Pharmacodynamic Model Research Articles

PK/PD Modeling to Inform Clinical Development of an Adeno-associated Virus Gene Transfer Therapy for Duchenne Muscular Dystrophy (S48.005)

<h3>Objective:</h3> To evaluate the pharmacokinetic (PK)/pharmacodynamic (PD) relationship between tissue vector genome exposure, biological efficacy and functional outcome in an animal model of Duchenne muscular dystrophy (DMD) (DMD^mdx mice) following treatment with delandistrogene moxeparvovec (SRP-9001). <h3>Background:</h3> Delandistrogene moxeparvovec is an investigational gene transfer therapy developed to address the root cause of DMD through targeted skeletal and cardiac muscle expression of SRP-9001 dystrophin protein, which contains key functional domains of dystrophin. <h3>Design/Methods:</h3> We evaluated vector biodistribution, expression, and clinical dose selection of delandistrogene moxeparvovec using a novel application of a PK and PD modeling approach applied to data collected from DMD^mdx mice. We analyzed PK/PD relationships between dose, tissue vector genome exposure, SRP-9001 dystrophin protein expression (percent dystrophin positive fibers [PDPF] and western blot), and functional improvement (relative specific force from tibialis anterior and diaphragm). <h3>Results:</h3> Linear kinetics with a dose-proportional increase in tissue drug exposure were demonstrated across the nearly 10-fold dose range (4.43×10¹³–4.01×10¹⁴ vg/kg), and in all tissues. The relationship between tissue vector exposure and PD endpoints (PDPF, motor function outcome) showed a saturable response across a wide range of vector exposures. The vector exposure at 1.33×10¹⁴ vg/kg (the clinical dose) approached the maximum treatment response. Relative specific force and PDPF were significantly correlated (<i>P</i>=4.43×10⁻⁶). However, the relationship appeared to be nonlinear, with increased PDPF expression approaching the maximal functional improvement. Relative specific force and western blot were not significantly correlated. <h3>Conclusions:</h3> For the first time, biodistribution, biomarker and functional efficacy data were used to quantify and demonstrate PK/PD relationships for an adeno-associated virus (AAV)-based gene transfer therapy in a DMD animal model. The results continue to support the expected therapeutic benefit and clinical dose of delandistrogene moxeparvovec, an AAV-based gene transfer therapy. <b>Disclosure:</b> Mrs. East has received personal compensation for serving as an employee of Sarepta Therapeutics. Rachael Potter has received stock or an ownership interest from Sarepta Therapeutics. Dr. Snedeker has received personal compensation for serving as an employee of Sarepta Therapeutics. Dr. Snedeker has stock in Sarepta Therapeutics. Dr. Haile has nothing to disclose. Christopher Wier has received personal compensation for serving as an employee of Sarepta Therapeutics. Christopher Wier has stock in Sarepta Therapeutics. Ms. Rodino-Klapac has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc.. Ms. Rodino-Klapac has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received intellectual property interests from a discovery or technology relating to health care.

Haemoglobin response modelling under erythropoietin treatment: Physiological model‐informed machine learning method

AbstractPatients with renal anaemia are usually treated with recombinant human erythropoietin (EPO) because of insufficient renal EPO secretion. The establishment of a good haemoglobin (Hgb) response model is a necessary condition for dose optimization design. The purpose of this paper is to apply physics‐informed neural networks (PINN) to build the Hgb response model under EPO treatment. Neural network training is guided by a physiological model to avoid overfitting problems. During the training process, the parameters of the physiological model can be estimated simultaneously. To handle differential equations with impulse inputs and time delays, we propose approximate model equations for the pharmacokinetic (PK) model and the pharmacodynamic (PD) model, respectively. The modified PK/PD model was incorporated into PINN for training. Tests on simulated data and clinical data show that the proposed method has better performance than data‐driven modelling methods and the traditional physiological modelling based on the least squares method.

Physiologically based pharmacokinetic and pharmacodynamic modelling of alprazolam: Implications for anxiety and addiction.

