Nonlinear Clearance Research Articles

Precision Dosing of Intravenous Tocilizumab: Development of Pharmacokinetic Model-Derived Tapering Strategies for Patients With Rheumatoid Arthritis.

Tocilizumab targets the interleukin-6 receptor, and dosing is complex owing to its nonlinear clearance related to target binding. Therefore, tapering tocilizumab requires a different approach than that of tumor necrosis factor inhibitors (TNFi). This study aimed to identify these differences and enable personalized treatment of rheumatoid arthritis (RA) beyond TNFi therapy. A population pharmacokinetic model of intravenous tocilizumab was developed using data from a randomized controlled trial of dose tapering in patients with RA. Subsequent population-level Monte Carlo and individual Bayesian simulations were performed to create tapering strategies involving dose reduction and interval extension. The target trough concentration of tocilizumab was 5 mg/L. Finally, the drug savings were compared between the 2 methods. The pharmacokinetic of tocilizumab was described with a 2-compartment model with parallel linear (CL 0.20 L/d) and nonlinear (VM 5.2 mg/d, KM 0.19 mg/L) elimination. The linear clearance rate and central volume of distribution increased with lean body mass, and men exhibited higher clearance rates than women. The simulated concentration-time profiles demonstrated that, owing to nonlinear clearance, drug concentrations decreased more than dose-proportionally with lower doses. Tapering based on an individual Bayesian approach emerged as the most promising strategy, yielding a 39% reduction in drug use across virtual populations. Tapering strategies were developed for intravenous tocilizumab, offering potential application in patients with RA who have reached low disease activity or remission, pending clinical validation. The developed strategies demonstrate that the tapering of tocilizumab should be approached more carefully and in smaller steps than that of TNFi.

B-280 Nmr-based biomaker measurement determines high-dose methotrexate elimination rates in lymphoma and leukemia treatment

Abstract Background The cytotoxic methotrexate (MTX) is used in high doses in lymphoma and acute lymphocytic leukemia (ALL) treatment. A therapeutic plasma dose range is crucial to minimize MTX accumulation and prolonged exposure, which can lead to myelosuppression and other adverse effects. Determining MTX elimination prior to drug administration is difficult, given its non-linear clearance. Here we present a model to predict MTX elimination rates based on metabolite measurement in patients receiving high-dose methotrexate, using nuclear-magnetic resonance (NMR) spectroscopy. Methods A series of 26 residual sera from patients receiving MTX infusions as per treatment protocols for CNS lymphoma (MATRIX protocol, 3.5 g/m2 over four hours) and ALL (GMALL protocol, 1.5 g/m2 over 24 hours) were collected from patients at the University Hospital Regensburg at four timepoints (t0, t24, t42, and t48). Serum was NMR-measured in five replicates. NMR spectra for each sample were characterized and relevant parameters extracted. First order elimination constants were modeled for two MTX dosage regimes (<4 g, ≥4 g) using characterized NMR features from samples measured at t0. Results Metabolomic and lipidomic biomarkers measured at baseline (t0) were able to accurately predict MTX elimination rate constant k, determined by fitting MTX levels at a t24, t42, and t48, using first order c(t)∼c0*e(-kt) kinetic function (>4 g: R2 = 0.475, p-value < 0.05; ≤4 g: R2 = 0.918, p-value < 0.01) (Fig. A). Results were cross-validated with five-time repeated three-fold cross-validation. Performance values are given as means of the folds. Conclusions NMR-measured biomarkers can predict dose-dependent MTX elimination rates in patients receiving high-dose MTX, presenting a novel method to predict MTX clearance, allowing for personalized dose-monitoring and minimization of adverse events. Validation with a larger cohort is required.

Pharmacokinetics and pharmacodynamics of intravenous delafloxacin in healthy subjects: model-based dose optimization.

Delafloxacin, a fluoroquinolone antibiotic to treat skin infections, exhibits a broad-spectrum antimicrobial activity. The first randomized, open-label phase I clinical trial was conducted to assess the safety and pharmacokinetics (PK) of intravenous delafloxacin in the Chinese population. A population pharmacokinetic (PopPK) model based on the clinical trial was conducted by NONMEM software. Monte Carlo simulation was performed to evaluate the antibacterial effects of delafloxacin at different doses in different Chinese populations. The PK characteristics of delafloxacin were best described by a three-compartment model with mixed linear and nonlinear clearance. Body weight was included as a covariate in the model. We simulated the AUC0-24h in a steady state at five doses in patient groups of various weights. The results indicated that for patients weighing 70 kg and treated with methicillin-resistant Staphylococcus aureus (MRSA) infections, a minimum dose of 300 mg achieved a PTA > 90% at MIC90 of 0.25 µg/mL, suggesting an ideal bactericidal effect. For patients weighing less than 60 kg, a dose of 200 mg achieved a PTA > 90% at MIC90 of 0.25 µg/mL, also suggesting an ideal bactericidal effect. Additionally, this trial demonstrated the high safety of delafloxacin in single-dose and multiple-dose groups of Chinese. Delafloxacin (300 mg, q12h, iv) was recommended for achieving optimal efficacy in Chinese bacterial skin infections patients. To ensure optimal efficacy, an individualized dose of 200 mg (q12h, iv) could be advised for patients weighing less than 60 kg, and 300 mg (q12h, iv) for those weighing more than 60 kg.

