Therapeutic Dose Levels Research Articles

Identifying SCS Trial Responders Immediately After Postoperative Programming with ECAP Dose-Controlled Closed-Loop Therapy.

Drawbacks of fixed-output spinal cord stimulation (SCS) screening trials may lead to compromised trial outcomes and poor predictability of long-term success. Evoked compound action potential (ECAP) dose-controlled closed-loop (CL) SCS allows objective confirmation of therapeutic neural activation and pulse-to-pulse stimulation adjustment. We report on the immediate patient-reported and neurophysiologic treatment response post-physiologic CL-SCS and feasibility of early SCS trial responder prediction. Patient-reported pain relief, functional improvement, and willingness to proceed to permanent implant were compared between the day of the trial procedure (Day 0) and end of trial (EOT) for 132 participants in the ECAP Study undergoing a trial stimulation period. ECAP-based neurophysiologic measurements from Day 0 and EOT were compared between responder groups. A high positive predictive value (PPV) was achieved with 98.4% (60/61) of patients successful on the Day 0 evaluation also responding at EOT. The false-positive rate (FPR) was 5.6% (1/18). ECAP-based neurophysiologic measures were not different between patients who passed all Day 0 success criteria ("Day 0 successes") and those who did not ("needed longer to evaluate the therapy"). However, at EOT, responders had higher therapeutic usage and dose levels compared to non-responders. The high PPV and low FPR of the Day 0 evaluation provide confidence in predicting trial outcomes as early as the day of the procedure. Day 0 trials may be beneficial for reducing patient burden and complication rates associated with extended trials. ECAP dose-controlled CL-SCS therapy may provide objective data and rapid-onset pain relief to improve prognostic ability of SCS trials in predicting outcomes. The ECAP Study is registered with ClinicalTrials.gov (NCT04319887).

A sub-pharmacological test dose does not predict individual docetaxel exposure in prostate cancer patients.

Docetaxel is a cytotoxic drug used for first-line treatment of various malignancies. It has a narrow therapeutic index and shows wide interpatient variability in clearance and toxicity. Tools for individual dose optimization are needed to maximize efficacy and avoid toxicity. We performed a proof-of-concept study (EudraCT 2016-003785-77) to evaluate whether pharmacokinetics after a sub-pharmacological test dose of 1000µg docetaxel (millidose) could be used to predict therapeutic dose exposure. Thirty prostate cancer patients eligible for treatment with docetaxel as part of routine clinical care were included. An intravenous docetaxel millidose was administered 1-7 days prior to therapeutic docetaxel. After both doses plasma docetaxel concentrations were measured by ultra- high performance liquid chromatography-tandem mass spectrometry. The docetaxel clearance was estimated with non-linear mixed effects modeling. Geometric mean docetaxel clearance was 57.9L/h (GCV 78.6%) after admission of a millidose and 40.3L/h (GCV 60.7%) after admission of a therapeutic dose. The millidose and therapeutic dose in a single patient were not significantly correlated (Spearman's rho R = 0.02, P = 0.92). Docetaxel pharmacokinetics at milli- and therapeutic dose level showed insufficient correlation for individual dose optimization. However, the clearance of a docetaxel millidose and full dose are within the same order of magnitude. Therefore, docetaxel millidose pharmacokinetics could potentially facilitate prediction of docetaxel pharmacokinetics at a population level in situations where therapeutic dose levels are impractical, such as pharmacokinetic drug-drug interaction studies or pediatric studies.