Alprazolam is an anxiolytic compound that can lead to psychological and physiological dependence especially with prolonged use. This study utilized physiologically based pharmacokinetic (PK) and pharmacodynamic (PD) modelling to further examine the underlying mechanisms of anxiety treatment and addiction. Data and parameter values for this study were obtained from PubMed and DrugBank literature searches. The physiologically based PK models for alprazolam were developed using PK-Sim software and PD models were implemented with the MonolixSuite 2021R platform. After single administrations, peak unbound interstitial brain concentrations range from 4 to 33 nM for 0.25-2mg-doses of the immediate-release form and 3-54 nM for 0.5-10-mg doses of the extended-release form. With repetitive administrations, peak concentration is 59 nM for a 2-mg alprazolam immediate-release dose and 122 nM for a 10-mg extended-release dose. Potentiation of EC10 GABA-gated currents from recombinant GABAA Rs composed of α1β2γ2, α2β3γ2 and α5β3γ2 subunit combinations is 92, 150 and 75%, respectively, for an alprazolam concentration of 59 nM. The 10-90% rise times for the brain concentration-time profile following a single 1-mg immediate-release administration is 22.8min and 3.8h for a 3-mg extended-release administration. Unbound interstitial brain concentration-time profiles of alprazolam corresponded to changes in β rhythm activity, peak saccade velocity, mood improvement, cognitive speed slowing and digit symbol substitution test scores. PD models for these endpoints suggest that alprazolam immediate-release maximal effects on cognitive slowing, cognitive impairment, sedation and mood improvement occur sequentially following the brain concentration-time profile.

In vitro and ex vivo antibacterial activity of levofloxacin against Pasteurella multocida and Escherichia coli isolated from rabbits (Oryctolagus cuniculus) - A preliminary study.

Levofloxacin veterinary formulations are available in Argentina, China and India for the use in dogs, cattle, pig and sheep, but not currently in the rabbit. Only the extra-label use in rabbits is possible. Levofloxacin is not labelled for veterinary use in the EU or the USA. The activity of levofloxacin against rabbit pathogens Pasteurella multocida (P. multocida) and Escherichia coli (E. coli) was evaluated. Minimum inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were determined in broth and serum for 10 P. multocida isolates and 5 E. coli isolates from rabbits. One isolate of each bacterial species was used for the time-killing curve study in vitro and ex vivo. In vitro AUC24 /MIC ratios were used for building the inhibitory pharmacodynamic Imax model. The P. multocida MIC were 0.008-0.5 μg/mL, MBC - 0.015-0.5 μg/mL. Escherichia coli MIC was 0.008-0.03 μg/mL and MBC - 0.03-0.25 μg/mL. Bacterial counts were reduced to the limit of detection after 24 h with levofloxacin concentrations of 2 MIC and higher. All serum samples from rabbits treated with levofloxacin eliminated the bacteria within 24 h. AUC24 /MIC ratios for bacteriostatic, bactericidal and bacterial elimination effects for P. multocida and E. coli isolates were 21, 29 and 75 h and 27, 32 and 60 h, respectively. Proposed daily doses against P. multocida (MIC = 0.015 μg/mL) and E. coli (MIC = 0.03 μg/mL) isolates were calculated as ≤0.91 and ≤1.43 mg/kg, respectively. Fluoroquinolones are categorized by WHO as 'highest priority critically important antimicrobials'. Considering the increasing importance of antimicrobial stewardship, antimicrobials from a lower importance category that are active against the isolate of interest should be used in preference to fluoroquinolones. Fluoroquinolone use in veterinary medicine should be based on antimicrobial susceptibility testing in order to mitigate the risk to public health and prevent the spread of bacterial resistance.

Abstract LB318: SB-4826, a first-in-class oral, covalent inhibitor of SUMO E1 that induces IFN signaling and inhibits tumor growth as monotherapy and in combination with immune checkpoint blockade