Modelling and application of typical nonlinear torsional elements in vibro-impact analysis of pickup truck driveline system

The torsional element method for the dynamic modelling of torsional system was proposed by Crowther and Zhang, which provides a modular modeling approach with high modeling efficiency and has a good application prospect in vibro-impact analysis of vehicle driveline system. The main purpose of this paper is to further enrich the element types of the torsional element method and to establish a nonlinear dynamic model for a pickup truck driveline system by applying the torsional element method to analyze the vibro-impact phenomenon. A general nonlinear clearance element with different contact stiffness and damping, a nonlinear friction element with smooth Stribeck effect and a nonlinear multistage stiffness-damping element with different torque transfer characteristics are developed. A dynamic lumped parametric model with 10 degrees of freedom for a pickup truck driveline system is established by assembling the developed nonlinear torsional elements. The transient vibro-impact phenomenon caused by the clearance, the stick-slip phenomenon caused by the friction and the transient hysteresis cycle phenomenon caused by the nonlinear multistage damper during transient engagement of clutch are numerically investigated. Furthermore, a real-vehicle experimental study is conducted to confirm the transient vibro-impact phenomenon in pickup truck driveline system during transient clutch engagement and to verify the correctness of the dynamic lumped parameter model. On these bases, the influence of the key parameters of the nonlinear torsional element on the transient vibro-impacts are investigated, the effective engineering countermeasures to reduce the vibro-impact of the vehicle driveline system are put forward.

Phase I dose escalation trial of the first-in-class TNFR2 agonist monoclonal antibody, HFB200301, in monotherapy and in combination with tislelizumab, an anti-PD-1 monoclonal antibody, in adult patients with advanced solid tumors.

2526 Background: Tumor necrosis factor receptor-2 (TNFR2) is expressed on effector CD8+, CD4+, and regulatory T (Treg) cells, natural killer (NK) cells, and myeloid cells. Activation of TNFR2 is anticipated to yield effective anti-tumor immunity by stimulating T-cell and NK-cell activation and proliferation in the tumor microenvironment. HFB200301 is a first-in-class anti-TNFR2 agonistic monoclonal antibody that triggers both innate and adaptive immune stimulation by binding to a specific epitope on TNFR2. We report initial results of an ongoing Phase I dose escalation, multicenter study (NCT05238883) of HFB200301 in monotherapy and in combination with tislelizumab (TIS) in patients (pts) with advanced refractory solid tumors. Methods: A Phase I trial designed to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), and initial efficacy of HFB200301 in monotherapy and in combination with TIS. Eligible pts, ≥18 years with an ECOG PS 0-1 and advanced solid tumors, will be enrolled in dose escalation at 5 different dose cohorts in monotherapy (Q4W), 3 different dose cohorts in combination with TIS (Q4W), or in dose expansion following determination of safety. Radiographic response is assessed every 8 weeks. Results: A total of 39 pts have been enrolled, 27 pts in monotherapy and 12 pts in combination. All pts received prior systemic therapy (median 2, range 1-4); 23 pts (59%) had prior checkpoint inhibitor treatment. No dose limiting toxicities were observed in either the monotherapy or combination arms. Treatment-related adverse events (TRAEs) occurred in 44% of monotherapy and in 50% of combination pts, with pruritis (11%), tremor (7%), fatigue (7%), asthenia (7%) and nausea (7%) being the most common TRAEs. No ≥ Grade 3 TRAEs were reported, and there were no drug discontinuations due to TRAEs. Preliminary HFB200301 PK analysis demonstrated non-linear clearance of HFB200301, with dose-proportional maximum concentration [Cmax], achieving sufficient exposures for peripheral target engagement in all tested doses. Emerging PD data demonstrates evidence of immune activation and expansion of CD8+ T cells, but not Tregs, in the tumor microenvironment and peripheral blood. Single cell RNAseq analysis of peripheral blood mononuclear cells demonstrated PD modulation in TNFR2 positive immune cell types post-HFB200301 treatment. Early response evaluation reveals ongoing durable clinical responses (> 6 months) in a PD-L1+ pleural mesothelioma pt and an EBV+ gastric cancer pt from combination cohorts. Conclusions: HFB200301 demonstrates a favorable safety profile, dose-dependent PK, with PD and preliminary clinical activity in monotherapy and in combination with TIS in pts with heavily pre-treated refractory solid tumors. Clinical trial information: NCT05238883 .

