bluuebunny/crossref_metadata_2025 huggingface dataset:
The reference corrected VPC (rcVPC) - An informative model diagnostic for assessing underlying exposure-response relationships
Authors: Bergstrand Martin , Ibrahim Moustafa M. A. , Jonsson Niclas E.
Published: February 2025

Objectives: To compare visual predictive check (VPC), prediction corrected VPC (pcVPC) [1] and rcVPC model diagnostics for their ability to visually characterize a models ability to capture underling exposure-response (ER) relationships for models with delayed effect onset. Methods: The rcVPC is a novel model diagnostic based on the definition of a reference dataset with user defined independent variables (e.g. covariates, dose, inter dose interval and time) but otherwise with the same dimensions as the analysis dataset (introduced at PAGE 2024). We used a real life inspired PKPD examples for the comparison. Example 1 was a one compartment PK model with first order absorption and an indirect response PD model for body weight (BW). The drug plasma concentrations (PC) had an ihibitory effect on the production rate (KIN) through an Emax function. The data came from two studies: An MRD study with 5 doses levels (100 mg, 200 mg, 400 mg, 600 mg and 800 mg and 5 subjects/dose level) and 6 weeks of treatment and 4 weeks of follow up, and a Phase IIa study with 20 patients on 600 mg, for 16 weeks of treatment and 2 weeks of follow up. VPCs, pcVPCs and rcVPCs were used to plot BW and the change from baseline BW vs drug PC. Models featuring the true as well as misspecified ER relationships was evaluated with the model diagnostics. NONMEM version 7.5 in combination PsN was used for simulation and re-estimation purposes and all data post processing and graphical representation was done using R.Results: The rcVPC model diagnostic normalized to change from baseline BW after 16 weeks of treatment allowed to visualize and diagnose the underlying ER without the influence of the delayed effect onset. Fitting a model with a linear ER relationship instead of the true Emax relationship did not result in any clearly identified model misspecifications with the traditional VPC or pcPVC model diagnostics. The rcVPC on the other hand clearly indicated the actual misspecified ER relationships in a way that was intuitive to interpret. Conclusions: The possibility for a user defined set of reference characteristics (independent variables) with the rcVPC makes it not only a powerful model diagnostic but also a vehicle for efficient communication of modeling results to a wider audience. The rcVPC have been demonstrated to be especially useful for an intuitive evaluation of underlying ER relationships in the presence of delayed effect onset in a way that isn’t possible a traditional VPC or pcPVC plots.Citations: [1] Bergstrand M, Hooker AC, Wallin JE, Karlsson MO. Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 2011 Jun;13(2):143-51
Adaptation of the Glucose, Glucagon, Gastric-Inhibitory Peptide, Glucagon-like Peptide-1, and Insulin (4GI) Model for Simulation of Acute Meal Challenges with Infused Antagonists
Authors: Rieger Theodore
Published: February 2025

Objectives: Agonists of glucagon-like peptide-1 (GLP-1) are potent therapies for both type 2 diabetes and obesity. Recently, there has been interest in examining other incretins, such as gastric-inhibitory peptide (GIP) as a complement to GLP-1. Interestingly, GIP as a target has been tested clinically both as a purported agonist (1) and as an antibody (2). While most of the literature examines the effect of agonizing GLP-1 and GIP, we wished to develop a model to better understand quantitatively the physiological effects of antagonism, particularly in acute challenges. Methods: We adapted a published model of glucose-insulin-incretin dynamics (4GI model) as the base model for our analysis (3). This model was selected because it has been validated for glycemic efficacy against several GLP-1 agonists and thus contained sufficient biological scope. To adapt the 4GI model to simulate acute challenges of incretin antagonists, we tested the model against a series of challenges published by Gasbjerg et al. (4, 5). In these acute challenges antagonists of GIP, GLP-1, or the combination thereof was infused along with either a meal challenge or nutrient infusion. Outcomes of interest for evaluating the performance of the model included changes in glucose, insulin, glucagon, and incretin hormones. Results: We calibrated the baseline model to represent the healthy volunteers of the studies. Global sensitivity was performed to obtain a list of the most sensitive parameters at baseline and following meal challenges, allowing us to reduce the number of fitted parameters. With these parameters, we adequately captured the means and variability for all the observables. To correctly account for the loss of GIP signaling, we extended the model to account for the convergence of both GLP-1 and GIP on cAMP in beta cells (6). The updated model then adequately captured the response to the acute challenges with both antagonists. Conclusions: With updates to GLP-1 and GIP signaling, the 4GI model captures the expected antagonist response in healthy individuals following a meal or infusion challenge. Future work can extend to patients with type 2 diabetes and challenges following chronic treatment.Citations: 1. A. M. Jastreboff et al., N Engl J Med 387, 205-216 (2022).2. M. M. Veniant et al., Nat Metab 6, 290-303 (2024).3. R. Bosch et al., CPT Pharmacometrics Syst Pharmacol 11, 302-317 (2022).4. L. S. Gasbjerg et al., Diabetes 68, 906-917 (2019).
Quantitative system pharmacology model for tri-specific HER2xCD3xCD28 T-Cell Engager SAR443216
Authors: Barua Dipak , Rharbaoui Faiza , Masciari Serena , Wang Lei
Published: February 2025