Abstract Sumoylation is a reversible post-translational modification of proteins by small ubiquitin-like modifier (SUMO) that regulates protein function and contributes to cellular response to stress. Sumoylation is an essential pathway for all cells and is involved in diverse processes such as inflammation, DNA damage response, signaling and cell survival/apoptosis. Due to its involvement in such cellular functions, sumoylation intersects with the majority of the hallmarks of cancer. Many cancers display elevated expression of SUMO pathway components, a mechanism co-opted by tumors to survive under stressful conditions. In addition to its tumor intrinsic functions, sumoylation has emerged as a novel target for activating anti-tumor immunity due to its role in regulating type I interferon (IFN) signaling. Targeting sumoylation is a compelling anti-cancer strategy due to the multiple mechanisms of action that may drive anti-tumor activity for cancer patients. We report the discovery of SB-4826, a novel, orally active, covalent small molecule inhibitor of the Sumo Activating Enzyme (SUMO E1), the initiating enzyme of the sumoylation cascade. SB-4826 selectively and irreversibly binds an allosteric pocket of SUMO E1 and drives potent biochemical and cellular activity. SB-4826 inhibits global sumoylation in cells and blocks proliferation across a broad panel (100+) of cancer cell lines. Cysteine-proteome profiling by mass spectrometry indicated that Cys-30 of SUMO E1 was the only cysteine-containing peptide (out of 14,541 measured) that met the criteria for covalent engagement indicating exquisite selectivity across the cellular proteome. In an in vivo pharmacodynamic model measuring IFN signaling SB-4826 treatment led to dose- and time-dependent induction of IFN regulated cytokines. SB-4826 treatment resulted in significant tumor growth inhibition in multiple in vivo models. In a syngeneic A20 lymphoma model SB-4826 led to tumor stasis. In a human RAJI xenograft model, SB-4826 induced near-complete inhibition of tumor growth as a single agent and resulted in tumor regression when combined with rituximab. In a mouse CT-26 colorectal tumor model which is generally refractory to anti-PD-1 treatment, SB-4826 significantly inhibited tumor growth as monotherapy and led to 60% complete tumor responses when combined with anti-PD-1. SB-4826 caused increased CD8+ T cell infiltration in CT-26 tumors supporting the role of SB-4826 in inducing IFN signaling and leading to a tumor microenvironment that is more responsive to immune checkpoint inhibition. SUMO E1 is a clinically validated cancer target as evidenced by recent data showing encouraging responses to TAK-981, an IV-administered, ATP-competitive inhibitor. SB-4826 is a differentiated and optimized SUMO E1 inhibitor that is administered orally and demonstrated improved activity in preclinical models. SB-4826 has favorable properties for development, is a new and promising cancer therapy, and is entering phase 1 clinical studies in 2023. Citation Format: Jude R. Canon, Ashley Callinan, Sarah Bradley, Laurie Wang, Mackenzie Kui, Ariel Wein, Gabriele Sulli, Peter Buchowiecki, Fang-Tsao Hong, Miles Kubota, Mary Walton, Victor J. Cee. SB-4826, a first-in-class oral, covalent inhibitor of SUMO E1 that induces IFN signaling and inhibits tumor growth as monotherapy and in combination with immune checkpoint blockade [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 LB318.

Pharmacodynamic-Mediated Drug Disposition (PDMDD) Model of Daratumumab Monotherapy in Patients with Multiple Myeloma.

We aimed to quantify the daratumumabconcentration- and CD38 dynamics-dependent pharmacokinetics using a pharmacodynamic mediated disposition model (PDMDD) in patients with multiple myeloma (MMY) following daratumumab IV or SC monotherapy. Daratumumab, a human IgG monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action, has been approved to treat patients with multiple myeloma (MM). In total, 7788 daratumumab plasma samples from 850 patients with diagnosis of MMY were used. The serum concentration-time data of daratumumab were analysed using nonlinear mixed-effects modeling with NONMEM®. The PDMDD with quasi steady-state approximation (QSS) was compared to the previously developed Michaelis-Menten (MM) approximation with respect to the parameter estimates, the goodness-of-fit plots and prediction-corrected visual predictive check, as well as model-based simulations. The effect of patients' covariates on daratumumab pharmacokinetics was also investigated. The QSS approximation characterized the concentration- and CD38 dynamics-dependency of daratumumab pharmacokinetics within the doses ranging from 0.1 to 24 mg/kg after IV administration and 1200 and 1800 mg after SC administration in patients with MMY, mechanistically describing the binding of daratumumab and CD38, the internalization of the daratumumab-CD38 complex and the CD38 turnover. Compared to the previously developed MM approximation, the MM approximation with the non-constant total target and dose-correction provided substantial improvement of the model fit, but it was still not as good as the QSS approximation. The effect of the previously identified covariates as well as the newly identified covariate (baseline M protein) on daratumumab pharmacokinetics was confirmed, but the magnitude of the effect was deemed not clinically relevant. Accounting for the CD38 turnoverand its binding capacity to daratumumab, the QSS approximation provided a mechanistic interpretation of daratumumab PK parameters and consequently well described the concentration- and CD38 dynamics-dependency of daratumumab pharmacokinetics. CLINICAL STUDIES INCLUDED IN THE ANALYSIS WERE REGISTERED WITH THE NCT NUMBER BELOW AT HTTP://WWW. GOV : MMY1002 (ClinicalTrials.gov: NCT02116569), MMY1003 (NCT02852837), MMY1004 (NCT02519452), MMY1008 (NCT03242889), GEN501 (NCT00574288), MMY2002 (NCT01985126), MMY3012 (NCT03277105).