Research on the EMA Control Method Based on Transmission Error Compensation

This research investigates the impact of nonlinear clearance factors on position tracking accuracy in the servo drive system of a harmonic reducer. The study introduces a technique for modeling and compensating for transmission errors, thereby improving position tracking accuracy through online compensation combined with an auto-disturbance rejection controller. Initially, the mathematical model of the permanent magnet synchronous motor is outlined, and the current loop and speed loop control models are derived. Subsequently, an electromechanical actuator (EMA) simulation model with clearance is established, and detailed simulation analysis is conducted to verify the impact of clearance on tracking accuracy. A model for online compensation of transmission errors is then developed. Following the principles of active disturbance rejection control (ADRC), a second-order ADRC is formulated for real-time compensation of transmission errors in EMA position mode. Finally, through no-load and load experiments, the change in position tracking error with and without transmission error compensation is compared and analyzed. The results demonstrate that utilizing automatic disturbance rejection control with transmission error compensation achieves the highest position tracking accuracy. Compared to the proportion integration differentiation (PID) control method, the root mean square of position tracking error is reduced by approximately 12.8% and 17.3% under no-load and load conditions, respectively. By compensating for position errors online, the accuracy of the EMA position can be improved.

Clearance Nonlinear Control Method of Electro-Hydraulic Servo System Based on Hopfield Neural Network

The electro-hydraulic servo system has advantages such as high pressure, large flow, and high power, etc., which can also realize stepless regulation, so it is widely used in many engineering machineries. A linear model is sometimes only a simple approximation of an idealized model, but in an actual system, there may be nonlinear and transient variation characteristics in the systems. Coupling is reflected in the fact that the components or functional structures implemented by each system used for the design of hydraulic systems are not completely or independently related to each other, but affect each other. The nonlinear clearance between the actuator and the load reduces the control accuracy of the system and increases the impact, thus losing stable working conditions. In the paper, based on the nonlinear clearance problem of the electro-hydraulic servo system, a mathematical transfer model with clearance is established, and on this basis, a clearance compensation method based on the Hopfield neural network is proposed. In this way, clearance compensation can be realized by adjusting the parameters of neural network nodes, through simple and convenient operation. Finally, by setting different clearance values, the results of the step response and sine response curve before and after clearance compensation of the hydraulic system are compared, and the effectiveness of Hopfield neural network compensation clearance control is verified based on the comparison simulation results.

Anti-T-lymphocyte globulin exposure is associated with acute graft-versus-host disease and relapse in pediatric acute lymphoblastic leukemia patients undergoing hematopoietic stem cell transplantation: a multinational prospective study.

Anti-T-lymphocyte globulin (ATLG) is used in hematopoietic stem cell transplantation (HSCT) to prevent graft-versus-host disease (GVHD) and graft failure. To date, insight in ATLG pharmacokinetics and -dynamics (PK/PD) is limited, and population PK (POPPK) models are lacking. In this prospective study, we describe ATLG POPPK using NONMEM® and the impact of ATLG exposure on clinical outcome and immune reconstitution in a homogeneous cohort of pediatric acute lymphoblastic leukemia (ALL) patients transplanted with a matched unrelated donor and receiving uniform ATLG dosing. Based on 121 patients and 812 samples for POPPK analysis, a two-compartmental model with parallel linear and non-linear clearance and bodyweight as covariate, best described the ATLG concentration-time data. The level of ATLG exposure (day active ATLG <1 AU/mL, median 16 days post-HSCT) was strongly associated with aGVHD grade II-IV, with a lower incidence in patients with prolonged active ATLG exposure (≤day 16 50% vs. >day 16 8.2%; P<0.001). When stratified for remission state, patients transplanted in complete remission (CR) 2 or 3 with prolonged ATLG exposure had a higher relapse risk, while this effect was not seen in CR1 patients (P=0.010). High level ATLG exposure was associated with delayed CD4 T-cell recovery at 4 and 8 weeks post-HSCT, but not at 12 weeks, and overall and relapse-free survival were not influenced by CD4 recovery at 12 weeks post-HSCT. This study underlines the importance of individualized ATLG exposure with the use of model-informed precision dosing in order to optimize the HSCT outcome in pediatric ALL.