Objectives: SAR443216 is a tri-specific antibody targeting human epidermal growth factor receptor 2 (HER2)-expressing tumors. SAR443216 functions as a T cell engager (TCE) with anti-CD3, -CD28 and -HER2 sites capable of simultaneously engaging respective cell-specific membrane receptor proteins. The drug mediates pharmacological actions by forming synaptic bridges between CD3+/CD28+ T cells and HER2+ tumor cells. Formation of synapses leads to the activation of cytotoxic T cells followed by tumor cell killing by the activated T cells. This killing process also accompanies a variety of cytokine release that induce more T cell activation and tumor cell killing. Because of this complex mechanism of action (MoA), which involves intricate interactions among molecules and cells, it is interesting to conceptually understand the safety and therapeutic efficacy of SAR443216. A quantitative systems pharmacology (QSP) model is developed to characterize key factors governing the safety and efficacy profiles of SAR443216. Methods: A multiscale approach is taken to develop the QSP model for SAR443216. The multiscale model connects the drug’s pharmacokinetics to its MoA at the molecular and cellular scale to mechanistically explain its ex-vivo and in vivo pharmacological effects. The model explicitly incorporates cellular and molecular species representing T cells, tumor cells, and cell-specific membrane receptor proteins (CD3, CD28 and HER2). The molecular and cellular interactions included in the model capture the process of synapse formation between T cells and target cells, T cell activation and tumor cell killing. The model also accounts for a variety of cytokine biomarkers that characterize the compound's safety profile. The model is calibrated with a rich set of in-house data from in vitro and preclinical studies. Results: 1) The QSP model captured pharmacological effects of SAR443216 on different tumor cell lines with various levels of HER2 expression. Associated simulations led to the identification of factors governing the ex-vivo cytotoxicity response profile of SAR443216. 2) The model captured SAR443216 dose-dependent T cell activation and cytokine release profiles for tumor cell lines with variable target (Her2) expression. These simulations identified biological variables dictating ex-vivo cytokine response profiles of SAR443216. 3) The model characterized in vivo dose to response relationships for SAR443216-induced cytokine responses in cynomolgus monkeys. The simulations provided insights into the safety response profiles directly linked to the drug MoA or non-specific sources. Conclusions: The QSP model has served as a computational platform to test and validate SAR443216 MoA and its response characteristics in vitro and in vivo preclinical settings. The platform will serve as a foundation for modeling other emerging tri specific TCEs with similar MoA.Citations: N/A
Population pharmacokinetic and pharmacodynamic analysis of natural killer cell levels in response to TEV-53408, an anti-interleukin 15 monoclonal antibody, in healthy volunteers
Authors: Dotan Or , Radivojevic Andrijana , Schnir Victoria , Gutman Dikla , Singh Rajendra
Published: February 2025

Objectives: TEV-53408 is a human monoclonal antibody that binds to and neutralizes interleukin-15 (IL-15), which is involved in T cell and natural killer (NK) cell homeostasis and immune-mediated diseases. TEV-53408 is currently being evaluated in celiac disease. The objectives of this analysis were to characterize the pharmacodynamic (PD) effect on NK cell counts, based on the data collected during a Phase 1, first-in-human (FIH) study in 114 healthy participants, and further predict the PK/PD signature in patients for various indications. Methods: A population PK/PD model was used to describe the dynamics of NK cell counts in relation to serum TEV-53408 concentrations over time, and several structural models were evaluated. A set of demographic and baseline characteristics were tested to explain the interindividual variability in selected PK parameters (i.e., covariate analysis). During the model development, population PK/PD models were assessed using the evaluation of individual and population mean parameter estimates and their precision, as measured by the percent standard error of the population mean estimate relative to known priors or physiological values, and by graphical examination of standard diagnostic and population analysis goodness-of-fit plots. Various steps of analysis dataset preparation, exploratory analysis and simulations were performed in R and appropriate R packages. Nonlinear-mixed effect modeling was performed using NONMEM. Results: The serum concentration of TEV-53408 over time was best described by a two-compartment PK model with first-order absorption, linear and saturable apparent elimination, and body weight at baseline as a covariate on apparent clearance, maximum apparent clearance rate and apparent peripheral volume. The relationship between TEV-53408 exposures and NK cell count was best described by a PD model with proliferating and transport compartments1 that included a Michaelis-Menten equation for prediction of the NK cell counts, with treatment type (e.g., placebo or not) and the baseline level of NK cells as covariates on baseline circulation of NK cells (i.e., the level of NK cells in each PD compartment). The model was then used in simulation mode to anticipate outcomes with alternative doses and dosing regimens in a virtual participant population. Conclusions: The resulting population PK/PD model provides a robust quantitative platform for future decision making and informing dose selection for subsequent clinical trials.Citations: [1] Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 2002; 20(24): 4713-4721. doi:10.1200/JCO.2002.02.140
Risk Assessment for Drug-Induced Hyperbilirubinemia: A Mechanistic Approach
Authors: Kumar Ansu , Wingrove James
Published: February 2025