Abstract 2643: BL-M07D1, a novel HER2-targeting ADC, demonstrates potent anti-tumor efficacy in preclinical pharmacodynamic models

Abstract HER2 is a member of the epidermal growth factor receptor family. Activation of the HER2 signaling pathway has been shown to strongly promote carcinogenesis. It is therapeutically targeted in cancer owing to its overexpression and pathway dependence in a variety of human carcinomas, especially human breast cancers. We created a promising therapeutic anti-tumor agent, BL-M07D1, an anti-HER2-Ed-04 ADC. It is comprised of a humanized anti-HER2 antibody Trastuzumab, a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04), which is a derivative of the alkaloid camptothecin, driving cell cycle arrest at the S phase and subsequent apoptosis. The BL-M07D1 drug-to-antibody-ratio is 8:1 (DAR=8), similar to Trastuzumab Deruxotecan (DS-8201), while possessing a more stable linker. To evaluate the pharmacological potential of BL-M07D1, xenograft tumor inhibition assays were used to compare BL-M07D1 with the commercialized HER2-targeting ADCs, T-DM1 and DS-8201, which have been approved worldwide for patients with HER2-expressing tumors. Results from the in vivo murine studies show that BL-M07D1 has strong tumor inhibition effects in multiple cell line-derived xenograft (CDX) tumor models. 1) BL-M07D1 exhibited better anti-tumor efficacy than DS-8201 in CDX with low HER2 expression, human epidermal cancer A431 and human non-small cell lung cancer NCI-H1975. Both models are considered be T-DM1-insensitive. 2) BL-M07D1 exhibited better anti-tumor efficacy in comparison to either T-DM1 or DS-8201 in a CDX with JIMT-1, a HER2-positive human breast cancer cell line. 3) BL-M07D1 exhibits potent bystander effects in a heterogeneous xenograft model of HER2-positive and HER2-negative tumor cells composed of NCI-N87 and MDA-MB-468 cells. In this model, BL-M07D1 exhibited stronger tumor inhibition than T-DM1, consistent with bystander effects that are also exhibited by DS-8201. In conclusion, in vivo studies suggest that BL-M07D1, a novel HER2-targeting ADC, is potentially more efficacious in a broader patient population than T-DM1, and mediate superior anti-tumor efficacy than DS-8201. The clinical phase I is under way and the available data exhibit excellent efficacy in breast cancer therapy with acceptable tolerability. Citation Format: Weili Wan, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Gangrui Li, Jahan Salar Khalili, Sa Xiao, Yongqi Yan, Xuejiao Shen, Yi Zhu. BL-M07D1, a novel HER2-targeting ADC, demonstrates potent anti-tumor efficacy in preclinical pharmacodynamic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2643.

Review of the pharmacokinetics of nanodrugs

Abstract Nanodrug delivery systems (NDDSs) are a hotspot of new drug delivery systems with great development potential. They provide new approaches to fighting against diseases. NDDSs are specially designed to serve as carriers for the delivery of active pharmaceutical ingredients to their target sites, and their unique physicochemical characteristics allow for prolonged circulation time, improved targeting, and avoidance of drug resistance. Despite remarkable progress achieved in the preparation and efficacy evaluation of NDDSs, the understanding of the in vivo pharmacokinetics of NDDSs is still insufficient. Analysis of NDDSs is far more complicated than that for small molecular drugs; thus, almost all conventional techniques are inadequate for accurate profiling of their pharmacokinetic behaviour in vivo. In this article, we systematically reviewed the absorption, distribution, metabolism, and excretion of NDDSs and summarized the advanced bioanalytic techniques for tracing the in vivo fate of NDDSs. We also reviewed the physiologically based pharmacokinetic model of NDDS, which has been a useful tool in characterizing and predicting the systemic disposition, target exposure, and efficacy/toxicity of various types of drugs when coupled with pharmacodynamic modelling. We hope that this review will be helpful in improving the understanding of NDDS pharmacokinetics and facilitating the development of NDDSs.

An exploratory analysis of the performance of methylphenidate regimens based on a PKPD model of dopamine and norepinephrine transporter occupancy.