Abstract 7174: Pharmacokinetics and immunogenicity of anti-PD-1 antibody in humanized FcRn mouse models compared to immunocompetent mouse models

Abstract Introduction: The development and use of therapeutic antibodies in cancer therapy has increased significantly in recent years, led by the success of approved immune checkpoint blockade antibodies targeting PD-1 and PD-L1 axis. However, obtaining more clinically relevant pharmacokinetics (PK), safety and efficacy data for antibodies is still challenging in preclinical phase. Humanized FcRn (hFcRn) transgenic mouse model has a more faithful catabolism compared to WT mice, providing more accurate and predictable PK data of innovative antibody-based therapeutics at discovery stage[1]. In this study, we sought to investigate pharmacokinetics and immunogenicity characteristics of anti-PD-1 antibody in hFcRn transgenic mice and provide guidance for its differentiation of prediction value for drug PK and safety by comparing to WT mice. Methods: Non-tumor bearing hFcRn mice and wild type C57BL/6 mice were divided into 2 groups, 5 mice were enrolled into each group. Mice were administered anti-PD-1(Nivolumab) at 10 mg/kg single dose after grouping by intravenous (IV) injection. Blood samples at 12 timepoints (15min, 6h, 1, 2, 4, 7, 10, 14, 21, 28, 35, 42 days) post-dosing were collected for PK and Anti-Drug Antibody (ADA) analysis by MSD and ELISA. Results: Nivolumab clearance in hFcRn mice followed a typical linear profile with rapid distribution phase and slow elimination phase (t1/2 = 350 to 400 h). While the PK profile in C57BL/6 mice displayed non-linear clearance and very short elimination phase (t1/2 = 45 to 50 h). This data demonstrated that hFcRn mice have better correlated half-life with human (Nivolumab single dose by IV with 10mg/kg, t1/2 = 595 h) [2]. ADA analysis revealed that it was produced starting from Day 10 in wild type C57BL/6 mice and the frequency of ADA induced by Nivolumab in wild type mice (2/5) was higher than hFcRn mice (0/5). The variation of Nivolumab level was correlated with ADA production in wild type mice. This suggested hFcRn shows lower immunogenicity than wild type mice for human IgG drug and can potentially improve negative effect of ADA interference on PK evaluation. Conclusion: The result of this study demonstrated that the PK data in hFcRn mouse model was more predictive of human PK profile compared to wild type C57BL/6 mice. This advances innovation in antibody-based therapeutics and translational applications, with improved PK, safety and efficacy evaluation for preclinical human IgG drug development in cancer therapy.

Dynamic characteristics investigation of a dual rotor-casing system considering the comprehensive stiffness of the intermediate bearing

This paper focuses on the vibrational properties of a dual rotor-casing coupled system with nonlinear clearance in the intermediate bearing, considering both the oil film stiffness and Hertzian contact stiffness between rolling elements and raceways. A comprehensive stiffness model for the intermediate bearing has been developed based on elastohydrodynamic lubrication (EHL) and Hertz contact theory. Subsequently, a dynamical model of the dual rotor-bearing-casing system is established using the finite element method, thereby verifying the feasibility of simulating the casing with beam elements. The dimensionality of the system equation is reduced using the fixed-interface component mode synthesis (CMS) method, and the resulting reduced-dimensionality equation is solved using the improved Newmark-β method. The effects of casing support, rotational speed, and radial clearance on the vibration characteristics of the system are investigated. Then, the comprehensive stiffness and coupled vibration characteristics of the system are analyzed to elucidate its intrinsic mechanism. Finally, the contact characteristics within the intermediate bearing under dynamic load are also studied. The results indicate that the support stiffness of the casing has a more significant impact on the second resonance caused by both the inner and outer rotors. The system is prone to experiencing varying compliance (VC) resonance at low rotational speeds. The excessive bearing clearance leads to complex vibrational characteristics of the system, making it challenging to predict its motion. The impact of minor changes in stiffness on system vibration is small when the comprehensive stiffness is large. At this time, the limited effect of oil film stiffness allows it to be disregarded in terms of comprehensive stiffness. Furthermore, the speed significantly influences the contact characteristics within the intermediate bearing under the unbalanced force of the rotor and gravity.

Notes on the Use of Kirchhoff's Laws in Pharmacokinetics.

Recent publications by Benet and coworkers, Korzekwa and Nagar, and Rowland et al. signal disagreement regarding the use of Kirchhoff's laws in combining pharmacokinetic parameters, especially clearances and rate constants. Here, it is pointed out that Kirchhoff's laws as applied to pharmacokinetics simply assert that concentrations are well defined and that molar or mass balances hold. The real issue is how to combine parameters for clearance processes in sequence, which may be reversible, irreversible, or even active in either or both directions. It is also demonstrated that Kirchhoff's laws cannot be used to resolve contradictory results observed in liver transport and clearance. Finally, a simple argument is provided relating nonlinear clearance to apparently anomalous bioavailability observations.