Modern problems of preclinical studying feed additives for animals and ways to solve them

Resource-saving technology in agriculture is the use of stimulating additives in animal feeding rations that promote better absorption of feed. One of the measures to prevent toxicosis in industrial livestock and poultry farming is to determine the toxicity of feed. The variety of existing methods makes it possible to determine the level and class of drug toxicity at the initial stage. In the developed classification for veterinary drugs, the cumulation coefficient, therapeutic breadth index and dose level of toxic effect are used, which makes it possible to predict the nature and degree of their danger at the stage of preclinical study of feed additives. To determine the listed indicators, it is necessary to establish LD50and the cumulation coefficient. Since feed additives are introduced into the body through the digestive tract, during preclinical studies they are studied and classified according to their hepatotoxic effect. Bilirubin, albumin, and enzyme activity contained in the blood (glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and the ratio of alanine aminotransferase to alkaline phosphatase) are used as markers. It is necessary to determine the de Ritis, Schmidt coefficient and the R index. This will minimize the intake of toxic feed additives into the animals’ bodies and will contribute to an increase in their productivity.

From hazard to risk prioritization: a case study to predict drug-induced cholestasis using physiologically based kinetic modeling

Cholestasis is characterized by hepatic accumulation of bile acids. Clinical manifestation of cholestasis only occurs in a small proportion of exposed individuals. The present study aims to develop a new approach methodology (NAM) to predict drug-induced cholestasis as a result of drug-induced hepatic bile acid efflux inhibition and the resulting bile acid accumulation. To this end, hepatic concentrations of a panel of drugs were predicted by a generic physiologically based kinetic (PBK) drug model. Their effects on hepatic bile acid efflux were incorporated in a PBK model for bile acids. The predicted bile acid accumulation was used as a measure for a drug’s cholestatic potency. The selected drugs were known to inhibit hepatic bile acid efflux in an assay with primary suspension-cultured hepatocytes and classified as common, rare, or no for cholestasis incidence. Common cholestasis drugs included were atorvastatin, chlorpromazine, cyclosporine, glimepiride, ketoconazole, and ritonavir. The cholestasis incidence of the drugs appeared not to be adequately predicted by their Ki for inhibition of hepatic bile acid efflux, but rather by the AUC of the PBK model predicted internal hepatic drug concentration at therapeutic dose level above this Ki. People with slower drug clearance, a larger bile acid pool, reduced bile salt export pump (BSEP) abundance, or given higher than therapeutic dose levels were predicted to be at higher risk to develop drug-induced cholestasis. The results provide a proof-of-principle of using a PBK-based NAM for cholestasis risk prioritization as a result of transporter inhibition and identification of individual risk factors.

ACUTE AND SUB-ACUTE TOXICOLOGICAL STUDY OF VANGA BHASMA

Introduction: Vanga is a dhatu, that has been used externally since the Samhita period. During the rasa shastra era, vanga was utilized internally for Prameha, (urinary disorder ) Medoroga(diseases of medadhatu – fat tis-sue), Kapha Vikaras(diseases of kapha-bodily constitution ), and other purposes after Bhasmikara-na.(preaparation of Bhasma - medicine ) Objective: Evaluate Acute and Sub-acute toxicity of Vanga Bhasma. Materials &Methods: The acute and sub-acute toxicity studies of Vanga Bhasma were carried out on Wistar Albino rats using 425 and 407 OECD guidelines, respectively. Acute oral toxicity study of the test drug was car-ried out at the limit dose of 2000 mg/kg orally in rats. In a sub-acute toxicity study, Vanga bhasma was adminis-tered to rats for 28 consecutive days at doses of 22.5(TED-therapeutic equivalent dose), 112.5(TEDX5), and 225 mg/kg(TEDX10). The effects of the drug were assessed on haematological, biochemical, histological, and pon-deral parameters. Results: Acute toxicity: the study showed the LD 50 value of Vanga Bhasma is greater than 2000mg/kg. Sub-acute toxicity: this study did not produce any signs or symptoms of toxicity at TED, TEDX5, and TEDX10. Conclusion: The single dose of 2000mg/kg body weight evaluated by acute toxicity study is proved to be non-toxic. Overall analysis reveals that test drug vanga bhasma is very well tolerated at rat human therapeutic equivalent dose and multiples of it. Therefore, Vanga bhasma, prepared and administered in accord-ance with customary protocols, is safe to consume at therapeutic dose levels.