Methylphenidate (MPH) is a psychostimulant which inhibits the uptake of dopamine and norepinephrine transporters, DAT and NET, and is mostly used to treat Attention Deficit/Hyperactivity Disorder. The current dose optimization is done through titration, a cumbersome approach for patients. To assess the therapeutic performance of MPH regimens, we introduce an in silico framework composed of (i) a population pharmacokinetic model of MPH, (ii) a pharmacodynamic (PD) model of DAT and NET occupancy, (iii) a therapeutic box delimited by time and DAT occupancy, and (iv) a performance score computation. DAT occupancy data was digitized (n = 152) and described with Emax models. NET occupancy was described with a KPD model. We used this integrative framework to simulate the performance of extended-release (18-99mg) and tid MPH regimens (25-40mg). Early blood samples of MPH seem to lead to higher DAT occupancy, consistent with an acute tolerance observed in clinical rating scales. An Emax model with a time-dependent tolerance was fitted to available data to assess the observed clockwise hysteresis. Peak performance is observed at 63mg. While our analysis does not deny the existence of an acute tolerance, data precision in terms of formulation and sampling times does not allow a definite confirmation of this phenomenon. This work justifies the need for a more systematic collection of DAT and NET occupancy data to further investigate the presence of acute tolerance and assess the impact of low MPH doses on its efficacy.

Pharmacokinetics and Pharmacodynamics of Anthocyanins after Administration of Tart Cherry Juice to Individuals with Gout.

Tart cherries (TCs) contain high levels of anthocyanins that exert potent antioxidant and antiinflammatory effects and potentially benefit individuals with gout. This study aims to quantitate the major anthocyanins in TC Juice Concentrate (TCJC) and identify the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of the major anthocyanin cyanidin-3-glucosylrutinoside (C3GR). A PK-PD study enrolling human subjects with a history of gout is performed. Subjects are randomized to receive either 60 or 120mL of TCJC. Anthocyanins are quantitated using liquid chromatography-mass spectroscopy (LCMS). Antioxidant and antiinflammatory mRNA expression is measured using real-time qPCR before and after the administration of TCJC. A population PK model (popPK) is fit to the experimental data, and an indirect PD model (IDR) is constructed in Monolix. Of the bioavailable anthocyanins, C3GR achieves the highest plasma concentration in a dose-dependent manner. A popPK predicts anthocyanin exposure, and an IDR produces reasonable approximations of PD effects.

Establishment of a fexofenadine population pharmacokinetic (PK)–pharmacodynamic (PD) model and exploration of dosing regimens through simulation

Establishment of a fexofenadine population pharmacokinetic (PK)–pharmacodynamic (PD) model and exploration of dosing regimens through simulation

Pharmacokinetic/Pharmacodynamic Analysis of Savolitinib plus Osimertinib in an EGFR Mutation-Positive, MET-Amplified Non-Small Cell Lung Cancer Model.

Osimertinib is a third-generation, irreversible, oral EGFR tyrosine kinase inhibitor (TKI) recommended as first-line treatment for patients with locally advanced/metastatic EGFR mutation-positive (EGFRm) non-small cell lung cancer (NSCLC). However, MET amplification/overexpression is a common acquired osimertinib resistance mechanism. Savolitinib is an oral, potent, and highly selective MET-TKI; preliminary data suggest that combining osimertinib with savolitinib may overcome MET-driven resistance. A patient-derived xenograft (PDX) mouse model with EGFRm, MET-amplified NSCLC was tested with a fixed osimertinib dose [10 mg/kg for exposures equivalent to (≈)80 mg], combined with doses of savolitinib (0-15 mg/kg, ≈0-600 mg once daily), both with 1-aminobenzotriazole (to better match clinical half-life). After 20 days of oral dosing, samples were taken at various time points to follow the time course of drug exposure in addition to phosphorylated MET and EGFR (pMET and pEGFR) change. Population pharmacokinetics, savolitinib concentration versus percentage inhibition from baseline in pMET, and the relationship between pMET and tumor growth inhibition (TGI) were also modeled. As single agents, savolitinib (15 mg/kg) showed significant antitumor activity, reaching ∼84% TGI, and osimertinib (10 mg/kg) showed no significant antitumor activity (34% TGI, P > 0.05 vs. vehicle). Upon combination, at a fixed dose of osimertinib, significant savolitinib dose-related antitumor activity was shown, ranging from 81% TGI (0.3 mg/kg) to 84% tumor regression (15 mg/kg). Pharmacokinetic-pharmacodynamic modeling showed that the maximum inhibition of both pEGFR and pMET increased with increasing savolitinib doses. Savolitinib demonstrated exposure-related combination antitumor activity when combined with osimertinib in the EGFRm MET-amplified NSCLC PDX model.

Deriving mechanism-based pharmacodynamic models by reducing quantitative systems pharmacology models: An application to warfarin.