Abstract A137: Pharmacokinetics and pharmacodynamics of IGM-8444, a first-in-class engineered pentameric DR5-targeting agonist IgM monoclonal antibody, in patients with R/R and newly diagnosed cancers

Abstract Introduction: IGM-8444 is an engineered DR5 agonist IgM antibody with 10 binding sites that efficiently multimerizes DR5 to induce tumor cell apoptosis. The first-in-human Phase 1a/1b study of IGM-8444 (NCT04553692) is ongoing, and preliminary results show that IGM-8444 is well-tolerated as a single agent (SA) and in combination with chemotherapeutic and targeted agents. Encouraging efficacy is also observed with IGM-8444 combined with FOLFIRI +/- bevacizumab (bev) in patients with relapsed/refractory mCRC. Here we present pharmacokinetic (PK) and pharmacodynamic biomarker data from Phase 1a participants treated with IGM-8444 as SA or in combination at doses of 0.15 to 5 mg/kg given weekly (QW) or 0.3 to 10 mg/kg given every 2 weeks (Q2W). Methods: Blood samples for PK and biomarker analysis were collected at multiple timepoints during cycles 1 and 2. Sparse sampling was utilized at later cycles. Plasma biomarker evaluation included measurement of M30 by ELISA and total caspase-3 (casp-3) by MSD. Tumor biomarkers were assessed in baseline and on-treatment tissue through immunohistochemistry for DR5 and cleaved caspase-3 (CC3). Initial population PK modeling was conducted to assess the PK characteristics of IGM-8444 as SA and in combination, and to enable simulations of different doses and dosing regimen scenarios. Results: Treatment-related increases in plasma levels of apoptotic markers casp-3 (up to 25-fold) and M30 (up to 6-fold) were observed across dose levels. These changes occurred independently of any ALT or AST fluctuations, suggesting tumor-specific apoptosis induction. Dose-dependent increases in casp-3 and CC3 were observed in blood and tumor, respectively, indicating activation of DR5 pathway. At 3 mg/kg, on-treatment tumor CC3 levels were up to 10-fold higher in FOLFIRI combo, signifying enhanced apoptosis when IGM-8444 is combined with chemotherapy. Population PK analysis indicates that IGM-8444 PK is best described by a two-compartment model with parallel linear and nonlinear clearance. Terminal half-life at 10 mg/kg Q2W was &amp;gt;2 days. PK simulations suggest that IGM-8444 administered at 3 or 10 mg/kg Q2W sustains average concentrations within the range as those observed at efficacious doses of IGM-8444 in preclinical mouse tumor models, where SA IGM-8444 exhibits dose-dependent efficacy with no evidence of a bell-shaped response. To date, ADAs have been detected in ~25% of participants. ADA titers in confirmed ADA-positive participants remain relatively low and the available data do not indicate a significant effect of ADAs on the PK of IGM-8444. Conclusions: Pharmacodynamic changes in blood and tissue confirm the biologic activity of IGM-8444 and demonstrates that targeted therapy with an engineered IgM antibody can result in tumor penetration and target engagement within tumor tissue. Taken together, the biomarker and PK data support the use of IGM-8444 at a dose of 3 mg/kg or above for combination studies. The randomized Phase 1b is underway and evaluates the activity of FOLFIRI+bev +/- IGM-8444 in 2L mCRC. Citation Format: Genevive Hernandez, Sanela Bilic, Yinghui Guan, John So, Sabya Bhattacharya, Beatrice Wang, Maya Kotturi, Miho Oyasu, Melanie Desbois, Yuan Cao, Eric Humke, Sean Ahern, Angus Sinclair, Susanna Ulahannan, Vivek Subbiah, Merideth Pelster, Patricia Lorusso, Gerald Falchook, Judy Wang, Minal Barve, Jaspreet Grewal, Warren Chow, Jason Henry, Michael Cecchini, Chris Takimoto, Maya Leabman. Pharmacokinetics and pharmacodynamics of IGM-8444, a first-in-class engineered pentameric DR5-targeting agonist IgM monoclonal antibody, in patients with R/R and newly diagnosed cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A137.

Population Pharmacokinetic Modeling of Different Formulations of Inclacumab Using Phase 1 Data in Healthy Participants