Objectives: Hyperbilirubinemia, characterized by elevated total blood bilirubin levels including both unconjugated and conjugated forms, serves as an important diagnostic marker for drug-induced liver toxicity associated with a wide range of medications. This study aims to develop a mechanistic model for assessing the risk of hyperbilirubinemia, using genetic markers.Methods: We developed an ordinary differential equations (ODE) based mechanistic model of human bilirubin metabolism incorporating key biological processes such as the synthesis of unconjugated bilirubin, its hepatic uptake, conjugation, and elimination through hepatic and renal pathways. The model includes hepatic transporters and enzymes, such as OATP1B1, MRP2, MRP3, and UGT1A1, which are involved in the hepatic uptake and elimination of bilirubin. The model was parametrized using in-vitro and published human data and validated using bilirubin disposition in healthy subjects as well as individuals with genetic diseases such as Gilbert’s and Dubin-Johnson syndromes. The impacts of genetic mutations and therapies on these enzymes and downstream bilirubin levels were assessed using the mechanistic model.Results: A 90% reduction in OATP1B1 activity increased both unconjugated and conjugated bilirubin (1.58-fold and 2.2-fold respectively), mimicking data from individuals with mutations in OATP1B1. Sensitivity analysis of OATP1B1, MRP2, and UGT1A1 revealed increased OATP1B1 sensitivity in the presence of low UGT1A1 activity. Model simulations linked nilotinib-induced hyperbilirubinemia to UGT1A1 mutations, and were also used to assess the risk of hyperbilirubinemia associated with varying doses of nelfinavir, atazanavir, and TAK-875, based on their off-target effects on transporters. The results demonstrated that uncertainty in free drug concentration could be a crucial factor in hyperbilirubinemia, especially for highly protein-bound drugs.Conclusions: We used a mechanistic model of human bilirubin metabolism to identify critical factors involved in drug-induced hyperbilirubinemia. This approach may help determine risk assessment for hyperbilirubinemia, using drugs inhibitory in vitro data coupled with patient pharmacogenetic data associated with OATP1B1, UGT1A1 and MRP2 mutations. Patient-specific pharmacogenetic data is necessary for further validation of this approach to assess the risk of drug-induced hyperbilirubinemia.Citations: 1. Devarbhavi H. (2012). An Update on Drug-induced Liver Injury. Journal of clinical and experimental hepatology, 2(3), 247–259.2. Abumiya, M., Takahashi, N., Niioka, T., Kameoka, Y., Fujishima, N., Tagawa, H., Sawada, K., & Miura, M. (2014). Influence of UGT1A1 6, 27, and 28 polymorphisms on nilotinib-induced hyperbilirubinemia in Japanese patients with chronic myeloid leukemia. Drug metabolism and pharmacokinetics, 29(6), 449–454.3. Tan, Y., Ye, Y., & Zhou, X. (2020). Nilotinib-induced liver injury: A case report. Medicine, 99(36), e22061.
Model-informed simulations to determine optimal Piperacillin-Tazobactam Dosing regimens in Pediatric Perioperative Care: Effect of body size and renal function
Authors: Tan Wen Rui , Irie Kei , McIntire Carter , Torres Julie Luna , Jones Rhonda , Gibson Abigayle , Mizuno Tomoyuki , Girdwood Sonya Tang
Published: February 2025

Objectives: Current global standards recommend a pediatric intraoperative dosing regimen for piperacillin/tazobactam (PTZ) to be 90-112.5 mg/kg (80-100 mg/kg as piperacillin (PIP)) administered every 2 hours (Q2H)1. However, concerns regarding potential for nephrotoxicity from high piperacillin levels and the complexity of maintaining Q2H dosing schedule have prompted the need for new dosing guidelines. This study aims to provide new dosing recommendations for peri-operative pediatric patients, accounting for body size and renal function, with model-based simulations using a previously developed PK model for this population.Methods: Based on a population PK model built by our research group2, this study utilized Pop PK model-based simulations to determine tailored dosing regimens that ensure therapeutic target attainment while minimizing nephrotoxic risk. Simulations stratified patients into groups based on creatinine clearance and body weight groups to customize doses according to the patient's renal function and body weight; these ranged from 20-29 mL/min/1.73 m2 ,30-59 mL/min/1.73 m2, 60-89 mL/min/1.73 m2, 90-129 mL/min/1.73 m2 and ≥130 mL/min/1.73 m2 ;10-29 kg, 30-49 kg, 50-69 kg and ≥70 kg. Target attainment was defined as concentrations above 1x and 4x minimum inhibitory concentration (MIC) for 100% of the time, with 1 and 4x MIC values set at 8 mg/L and 32 mg/L, respectively, for Enterococcus and Enterobacterales. The strategy focused on determining the minimum doses necessary for PD target attainment to minimize the risk of nephrotoxicity.Result: In our study, the lowest effective PIP dose for pediatric perioperative patients Q2H was found to be 6 mg/kg for certain subgroups and the highest effective dose for 4x MIC levels reached 55 mg/kg, which is significantly lower than current guidelines suggest. For continuous infusion, dosing ranged from a loading dose of 10 mg/kg followed by 1.0 to 2.5 mg/kg/hour for 1x MIC and up to 20 mg/kg loading dose followed by a maintenance dose as high as 9.25 mg/kg/hour for 4x MIC. Conclusion: This study leverages Pop PK model-based simulations to establish tailored dosing guideline for PTZ in pediatric perioperative patients. Findings show that effective Q2H dosages can be substantially lower than current guideline suggested, reducing nephrotoxicity risks while ensuring therapeutic levels. Furthermore, continuous infusion strategies mitigate practical challenges associated with frequent dosing intervals. Future research will involve a larger, prospective study to validate these proposed dosing schedules.Citations: 1. Bratzler et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Surgical Infections. 2013;14(1):73-156.2. Tan et.al (2024), LB-019, American Society for Clinical Pharmacology and Therapeutics. Clin Pharmacol Ther, 115: S5-S125.
Population pharmacokinetic analysis of Dato-DXd, a TROP2-targeting ADC, in NSCLC and HR-positive, HER2-negative breast cancer patients
Authors: Tang Zoey , Lim KyoungSoo , Jiang Yu , Dai David , Yang Haitao , Cheerla Raju , Bachina Srinivas , Chen Cecil , Pan Yuzhuo , Hong Ying , Ren Song , Phipps Alex , Zhou Diansong
Published: February 2025