Quantitative systems pharmacology (QSP) models integrate comprehensive qualitative and quantitative knowledge about pharmacologically relevant processes. We previously proposed a first approach to leverage the knowledge in QSP models to derive simpler, mechanism-based pharmacodynamic (PD) models. Their complexity, however, is typically still too large to be used in the population analysis of clinical data. Here, we extend the approach beyond state reduction to also include the simplification of reaction rates, elimination of reactions, and analytic solutions. We additionally ensure that the reduced model maintains a prespecified approximation quality not only for a reference individual but also for a diverse virtual population. We illustrate the extended approach for the warfarin effect on blood coagulation. Using the model-reduction approach, we derive a novel small-scale warfarin/international normalized ratio model and demonstrate its suitability for biomarker identification. Due to the systematic nature of the approach in comparison with empirical model building, the proposed model-reduction algorithm provides an improved rationale to build PD models also from QSP models in other applications.

Pharmacodynamic Modeling Identifies Synergistic Interaction Between Chloroquine and Trastuzumab in Refractory HER2- positive Breast Cancer Cells.

Despite improvements in HER2-positive breast cancer (BC) patients' outcomes with trastuzumab, the occurrence of intrinsic or acquired resistance presents a clinical challenge. Here, we quantitatively assess the combinatorial effects of chloroquine, an autophagy inhibitor, with trastuzumab on JIMT-1 cells, a HER2-positive BC cell-line primarily resistant to trastuzumab. The temporal changes in JIMT-1 cellular viability were assessed using the CCK-8 kit, where JIMT-1 cells were exposed for 72-h to trastuzumab (0.007-17.19 μM) or chloroquine (5-50 μM) as single-agents, in combination (trastuzumab: 0.007-0.688 μM; chloroquine: 5-15 μM), or control (no drug). Concentration-response relationships were built for each treatment arm to determine drugs' concentrations inducing 50% of cell-killing (IC50). Cellular pharmacodynamic models were built to characterize the time-trajectory of JIMT-1 cellular viability under each treatment arm. The nature of trastuzumab and chloroquine interaction was quantified by estimating the interaction parameter (Ψ). The IC50 were estimated at 19.7 and 24.4 μM for trastuzumab and chloroquine. The maximum killing effect was about thrice higher for chloroquine than trastuzumab (0.0405 vs. 0.0125 h-1), validating chloroquine's superior anti-cancer effect on JIMT-1 cells compared to trastuzumab. The time-delay for chloroquine cell-killing was twice longer than that for trastuzumab (17.7 vs. 7 h), suggesting a chloroquine time-dependent anti-cancer effect. The Ψ was determined at 0.529 (Ψ<1), indicating a synergistic interaction. This proof-of-concept study on JIMT-1 cells identified chloroquine and trastuzumab synergistic interaction, warranting further in vivo investigations.

Preconditioning for the integration of a spatiotemporal pharmacodynamic system

AbstractWe address efficient modeling of the intracellular action of a drug binding to the nuclear pregnane X receptor. The binded complex enters the cell nucleus and acts on DNA, resulting in enhanced production of an enzyme which metabolizes, among others, co‐administered drugs. Pharmacodynamic modeling is traditionally based on a compartmental approach, which simplifies the complex processes in the human body through the definition of a small number of compartments representing organs, tissues, cells, cytoplasm or abstract units. Inside a compartment, the concentrations of all substances are assumed to be distributed homogeneously, i.e. there is no spatial dependence. They lead to a system of ODEs for the time‐dependence of the concentrations of the active substances. We will present an extension of a model from the literature for the action of the tuberculose‐drug Rifampicin. The extension consists of a first attempt to add spatial resolution for substances that are active in the cytoplasm. Spatial resolution can be benecifial to analyze important issues like, among others, local exceeding of toxic drug levels, delay of transport and drug‐drug interactions. We address efficient solution of the linear systems arising when numerically integrating the resulting PDE's and consider some preconditioning techniques based on properties of the underlying biochemical network.