Introduction: P-selectin is a cell adhesion molecule that contributes to vaso-occlusive crises (VOCs) in sickle cell disease (SCD). Inclacumab is a recombinant, fully human, immunoglobulin G4 monoclonal antibody that selectively binds to P-selectin to prevent binding with P-selectin glycoprotein ligand-1. Inclacumab was previously evaluated by Roche in clinical trials with healthy participants and patients with cardiovascular disease and is now being developed as a potential treatment to reduce the frequency of VOCs in individuals with SCD. Changes in the manufacturing of inclacumab have resulted in 3 formulations/drug materials: Roche v0.1, Roche v0.2, and Global Blood Therapeutics (GBT). GBT-manufactured inclacumab utilizes a similar formulation and the same cell line as Roche v0.2 (Roche v0.1 utilizes a different cell line), and analytical and nonclinical comparability between Roche v0.2 and GBT inclacumab have been demonstrated (Mihaila et al. Expert Opin Biol Ther 2022). Here we report results from a population pharmacokinetic (PopPK) model developed to compare the pharmacokinetics (PK) of different formulations using data from 4 phase 1 clinical studies in healthy participants administered Roche v0.1, Roche v0.2, or GBT inclacumab. The objectives were to develop a PopPK model to describe inclacumab PK in healthy adult participants and to quantify potential differences in inclacumab PK associated with different formulations/drug materials. Methods: A PopPK model was developed using single- and multiple-dose PK data from healthy participants who received intravenous (IV) inclacumab across 4 studies (BP21112 [Roche v0.1, single ascending dose (SAD)], BP21617 [Roche v0.1, multiple ascending dose], BP28134 [Roche v0.2, SAD], and GBT2104-111 [GBT, SAD]). Evaluable participants had ≥1 measurable postdose concentration with an associated sample time, relevant dosing information prior to each measurable concentration, and no protocol violation that could confound PK analyses. A nonlinear mixed effects model was fit to the inclacumab plasma concentration-time data using first-order conditional estimation with eta-epsilon interaction in NONMEM ® (v7.3). Model selection was based on the plausibility of parameter estimates, goodness-of-fit plots, and the objective function value. The final model was evaluated using a prediction-corrected visual predictive check (pcVPC). Results: The PopPK dataset comprised 145 healthy participants, of which 2622 inclacumab plasma concentrations (84.9%) from 143 participants were evaluable (Roche v0.1: n=68 [47.6%]; Roche v0.2: n=60 [42.0%]; GBT: n=15 [10.5%]). Median (range) age and body weight were 42 (21-63) years and 73.2 (45.8-109) kg, respectively. Nominal doses ranged from 0.03 to 40 mg/kg IV; 23.8% of participants received 3 mg/kg and 29.4% received 20 mg/kg. A 3-compartment disposition model with parallel linear clearance (CL=0.125 L/d) and nonlinear (concentration-dependent; V max=1.19 mg/d; K m=0.784 μg/mL) clearance from the central compartment described the plasma concentration-time data. The effect of drug material was incorporated a priori as relative bioavailability term F in the base model using exploratory analyses of observed exposures. Dosing of Roche v0.1 and Roche v0.2 inclacumab resulted in 23% and 2% higher exposure than GBT inclacumab, respectively. Between-subject variability was estimated for linear clearance, nonlinear clearance, and all volume parameters, and residual error was described using a proportional model (Table). Of the tested covariates, baseline body weight was a statistically significant covariate effect and was included on all linear clearance and volume terms. Model qualification by pcVPC showed good predictive performance of the final model. Conclusions: The PopPK of IV inclacumab in healthy participants was described by a 3-compartment disposition model with parallel linear and nonlinear clearances. Estimated relative exposure of Roche v0.2 and GBT-manufactured inclacumab was similar, indicating comparability in drug exposure. Understanding the relationship between exposure and dose for different formulations facilitates more accurate assessment of safety data across multiple clinical studies. These data provide support for the ongoing phase 3 clinical development in SCD using GBT-manufactured inclacumab without further clinical comparability testing.

Sutimlimab Pharmacokinetics and Pharmacodynamics in Patients with Cold Agglutinin Disease.

Sutimlimab, a humanized monoclonal antibody targeting the classical complement pathway, is approved in the US, Japan, and EU for the treatment of hemolytic anemia in adults with cold agglutinin disease. The objectives of this study were to support dose selection for Phase 3 studies, assess dose recommendations, and establish the relationship between sutimlimab exposure and clinical outcome (hemoglobin [Hb] levels). Clinically meaningful biomarkers were graphically analyzed and the exposure-response relationship was proposed. The pharmacokinetic (PK) characteristics of sutimlimab were best described by a two-compartment model with parallel linear and non-linear clearance terms. Body weight was a significant covariate for the volume of distribution in the central compartment (Vc) and total body clearance of sutimlimab. Ethnicity (Japanese, non-Japanese) was a covariate on Vc and maximal non-linear clearance. There were no PK differences between healthy participants and patients. Following graphical exposure-response analysis for biomarkers, a pharmacokinetic-pharmacodynamic model was developed by integrating an indirect response/turnover model for Hb with a maximum effect (Emax) model, relating the Hb-elevating effect of sutimlimab to plasma exposure. Renal function and occurrence of blood transfusion were identified as covariates on Hb change from baseline. Simulations showed that Emax was attained with the approved dosing (6.5 g in patients <75 kg, and 7.5 g in patients {greater than or equal to}75 kg), independent of covariate characteristics, and provided adequate sutimlimab exposure to maximize effects on Hb, bilirubin, and total complement component C4 levels. A change in Hb from baseline at steady state of 2.2 g/dL was projected, consistent with Phase 3 study observations. Significance Statement The final validated population PK and PK/PD models confirm that the approved dosing regimen for sutimlimab (6.5 g in patients <75 kg, and 7.5 g in patients ≥75 kg) is sufficient, without the need for further dose adjustments in populations of patients with cold agglutinin disease.