Objectives: Dato-DXd, a TROP2-targeting antibody-drug conjugate, has demonstrated clinically meaningful efficacy and a manageable safety profile in multiple tumour types1. A population pharmacokinetic (PopPK) model describing PK profiles of Dato-DXd and the released drug (DXd) was developed based on data from the TROPION-PanTumor01, TROPION-Lung05, and TROPION-Lung01 studies, including 644 NSCLC patients and 85 breast cancer patients2. Data from patients in TROPION-Breast01 was added to the previously developed PopPK model to examine the impact of intrinsic and extrinsic covariates on Dato-DXd and DXd PK, and to evaluate if Dato-DXd dose adjustment is needed for HR-positive, HER2-negative breast cancer patients. Methods: The previously-developed model served as a starting point for the model refinement. From the full covariate model, backward elimination was conducted to find a statistically parsimonious model. After backward elimination, prespecified covariates of interest (e.g., tumor type) were tested by including them in a step-wise addition (forward selection). The adequacy of the final model was evaluated by prediction-corrected visual prediction check (pcVPC) and non-parametric bootstrap method. The impact of covariates of interest were investigated in post-hoc analyses Results: PK data from 1081 patients, including 437 breast cancer patients (40% of the total patients), were included in the PopPK analysis dataset. Consistent with prior results, Dato DXd PK was well-characterized by a two compartmental distribution model with parallel Dato DXd linear clearance (CLlinDatoDXd) and Dato DXd nonlinear Michaelis Menten clearance (CLnonlinDatoDXd) from the central compartment. DXd PK was well-characterized by a one compartment model with first order elimination kinetics from the central compartment. The release of DXd from intact Dato-DXd was equal to the total (linear + nonlinear) elimination rate of Dato DXd. The payload:intact ratio (PIR) decreased with time both within the dosing cycle and between cycles (cycle 1 vs later cycles). The evaluated covariates of clinical interest were not associated with a clinically significant impact on Dato-DXd or DXd PK. At 6 mg/kg, the difference in Dato-DXd AUC at the steady state (cycle 3 AUC, or AUC3) between lung cancer and breast cancer patients was 1.51%. DXd AUC3 of breast cancer patients was 1.74% higher than lung cancer patients. Neither difference was considered to be clinically relevant. Conclusions: The current PopPK analysis suggested no Dato-DXd dose adjustment is needed for HR-positive, HER2-negative breast cancer patients, further justifying the Dato-DXd 6 mg/kg Q3W dose in this patient population.Citations: 1Lu, Yasong, et al. CPT: Pharmacometrics & Systems Pharmacology 13.1 (2024): 23-28 2PAGE 2024
Population Pharmacokinetic Analysis of Fenebrutinib in Patients with Relapsing Multiple Sclerosis
Authors: Moein Anita , Nguyen Jonas , Chan Phyllis , Xu Yan , Kassir Nastya , Kuruvilla Denison
Published: February 2025

OBJECTIVES: Fenebrutinib (FEN) is a potent orally administered CNS penetrant Bruton's tyrosine kinase inhibitor that is highly selective and noncovalent, leading to reversible binding [1]. FEN inhibits both B-cell proliferation and microglia activation that are drivers of acute and chronic inflammation in relapsing multiple sclerosis (RMS) [2]. FENopta study (NCT05119569) is a Phase 2 study evaluating the efficacy, safety, and pharmacokinetics (PK) of FEN in patients with RMS receiving 200 mg twice-a-day oral fenebrutinib or placebo for 12 weeks. The objective of this study was to utilize a historical population pharmacokinetic (popPK) model to characterize the PK of fenebrutinib in patients with RMS [3].METHODS: The popPK analysis was conducted using previously published model constructed with PK data from two Phase 1 studies in healthy volunteers (NCT03596632, NCT02699710) and a Phase 2 study in rheumatoid arthritis patients (NCT02833350) [3]. Pooled popPK analysis was performed with addition of FENopta data to characterize fenebrutinib PK in RMS. Model evaluation was based on the inspection of graphical diagnostics, relative standard errors and plausibility of the parameter estimates. RESULTS: The popPK analysis dataset included a total of 4530 PK observations from 458 subjects, of which 73 subjects were patients with RMS (471 PK observations). The popPK model was a three-compartment model with linear clearance (CL/F) from the central compartment and a flexible transit compartment absorption model to describe the fenebrutinib absorption rate. Population typical values were estimated as 19.1 L/hr for CL/F, 323.8 L for volume of central compartment, and 0.757 hr for mean transit time. These results were comparable to historical popPK estimates [3].The median (1st and 3rd quantile) values of the patients with RMS were 55.5 (50.5-63.4) L/hr for CL/F, 250.5 (227.1-318.4) L for volume of central compartment, and 0.703 (0.610-0.810) hr for mean transit time. The performance and adequacy of the model to predict RMS data was demonstrated using goodness-of-fit plots including prediction-corrected visual predictive checks.CONCLUSIONS: The final popPK model captured the observed FENopta data well and adequately described the fenebrutinib concentration versus time profiles in patients with RMS. Final popPK model was used to derive individual predictions of fenebrutinib exposure for exposure-response analysis of FENopta study.Citations: [1] Crawford JJ, et al. Discovery of GDC-0853: a potent, selective, and noncovalent Bruton's tyrosine kinase inhibitor in early clinical development. J Med Chem 61(6):2227–45 (2018). [2] Krämer J, et al. Bruton tyrosine kinase inhibitors for multiple sclerosis. Nat Rev Neurol 19, 289–304 (2023). [3] Chan P, et al. Population Pharmacokinetics, Efficacy Exposure-response Analysis, and Model-based Meta-analysis of Fenebrutinib in Subjects with Rheumatoid Arthritis. Pharm Res 37, 25 (2020).
Quantitative Systems Toxicology Modeling of Otenaproxesul Liver Enzyme Elevations Leads to Prediction of Liver Safety for Acute Otenaproxesul Dosing
Authors: Woodhead Jeff , Hamzavi Nader , Bhargava Pallavi , Lakhani Vinal , Howell Brett
Published: February 2025