Abstract OT1-03-06: Phase 1b/2 study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of triple-negative breast cancer (SGNLVA-002, trial in progress)

Abstract Background Patients with metastatic triple-negative breast cancer (mTNBC) have a poor prognosis. Treatment combinations of anti-programmed death protein 1 (anti–PD-1) agents with chemotherapy have shown promise in mTNBC. Ladiratuzumab vedotin (LV) is an investigational antibody-drug conjugate directed to LIV-1, a protein highly expressed on breast cancer cells, via a humanized IgG1 monoclonal antibody conjugated to approximately 4 molecules of monomethyl auristatin E (MMAE) by a protease-cleavable linker. LIV-1–mediated delivery of MMAE disrupts microtubules and induces cell cycle arrest and apoptosis. LV has also been shown to drive immunogenic cell death (ICD) to elicit an immune response. LV + pembrolizumab may result in synergistic activity through LV-induced ICD, creating a microenvironment favorable for enhanced anti–PD-1 activity. Interim results from an ongoing, multi-part, open-label study investigating the safety and efficacy of LV in patients with metastatic breast cancer (SGNLVA-001, NCT01969643), showed weekly LV monotherapy at doses up to 1.5 mg/kg were clinically active and generally well tolerated (Tsai 2021). Based on pharmacokinetic and pharmacodynamic modeling and simulation analysis, an intermittent LV + pembrolizumab dosing regimen is being evaluated to further enhance efficacy and improve the tolerability profile. Due to an unmet medical need for patients with unresectable locally advanced (LA)/mTNBC who are programmed death ligand 1 (PD-L1) low or negative, Part D will focus on this patient population. Trial Design SGNLVA-002 (NCT03310957) is an ongoing global single-arm, open-label phase 1b/2 study of LV + pembrolizumab as 1L therapy for patients with unresectable LA/mTNBC. Part D is currently enrolling ~40 patients. Eligible patients must have advanced disease with no prior cytotoxic/anti–PD-1 treatment, PD-L1 combined positive score &amp;lt; 10, measurable disease per RECIST v1.1, and an ECOG performance status ≤1. Patients with Grade ≥2 pre-existing neuropathy or active central nervous system metastases are not permitted. Patients will receive LV at 1.5 mg/kg on Days 1 and 8 every 21 days plus pembrolizumab 200 mg on Day 1 q3w. The primary objectives are to evaluate the safety/tolerability and objective response rate of LV + pembrolizumab. Secondary objectives include duration of response, disease control rate, progression-free survival, and overall survival. Safety and efficacy endpoints will be summarized with descriptive statistics. Global enrollment is ongoing in the US, EU, and Asia. Citation Format: Patrick Dillon, Reva Basho, Hyo S. Han, Hans-Christian Kolberg, Katherine Tkaczuk, George Zahrah, Maria Gion, Herman Voss, Jane Meisel, Timothy Pluard, Jenny Fox, Mafalda Oliveira, Ursa Brown-Glaberman, Erica Stringer-Reasor, Luis Manso, Sherko Küemmel, Lin Chi Chen, Sheng Wu, Brandon Croft, Valentina Boni. Phase 1b/2 study of ladiratuzumab vedotin (LV) in combination with pembrolizumab for first-line treatment of triple-negative breast cancer (SGNLVA-002, trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-03-06.

Population model-based analysis of the memory B-cell response following belimumab therapy in the treatment of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B-cell hyperactivity and breach of tolerance. Autoreactive memory B cells, which have a decreased activation threshold and the ability to survive in absence of antigen, are believed to contribute to chronicity in autoimmune diseases like SLE. Belimumab, the first approved biological treatment of active SLE and lupus nephritis, reduces B cells dependent on B-lymphocyte stimulator protein (BLyS) for survival, whereas memory B cells are spared; several studies reported circulating memory B-cell concentrations increase following BLyS neutralization. This analysis investigated the effect of dose, demographics, and disease status on memory B-cell response after starting belimumab treatment. Population pharmacodynamic models were fitted to a pooled dataset from seven belimumab SLE trials. The optimal model was selected using maximum likelihood methods and was then refit to the data using Bayesian analysis and used to simulate memory B-cell response by belimumab dose and covariate subgroups. At the belimumab approved doses (10mg/kg intravenously every 4 weeks, 200 mg subcutaneously every week), circulatory memory B cells increase in the first 4-8 weeks after belimumab initiation, typically returning to baseline levels over 76 weeks. The model analysis suggested belimumab stimulates memory B-cell transition from lymphoid and/or inflamed tissues into the circulation, rather than inhibiting trafficking in the reverse direction. Baseline BLyS and anti-double-stranded deoxyribonucleic acid antibody concentrations were statistically identifiable covariates of memory B-cell response, although their impact on predicting size and response duration was small.

Prediction of the Drug-Drug Interaction Potential between Tegoprazan and Amoxicillin/Clarithromycin Using the Physiologically Based Pharmacokinetic and Pharmacodynamic Model.