Abstract CT243: Clinical trial simulation to inform dose selection of zilurgisertib, an ALK2 inhibitor, in patients with anemia due to myelofibrosis (MF)

Abstract Disease-associated anemia is reported in over one-third of patients at MF diagnosis and can be exacerbated by currently available MF therapies. Further, anemia is associated with poor prognosis in MF. Activation of activin receptor-like kinase (ALK)-2 (also known as ACVR1) may contribute to MF-associated anemia via up-regulated levels of hepcidin. Zilurgisertib (INCB000928) is a potent and selective ALK2 inhibitor that has demonstrated dose-dependent improvement in hemoglobin levels in a cancer-induced anemia mouse model, in which maximum hemoglobin increase was observed when zilurgisertib trough concentration covered pSMAD IC50 for at least half of the dosing interval. Zilurgisertib is being evaluated as monotherapy or in combination with ruxolitinib in a phase 1/2 dose-escalation and -expansion study in patients with anemia due to MF (NCT04455841). The objective of the current study is to use modeling and simulation, which integrate both preclinical and clinical data, to inform dose finding for the ongoing phase 1/2 trial in MF patients. Population (Pop) PK analyses were conducted using a total of 3089 zilurgisertib plasma concentrations from 161 healthy subjects in 3 completed phase 1 studies: a single ascending dose study (64 subjects, 10-500 mg), a multiple ascending dose study (59 subjects, 50-400 mg QD and 300 mg BID), and a drug-drug interaction study (38 subjects, 100 mg single dose of zilurgisertib alone). A nonlinear mixed-effects modeling approach in Monolix software was used for the analyses. Zilurgisertib PK were well-characterized by a 3-compartment model with nonlinear clearance and inter-occasion variability on absorption rate constant and bioavailability. The diagnostic plots and visual predictive check demonstrated that the model appropriately characterized the zilurgisertib plasma concentrations. Because zilurgisertib PK are similar between MF patients and healthy subjects, as suggested by available PK data in MF patients receiving doses up to 200 mg, the pop PK model developed with data from healthy subjects was used to simulate steady-state exposures in MF patients receiving 200 to 600 mg daily dose. Simulation results showed that daily doses of ≥600 mg would result in &amp;gt;90% of patients achieving exposure similar to the observed exposure associated with maximum efficacy in the mouse model. The conclusions from this clinical trial simulation support the decision to continue dose escalation in MF patients receiving zilurgisertib monotherapy. Citation Format: Yan-ou Yang, Hong Yang, Betty Lamothe, Matthew Stubbs, Amanda McBride, Francis Seguy, Kevin Rockich, Jay Getsy, Phillip Wang, Xiang Liu, Jeff Jackson, Ekaterine Asatiani, Xuejun Chen. Clinical trial simulation to inform dose selection of zilurgisertib, an ALK2 inhibitor, in patients with anemia due to myelofibrosis (MF) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT243.

A 2-DOF-IMC method for suppressing transmission chain vibration of wind power generation system with a clearance

To address the vibration problem caused by gear clearance in the wind drivetrain, a two-degree-of-freedom internal model control (2-DOF-IMC) method was proposed to suppress the clearance’s nonlinear vibration. The two-mass wind drivetrain with clearance is the object of this paper’s research. First, we discuss the nonlinear characteristics of gear clearance and the mechanism by which vibration occurs. The nonlinear clearance unit is then decomposed into a linear unit and a nonlinear bounded disturbance unit. A suppression disturbance method based on 2-DOF-IMC was proposed to address nonlinear bounded disturbances. The 2-DOF-IMC overcomes the shortcoming of the PID control and the common internal model control (1-DOF-IMC) by allowing for independent adjustment of the anti-disturbance performance, effectively suppressing the nonlinear disturbance caused by gear clearance. A 2-DOF-IMC scheme and an IMC controller are designed, and the method’s effectiveness is validated through simulation.

Population Pharmacokinetics of Patritumab Deruxtecan in Patients With Solid Tumors.

Patritumab deruxtecan is an antibody-drug conjugate consisting of a fully human monoclonal antibody against human epidermal growth factor receptor3 (HER3) attached to a topoisomeraseI inhibitor payload via a tetrapeptide-based cleavable linker. As part of the pharmacometric analysis informing dose selection for later-stage development, population pharmacokinetics (PK) analysis of patritumab deruxtecan was conducted with pooled serum PK data from patients with HER3-expressing solid tumors (from 3 phase1/2 studies in breast, lung, and colorectal cancer; N=425) treated over the dose range of 1.6 to 8.0mg/kg intravenously every 3weeks. Population PK modeling for deruxtecan (DXd)-conjugated antibody (representing patritumab deruxtecan) and unconjugated MAAA-1181a (DXd, payload) was carried out sequentially. DXd-conjugated antibody PK was described using a 2-compartment model with parallel linear and nonlinear clearance. Unconjugated DXd PK was described using a 1-compartment model with linear clearance and release of DXd as a first-order, time-dependent function of the level of DXd-conjugated antibody in the central compartment. Preliminary covariate evaluation was conducted for prespecified covariates of pharmacological plausibility and clinical interest. The final model retained weight (on linear clearance and central volume) and albumin level, sex, and tumor type (on linear clearance) for DXd-conjugated antibody, and weight (on release rate constant) and hepatic function (on clearance) for unconjugated DXd. Effects of these covariates on the exposure metrics were generally mild and did not require dose adjustment for subpopulations in subsequent development. Further PK characterization for patritumab deruxtecan will evolve with emerging data.