Objectives: Otenaproxesul is a pain-reducing medicine consisting of naproxen bound to a 4-hydroxythiobenzamide moiety that releases the powerful antioxidant: hydrogen sulfide (H2S). This mechanism makes otenaproxesul less toxic to the gut tissue compared to naproxen alone. Liver enzyme elevations were observed in some chronic dosing clinical trials; these elevations occurred mostly after the cessation of dosing. Quantitative systems toxicology (QST) modeling using DILIsym® v8A was undertaken in order to explain the observed liver signals and predict acute dosing protocols that would be liver safe.Methods: A PBPK model for several formulations of otenaproxesul, including a novel rapid-release formulation, was constructed in GastroPlus® 9.8. DILIsym v8A was modified to represent the scavenging of reactive oxygen species (ROS) by the H2S released by otenaproxesul. In vitro experiments describing the potential mechanism of drug-induced liver signals for both otenaproxesul and its main metabolite, M25 (naproxen), were used to create a representation of otenaproxesul in DILIsym v8A. The representation was validated against clinical liver function test data and was used to predict the likelihood of liver enzyme elevations in several proposed acute dosing protocols.Results: Initial simulation results suggested that the post-treatment liver enzyme elevations were due to the replacement of endogenous antioxidant mechanisms with the drug-supplied H2S in certain individuals. In individuals with pre-existing capabilities or adaptation to elevated levels of ambient ROS, the influx of H2S would lead to a substantial decrease in ROS and, in time, to the cessation of the adaptive mechanisms (ie de-adaptation) that enabled hepatocytes to manage the elevated ambient ROS. Upon removal of the treatment, endogenous antioxidant mechanisms were slow to recover (ie re-adapt) while ambient ROS returned to pre-treatment levels, leading to liver injury. This hypothesis was able to explain all the post-treatment enzyme elevations observed in the clinic. The proposed acute dosing protocols were able to avoid full de-adaptation and thus were predicted to be liver-safe. Subsequent clinical experience validated the prediction of liver safety for one of the proposed acute dosing protocols.Conclusions: DILIsym modeling was used to propose a plausible hypothesis for otenaproxesul-related liver enzyme elevations, to demonstrate that the hypothesis was able to explain clinical liver function test abnormalities, and to use these results to propose shifting the dosing strategy for otenaproxesul towards safer acute dosing protocols that were later validated clinically. This demonstrates that the lessons gleaned from QST modeling about the causes of liver injury can be used to de-risk future clinical development.Citations: None
Comparing the Efficacy of Various Insulin Types: A Pharmacokinetic and Pharmacodynamic Modeling Study in Healthy Volunteers
Authors: Chang Yi Chien , Jusko William
Published: February 2025

Objectives: To compare the efficacy of different types of subcutaneous insulin, including rapid-acting, intermediate-acting, long-acting, and human regular insulin, using a mechanistic-based pharmacokinetic (PK) and pharmacodynamic (PD) model.Methods: An established [1] biophase/indirect response model was used to evaluate the effect of insulin on glucose utilization during euglycemic clamp studies and compare the PK and PD parameters between various types of insulin in healthy volunteers. The data were digitized from all published studies that could be found. Healthy subjects received two or three doses of insulin subcutaneously during the glucose clamp and their glucose infusion rates monitored using the Biostator. All data were modeled simultaneously using MONOLIX (Version 2024).Results: The subcutaneous insulin pharmacokinetics was described by two first-order absorption processes and first-order elimination. Insulin's effect on glucose was described by a combination of a biophase model and an indirect model reflecting insulin stimulation of tissue glucose uptake [1]. The different characteristics of each type of insulin necessitated independent PK parameters estimated. Pharmacodynamic parameters were estimated for all insulin jointly. The Smax depicted the maximum stimulation of glucose utilization, reflecting the efficacy of insulin, and SC50 represented the insulin concentration producing half-maximal stimulation of glucose utilization, indicating the potency of insulin. Pharmacodynamic parameter estimates were 133 for Smax and 873 (pmol/L) for SC50 for insulin aspart, lispro, regular human insulin, neutral protamine hagedorn (NPH) insulin, and insulin glargine, and 3679 for insulin detemir. Notably, insulin detemir showed similar efficacy with lower potency, consistent with the model fitting estimate.Conclusion: The comprehensive mechanism-based glucose-insulin model showed that most types of insulin demonstrated similar efficacy and potency, except for insulin detemir. The glucose-insulin model with a single set of Smax and SC50 parameters enables clinical optimization of insulin therapy by recognizing that most insulin forms differ markedly in PK but not in their intrinsic effects on glucose utilization.Citations: [1] Landersdorfer, C. B., & Jusko, W. J. (2010). Pharmacokinetic/pharmacodynamic modeling of glucose clamp effects of inhaled and subcutaneous insulin in healthy volunteers and diabetic patients. Drug Metabolism and Pharmacokinetics, 25(5), 418–429.
Physiologically Based Pharmacokinetic (PBPK) modeling of hepatic impairment using PK-Sim
Authors: Pendse Salil , Bartlette Kai , MacDonald Alex
Published: February 2025