Tegoprazan is a novel potassium-competitive acid blocker. This study investigated the effect of drug-drug interaction on the pharmacokinetics and pharmacodynamics of tegoprazan co-administered with amoxicillin and clarithromycin, the first-line therapy for the eradication of Helicobacter pylori, using physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) modeling. The previously reported tegoprazan PBPK/PD model was modified and applied. The clarithromycin PBPK model was developed based on the model provided by the SimCYP® compound library. The amoxicillin model was constructed using the middle-out approach. All of the observed concentration-time profiles were covered well by the predicted profiles with the 5th and 95th percentiles. The mean ratios of predicted to observed PK parameters, including the area under the curve (AUC), maximum plasma drug concentration (Cmax), and clearance, were within the 30% intervals for the developed models. Two-fold ratios of predicted fold-changes of Cmax and AUC from time 0 to 24 h to observed data were satisfied. The predicted PD endpoints, including median intragastric pH and percentage holding rate at pH above 4 or 6 on day 1 and day 7, were close to the corresponding observed data. This investigation allows evaluation of the effects of CYP3A4 perpetrators on tegoprazan PK and PD changes, thus providing clinicians with the rationale for co-administration dosing adjustment.

Population Pharmacokinetic and Pharmacodynamic Analysis of Valganciclovir for Optimizing Preemptive Therapy of Cytomegalovirus Infections in Kidney Transplant Recipients.

This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model of valganciclovir for preemptive therapy of cytomegalovirus (CMV) infection in kidney transplant patients. A population PK/PD model was developed with Monolix. Ganciclovir concentrations and CMV viral loads were obtained retrospectively from kidney transplant patients receiving routine clinical care. Ten thousand Monte Carlo simulations were performed with the licensed dosages adjusted for renal function to assess the probability of attaining a viral load target of ≤290 and ≤137 IU/mL. Fifty-seven patients provided 343 ganciclovir concentrations and 328 CMV viral loads for PK/PD modeling. A one-compartment pharmacokinetic model coupled with an indirect viral turnover growth model with stimulation of viral degradation pharmacodynamic model was devised. Simulations showed that 1- and 2-log10 reduction of CMV viral load mostly occurred between a median of 5 to 6 and 12 to 16 days, respectively. The licensed dosages achieved a probability of reaching the viral load target ≥90% at days 35 to 49 and 42 to 56 for the thresholds of ≤290 and ≤137 IU/mL, respectively. Simulations indicate that in patients with an estimated glomerular filtration rate of 10 to 24 mL/min/1.73m2, a dose increase to 450 mg every 36 h may reduce time to optimal viral load target to days 42 and 49 from a previous time of 49 and 56 days for the thresholds of ≤290 and ≤137 IU/mL, respectively. Currently licensed dosages of valganciclovir for preemptive therapy of CMV infection may achieve a viral load reduction within the first 2 weeks, but treatment should continue for ≥35 days to ensure viral load suppression.

Considerations for Intravenous Anesthesia Dose in Obese Children: Understanding PKPD.

The intravenous induction or loading dose in children is commonly prescribed per kilogram. That dose recognizes the linear relationship between volume of distribution and total body weight. Total body weight comprises both fat and fat-free mass. Fat mass influences the volume of distribution and the use of total body weight fails to recognize the impact of fat mass on pharmacokinetics in children. Size metrics alternative to total body mass (e.g., fat-free and normal fat mass, ideal body weight and lean body weight) have been proposed to scale pharmacokinetic parameters (clearance, volume of distribution) for size. Clearance is the key parameter used to calculate infusion rates or maintenance dosing at steady state. Dosing schedules recognize the curvilinear relationship, described using allometric theory, between clearance and size. Fat mass also has an indirect influence on clearance through both metabolic and renal function that is independent of its effects due to increased body mass. Fat-free mass, lean body mass and ideal body mass are not drug specific and fail to recognize the variable impact of fat mass contributing to body composition in children, both lean and obese. Normal fat mass, used in conjunction with allometry, may prove a useful size metric but computation by clinicians for the individual child is not facile. Dosing is further complicated by the need for multicompartment models to describe intravenous drug pharmacokinetics and the concentration effect relationship, both beneficial and adverse, is often poorly understood. Obesity is also associated with other morbidity that may also influence pharmacokinetics. Dose is best determined using pharmacokinetic-pharmacodynamic (PKPD) models that account for these varied factors. These models, along with covariates (age, weight, body composition), can be incorporated into programmable target-controlled infusion pumps. The use of target-controlled infusion pumps, assuming practitioners have a sound understanding of the PKPD within programs, provide the best available guide to intravenous dose in obese children.