mechanistic principles underlying AZD3458 and α-PD-(L)1 synergistic effects. Methods: The QSP model captures mechanistic, molecular and cellular interactions between PI3Kγ inhibition and checkpoint inhibitors, together with the pharmacokinetics acting on the respective targets. Features such as PI3Kγ inhibition-dependent tumor-associated macrophages, protein expression of immunosuppressive markers, reduction of MDSC activation and promotion of cytotoxic T-cell activation were included in the model. These immuno-changes were then linked to tumor cell death, resulting in macroscopic dynamic effects on tumor size. Some model parameters were taken from the literature and internal studies; some were estimated using NLME modeling of tumor size data. Results: The model adequately described individual and population tumor size patterns. Inter-animal variability was described using a random effect on a parameter related to the ability of T cells to infiltrate the tumor in response to systemic antigen. Additionally, the model incorporated in one quantitative framework data from 4 syngeneic tumors capturing respective changes in TME conditions. Simulations for the various treatments supported the mechanistic interpretation of the observed AZD3458 and α-PD-(L)1 synergistic effects. The model was further used to simulate treatment scenarios, to infer optimal dosing and scheduling for the combination and given underlying TME conditions. Conclusions: This study provides quantitative mechanistic insights into the links between PI3Kγ inhibition and anti-tumor immune responses, supporting our understanding of how AZD3458 may alleviate brakes in a myeloid immuno-suppressive TME and revert resistance to immunotherapy. This mechanistic understanding is critical when proceeding with dose escalation in an early clinical trial setting, as it allows to contextualize any potential compound-induced immuno-modulation in patients, for given doses and schedules. Citation Format: Pablo Morentin Gutierrez, Yuri Kosinsky, Kirill Peskov, Ivan Azarov, Lulu Chu, Veronika Voronova, Martin Johnson, Yingxue Chen, Larissa Carnevalli, Danielle Carroll, Michele Moschetta, Teresa Klinowska, Gabriel Helmlinger. Mechanistic insights and dose optimization for AZD3458, a novel selective PI3Kg immuno-modulator, using a quantitative systems approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 104.