Objectives: Hepatic impairment can impact drug concentration, dosing, and consequently drug labeling and prescribing. Cirrhosis patients undergo hepatic and extra-hepatic changes depending on severity of disease. PBPK modeling has shown utility for predicting the impact of hepatic impairment in a wide variety of drugs [ 1], and models have been reported using open-source model platforms accessible to all researchers [2,3]. However, access to accurate, harmonized PBPK models of hepatic impairment for use across multiple drugs, and disease severities, remains a challenge. We present an open-source PBPK model incorporating the key features of mild, moderate, and severe hepatically impaired patients, together with parameters consolidated across the available literature. Methods: Hepatic impairment physiological parameters and CYP abundance data were obtained from literature [2,3,4]. Physiological parameters from PK-Sim (V11) were exported and a new physiology for hepatic impairment was calculated. This yielded three parameter sets one each for mild (Child-Pugh (CP) A), moderate (CP B), and severe (CP C) hepatic impairment. Each parameter set still conserved body volume and blood flow rate. Plasma protein binding and enzyme expression was adjusted. Observed PK profiles of propranolol, alfentanil, pazopanib, and cabozantinib in cirrhotic patients were used to validate the model. Results: Predicted PK parameters for propranolol, alfentanil, pazopanib, and cabozatinib were within 2-fold of observed PK parameters for healthy controls and patients with liver impairment. Report clinical data for alfentanil was not divided by degree of liver impairment. Model predictions over estimated alfentanil PK in severe hepatic impairment group. Conclusion: An open-source PBPK model, was developed, incorporating the key features of hepatically impaired patients, together with parameters consolidated across the literature. The model was validated for drugs across several drug classes. This model can be used prospectively to predict the impact of hepatic impairment and used to aid clinical trial design, support regulatory interactions and potentially labeling.Citations: 1. Heimbach T et al. Physiologically Based Pharmacokinetic Modeling in Renal and Hepatic Impairment Populations: A Pharmaceutical Industry Perspective. Clin Pharmacol Ther. 2021;110(2):297-310.2. Edginton A et al. Physiology-based simulations of a pathological condition: prediction of pharmacokinetics in patients with liver cirrhosis. Clin Pharmacokinet. 2008;47(11):743-7523. Kalam M et al. Development and Evaluation of a Physiologically Based Pharmacokinetic Drug-Disease Model of Propranolol for Suggesting Model Informed Dosing in Liver Cirrhosis Patients. Drug Des Devel Ther. 2021;15:1195-1211. 4. Prasad B et al. Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study. Drug Metab Dispos. 2018;46(7):943-952
Coupling A Quantitative Systems Pharmacology Model With A Simple Statistical Layer To Predict Asthma Exacerbation Rate Reduction From Allergen Challenge Results
Authors: Arsène Simon , Galland Théo , Leon Cristhyne , Sansone Caterina , Chessex Anne Vaslin , Pasquali Christian , Lehr Lorenz , Kulesza Alexander
Published: February 2025

Objectives: Allergen challenge studies experimentally mimic triggers of asthma exacerbations by challenging sensitized animals or patients with an allergen, resulting in lung function alteration [1]. Effects of treatments have been tested in this setting as proof-of-concept, however, the gold standard in asthma is assessed in another context: in clinical trials that measure the reduction in the number of exacerbations over a long period of time (exacerbation trial). To bridge these two contexts, here we propose a computational tool which builds upon existing early preclinical and clinical data from allergen challenge studies to predict reduction in asthma exacerbation rate. Methods: We collected, for a number of different interventions and matching target populations, inhaled corticosteroids (ICS) vs long-acting beta-agonists (LABA) for example, the reported effect size in the two contexts: allergen challenge and exacerbation trial. We then assessed the correlation between reduction of FEV1%, relative to placebo, following allergen challenge and reduction of exacerbation rate, relative to placebo, for each type of intervention. Using this, we established a translational relationship between relative effect size in allergen challenge and in exacerbation trial. We then incorporated this into a statistical layer which outputs exacerbation rate and which is built on top of an already developed QSP model of allergen challenge (preclinical and clinical). For this, we integrated into this QSP model the effect of ICS and LABA in asthma. Results: We found a high correlation between relative reduction of exacerbation rate and relative FEV1% drop improvement following allergen challenge (r2 = 0.89). We used this relationship for the development of the exacerbation statistical layer built on top of our QSP allergen challenge model. This set up yielded a computational tool which, for a given intervention (type of treatment, dosing regimen etc), can simulate the effect in both contexts. Finally, we verified the approach by comparing the simulation outputs with the collected data. Conclusions: Here, we show how a computational approach based on a QSP model coupled with a simple statistical layer can bridge results obtained in the two main settings in asthma development: allergen challenges and clinical trials measuring exacerbation rates. This work paves the way towards an asthma computational platform with the potential for becoming a powerful tool for supporting trial design in asthma, by enabling the continuous integration of data produced throughout the entire development cycle.Citations: [1] G. M. Gauvreau, M. Y. Evans, Allergen Inhalation Challenge: A Human Model of Asthma Exacerbation. Contributions to Microbiology (2007), pp. 21–32.
Population pharmacokinetic and pharmacodynamic modeling of free serum interleukin-15 in response to TEV-53408, an anti-interleukin 15 monoclonal antibody, in healthy volunteers.
Authors: Tong Xiao , Kang Dongwoo , Dotan Or , Radivojevic Andrijana , Schnir Victoria , Gutman Dikla , Singh Rajendra
Published: February 2025