Population pharmacokinetics of zanidatamab, an anti-HER2 biparatopic antibody, in patients with advanced or metastatic cancer.

To characterize the pharmacokinetics (PK) of zanidatamab including evaluation of the impact of intrinsic and extrinsic patient factors. To investigate alternative dosing regimens to improve caregiver convenience and reduce zanidatamab wastage. Serum zanidatamab concentrations were obtained from 305 patients with advanced or metastatic breast cancer, gastroesophageal adenocarcinoma (GEA), biliary tract cancer, and other HER2-expressing cancers from four ongoing phase I and II clinical trials. Zanidatamab PK were described using population methods. The exposure of alternative dosing regimens and the impact of dose delay was estimated by model simulation. A two-compartment model with parallel linear and nonlinear clearance from the central compartment adequately described zanidatamab PK. At the recommended dose regimens of 20mg/kg Q2W and 30mg/kg Q3W, zanidatamab clearance was primarily linear at steady state. At steady state, 30mg/kg Q3W zanidatamab returns within 10% of the steady state trough after 2 subsequent doses following either a 1-week or 2-week dose delay. Statistically significant covariates included in the final model were body weight, sex, albumin, GEA cancer type, baseline tumor size, and presence of post-baseline anti-drug antibodies, all of which resulted in less than 30% impact on exposure. Model simulation predicts weight-based and two-tiered flat dosing will result in similar exposure and variability. The identified significant covariates were not considered clinically meaningful. Both weight-based (30mg/kg Q3W) and two-tiered flat dosing (1800/2400mg Q3W, 70kg threshold) strategies are expected to provide similar exposures of zanidatamab.

Model-Based Approach to Selecting Pegfilgrastim Dose for Pharmacokinetic and Pharmacodynamic Similarity Studies in Biosimilar Development.

This study applied modeling and simulation (M&S) approaches to evaluate the sensitivity of pegfilgrastim pharmacokinetics (PKs) and pharmacodynamics (PDs) to changes in dose amount, and linear or nonlinear clearance (CL) over pegfilgrastim subcutaneous dose of 2-6 mg. A previously published model was adapted to better describe pegfilgrastim PK and PD data in healthy subjects and used in simulation. Nonlinear CL accounts for 98% and 77%, respectively, of the total CL of pegfilgrastim at 2 and 6 mg. The sensitivity analyses showed: (i) PK of 2 and 6 mg doses are similarly sensitive to detect differences for a 5% change in dose; (ii) PK of 2 mg dose is more sensitive to changes in receptor binding affinity, a model parameter for nonlinear CL, and a product quality attribute characterized with orthogonal methods as part of demonstrating analytical similarity between products; (iii) PK of approved 6 mg dose is more sensitive to changes in linear CL, which has not been associated with any specific product quality attributes, and (iv) the PDs are not sensitive to changes in linear or nonlinear CL. Taken together, our analyses support that the approved pegfilgrastim dose of 6 mg is appropriate for detecting differences between a biosimilar and the reference products in pegfilgrastim PK and PD similarity studies. The described M&S approaches can be adopted to support dose selection for biosimilars with nonlinear PK and complex PK-PD interplay.

A PID Control Method Based on Internal Model Control to Suppress Vibration of the Transmission Chain of Wind Power Generation System

Vibrations occur in the wind turbine drivetrain due to the drivetrain’s elasticity and gear clearance. Typically, the PID control method is used to suppress elastic vibration, while the method with the disturbance suppression function is used to suppress nonlinear gear clearance vibration. The purpose of this paper is to propose an equivalent PID control method based on the internal model control (IMC) for suppressing vibration caused by the wind turbine drivetrain’s elasticity and gear clearance. The equivalent PID controller can suppresses elastic vibration; the IMC controller can suppresses gear clearance vibration. First, the vibration principle of the two-mass wind turbine drivetrain with clearance is discussed. After analyzing the nonlinear characteristics of the gear clearance, the nonlinear clearance system is decomposed into a linear unit and a nonlinear bounded disturbance unit. To suppress nonlinear bounded disturbances, a disturbance suppression method based on IMC is proposed; simultaneously, an equivalent PID controller based on IMC is designed to resolve the vibration issue caused by the wind turbine drivetrain’s elasticity. The simulation experimental results show that the clearance vibration is suppressed by the original IMC method. The PID controller obtained by the IMC equivalent transformation can suppress the elastic vibration.