Objectives: TEV-53408 is a human monoclonal antibody that binds to and neutralizes interleukin 15 (IL-15) currently being evaluated in celiac disease. The objective of this presented analysis was to develop a population pharmacokinetics/pharmacodynamics (PK/PD) model to describe the time course of free serum IL-15 following both single and multiple TEV-53408 subcutaneous (SC) doses in healthy participants.Methods: Data from 115 participants across 8 dose levels including placebo from the Phase 1 first-in-human study was used for model development and validation. A sequential approach was used for model development where population PK model was first developed to describe the TEV-53408 PK concentration-time profiles. The post-hoc individual PK exposures were then used as TEV-53408 drug concentrations to develop a PK/PD model for free serum IL-15 levels. Different PK/PD structural models were tested. The nonlinear-mixed effect modeling software NONMEM (version 7.5) was used for model development, and RStudio software (version 3.5.2) was used for exploratory analysis.Results: The final population PK/PD model consisted of a two compartment PK model with first-order absorption and linear and saturable apparent elimination to describe the TEV-53408 drug ligand profile; and a one compartment target-mediated drug disposition PD model incorporating delayed feedback to the free serum IL-15 compartment to describe the delayed increase beyond baseline1. The final model adequately described the free serum IL-15 levels post-dose reduction and subsequent increase beyond baseline at different dose levels. The time to increase beyond baseline of free serum IL-15 was also found to be dose dependent.Conclusions: A population PK/PD model was developed to describe the reduction and subsequent increase beyond baseline of free serum IL-15 following SC dose of TEV-53408. This model allowed for simulation of free serum IL-15 under different dosing scenarios and served as a guiding piece in dose selection of subsequent TEV-53408 clinical trials.Citations: 1. Aston PJ, Derks G, Agoram BJ, & van der Graaf PH. A mathematical analysis of rebound in a target-mediated drug disposition model: II. With feedback. J. Math. Biol. (2017) 75:33-84.
Speculative fiction or conspicuous discursive space: Mohsin Hamid’s the last white man as poetics of disruption
Authors: Perveen Dr. Ayesha , Rashid Faiqa , Aqeel Asim
Published: February 2025

The Last White Man employs speculative fiction techniques to challenge systemic inequality based on racial privileges. A world is imagined by Mohsin Hamid where the white undergo a racial transformation that is as loathsome as Kafkian metamorphosis into a cockroach. While this speculative aspect describes the racial transformation as fragile because it is something biological, it acts as a tool for social critique exposing the impact that race can have on one's identity particularly in face of the dominant stereotypes about race. Through its form, the novel destabilizes the traditional notions of racial privilege by exposing the socio-psychological and systemic structures based on power dynamics about the privilege of those born white. Simultaneously, it invokes horror by alluding to pandemics or biological conditions that can affect human color through diseases like vitiligo. Discontents of the civilization are conveyed through inexplicable racial metamorphosis that destabilizes the deep-rooted racial hierarchies inviting retrospective reflection about changing a worldview that is based on something fundamentally inherited. In this regard, I study the novel rendering poetics of disruption by becoming a conspicuous discursive space bringing into discussion contemporary social structures that are in need of inversion, an inversion which Hamid renders through the use of speculative techniques.
Error Iuris: el conocimiento de la antijuricidad y el artículo 14 del código penal
Authors: Felip Saborit David
Published: February 2025

El conocimiento de la antijuricidad es el requisito de la responsabilidad penal establecido en el artículo 14.3 del Código Penal. Sin embargo, quedan por aclarar aspectos esenciales. ¿Conocimiento de la antijuricidad general o sólo de la penal? ¿Cómo actuar en caso de duda? ¿Es suficiente con el conocimiento potencial? En la obra se efectúa un análisis de estas cuestiones fundamentales a la luz de la Jurisprudencia del Tribunal Supremo y del famoso caso de los "tiradores del Muro" en la frontera de la RDA.
Zmiany w polityce wymierzania kar pieniężnych za praktyki ograniczające konkurencję w świetle wyjaśnień Prezesa UOKiK publikowanych w latach 2008–2024 – zagadnienia wybrane
Authors:   Radca prawny, doradca w kancelarii Hansberry Tomkiel sp. k., Famirska Sabina
Published: February 2025

W artykule omówiono wybrane zagadnienia dotyczące zmian w polityce wymierzenia kar pieniężnych za stosowanie praktyk ograniczających konkurencję na przestrzeni ostatnich kilkunastu lat. W kolejnych częściach artykułu autorka przedstawia ramy prawne będące podstawą do opublikowania wyjaśnień Prezesa UOKiK zawierających metodę wymierzania kar pieniężnych oraz omawia treść tych dokumentów publikowanych w latach 2008–2024. Szerzej przedstawiono najnowsze zmiany w mechanizmie ustalania kar pieniężnych, będące następstwem implementacji, dyrektywy ECN+1, która pozwoliła na nakładanie kar pieniężnych na podmiot niebędący sprawcą naruszenia, tj. na przedsiębiorcę, wywierający decydujący wpływ na przedsiębiorcę naruszającego zakaz. W podsumowaniu autorka, próbuje dokonać predykcji modyfikacji praktyki decyzyjnej Prezesa UOKiK w przyszłości, opierając się na deklaracjach Prezesa UOKiK zawartych w jego oficjalnych wyjaśnieniach.
Hamid Pourazari : faire du théâtre comme traverser les frontières sociales de la ville
Authors: Zamani Mohammadamin , Pourazari Hamid
Published: February 2025

Sous la République islamique, la survivance du théâtre iranien a toujours été due aux tactiques développées par les artistes dans les brèches et les interstices de la stratégie de surveillance et de censure mise en place par le régime. L’oeuvre insolite du metteur en scène Hamid Pourazari, déployée dans des lieux non conventionnels, en dit long sur cette vie interstitielle et sur les compromis avec le pouvoir que celle-ci a toujours impliqués. Or, avec la révolution Femme, Vie, Liberté, toute entente avec le pouvoir devient impossible. Pourazari annonce alors la « fin du spectacle », soit la fin de la vie dans les interstices; le théâtre se produit désormais dans les rues.
Dismantling and its (dis-)contents: machine ecologies as staged encounters
Authors: Sormani Philippe
Published: February 2025

Dismantling? Other D-words have found their way into academic discourse and beyond, repurposed or invented words such as deconstruction, différance or diffraction. In contrast, this essay draws its inspiration from an ethnographic description of the routine dismantling of an exhibition – its démontage, as referred to by local curators. Over a year and a half, the exhibition introduced a broader public to new forms of “artificial intelligence”, framing “AI” as an intricate mystery, while guiding visitors through progressive demystification. In turn, this paper explicates exhibition dismantling in and through its heuristic moments, moments that allow(ed) us to analyse “machine ecologies” as staged encounters. A brief comparison with Nature of Robotics, a thematically related yet differently curated exhibition, is outlined. The comparison allows us to “expand the field”, if tentatively so.
Captivating objects and the taste of performance: probing the affects of scientific objects
Authors: Grob Bart , Nibbelink Liesbeth Groot
Published: February 2025

This paper describes a series of experimental set-ups in Rijksmuseum Boerhaave, the Dutch National Science Museum in Leiden, dedicated to probing the affects of scientific objects. These set-ups are part of an interdisciplinary research project centring around the issue of how to present and engage with immaterial or complex science technologies. This research combines two fields of expertise: curatorial practice in a science museum and scholarship in dramaturgy and scenography. It probes the potential of affect, understood as the capacity to affect and to be affected, while finding inspiration in new materialist theory. By using dialogue next to discursive argumentation, the paper discusses some questions and issues that were raised by these experimental set-ups and proposes that a focus on affect and materiality – thinginess, in brief – can inspire the collection and presentation of scientific objects. Attending to thinginess can expand the curatorial agenda and asks for scenographic strategies to support this.
Wide transition-state ensemble as key component for enzyme catalysis
Authors: Jara Gabriel E , Pontiggia Francesco , Otten Renee , Agafonov Roman V , Martí Marcelo A , Kern Dorothee
Published: February 2025

Transition-state (TS) theory has provided the theoretical framework to explain the enormous rate accelerations of chemical reactions by enzymes. Given that proteins display large ensembles of conformations, unique TSs would pose a huge entropic bottleneck for enzyme catalysis. To shed light on this question, we studied the nature of the enzymatic TS for the phosphoryl-transfer step in adenylate kinase by quantum-mechanics/molecular-mechanics calculations. We find a structurally wide set of energetically equivalent configurations that lie along the reaction coordinate and hence a broad transition-state ensemble (TSE). A conformationally delocalized ensemble, including asymmetric TSs, is rooted in the macroscopic nature of the enzyme. The computational results are buttressed by enzyme kinetics experiments that confirm the decrease of the entropy of activation predicted from such wide TSE. TSEs as a key for efficient enzyme catalysis further boosts a unifying concept for protein folding and conformational transitions underlying protein function.
Knowledge of Primary Prevention and Management of Type 2 Diabetes and Hypertension among Secondary School Children in Morogoro Municipality, Morogoro Region, Tanzania
Authors: Msollo Safiness Simon , Majaliwa Nuria Kudra
Published: February 2025

Purpose: Hypertension and diabetes used to occur in adults but are now prevalent in children however, there is no enough information on student’s knowledge on prevention and management of these conditions. Therefore, this study aimed at assessing knowledge on prevention and management of hypertension and diabetes among students in Morogoro Municipality.
Methods: A cross-sectional study was conducted at Kihonda and SUA secondary schools among 253 randomly selected students. Data were collected using KAP questionnaire adapted from the FAO and analyzed using the Statistical Package for Social Science™ Version 20.
Results: Over 95% of the students have never tested their blood pressure and glucose. Also, 34.4% have never measured body weight before the study. Majority (75.5%) understood that hypertension and diabetes can be prevented through managing diet and physical activity (19.2%) while 18.7% mentioned engaging in physical activities only. Furthermore, 64.4% and 69.2% did not know the management of diabetes and hypertension respectively. About 42% and 32% did not know any good and risk foods for hypertension respectively. Also, 38.3% and 35.2% did not know the appropriate and risk foods for diabetes patients respectively. Knowledge on prevention of diabetes and hypertension was associated with age AOR 1.421(95%CI: 1.015-1.989) p=0.040, education level AOR (1.118, 95%CI: 1.039-3.355) p< 0.01 and studying science subjects AOR 1.65 (95%CI: 1.306-1.692) p=0.028.
Conclusion: Majority of students do not actively monitor their health and have limited knowledge on prevention and management of diabetes and hypertension creating a need for improving knowledge as a window of opportunity for prevention of non-communicable diseases.