Abstract 2902: CA-4948 (emavusertib) improves treatment response of preclinical metastatic brain melanoma to anti-PD-1 immune checkpoint blockade

Abstract Background: Although recent advances in immunotherapy for metastatic melanoma have transformed the treatment paradigm for a disease that once carried a grim prognosis, nearly 50% of patients fail to reach a complete response to immune checkpoint blockade (ICB) due to multiple mechanisms of tumor-induced immune resistance. These challenges are amplified in the CNS tumor microenvironment (TME) where metastatic brain melanoma (MBM) demonstrates diminished clinical benefit to ICB treatment. A deeper understanding of these mechanisms are required to improve therapeutic response to ICB for these patients. Our group has previously identified that aberrant activation of the myddosomal cascade through downstream interleukin (IL)-1 receptor-associated kinase (IRAK-4) signaling results in chronic stimulation of MAPK and NF-κB in MBM. Further investigation reveals myddosome signaling emanates in large part from the TME, resulting in reflexive immune suppression. CA-4948 (emavusertib), a small molecule inhibitor of IRAK-4, is capable of reaching therapeutic dose levels in the brain where it demonstrates on-target inhibition of this pathway. These data highlight a unique therapeutic opportunity where selective inhibition of immune-suppressive signaling via targeted IRAK-4 blockade may sensitize MBM to anti-PD-1 ICB. Methods Multispectral imaging of patient MBM samples were analyzed for myddosome expression in the TME. Melanoma preclinical models, including both primary site (cutaneous) and metastatic brain disease, were evaluated for tumor burden and survival in response to CA-4948 treatment alone and in combination with anti-PD-1 ICB. Immunological responses of tumor to treatment were evaluated in two transgenic reporter models, CCR2RFPCX3CR1GFP and IFNγIRES-EYFP, to determine both the distribution and activation of infiltrating immune cells. Tumor-associated myeloid cells were assessed for phenotypic markers by multiparameter flow cytometry. Results Myddosome signaling was found to be elevated in tumor-associated immune cells in patient MBM specimens. Treatment of preclinical melanoma with CA-4948 combined with anti-PD-1 ICB resulted in significantly reduced tumor growth and improved survival in three independent models. CA-4948 treatment was associated with reduced tumor recruitment of peripherally derived tumor-associated macrophages, as well as increased lymphocyte infiltration and improved pro-inflammatory signaling measured by increased IFNγ expression in the combinatorial setting. Conclusion Targeted inhibition of IRAK-4 with CA-4948 improves immune surveillance and activation in preclinical models when combined with anti-PD-1 ICB, resulting in reduced tumor growth and increased survival. Thus, CA-4948 may be an effective adjuvant treatment strategy alongside anti-PD-1 ICB for the treatment of metastatic melanoma. Citation Format: Christina A. von Roemeling, Bently P. Doonan, Amanda M. Acevedo, Jeet A. Patel, Savannah L. Carpenter, Alisha Bhatia, Reinhard W. von Roemeling, Jamison Hoffman, Maureen Lane, Duane A. Mitchell. CA-4948 (emavusertib) improves treatment response of preclinical metastatic brain melanoma to anti-PD-1 immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2902.

A Phase 1 Trial of Salvage Stereotactic Body Radiation Therapy for Radiorecurrent Prostate Cancer After Brachytherapy

NCT03253744 is a phase 1 trial with the primary objective to identify the maximum tolerated dose (MTD) of salvage stereotactic body radiation therapy (SBRT) in patients with local prostate cancer recurrence after brachytherapy. Additional objectives included biochemical control and imaging response. This trial was initially designed to test 3 therapeutic dose levels (DLs): 40 Gy (DL1), 42.5 Gy (DL2), and 45 Gy (DL3) in 5 fractions. Intensity modulation was used to deliver the prescription dose to the magnetic resonance imaging and prostate-specific membrane antigen-based positron emission tomography imaging-defined gross tumor volume while simultaneously delivering 30 Gy to an elective volume defined by the prostate gland. This phase 1 trial followed a 3+3 design with a 3-patient expansion at the MTD. Toxicities were scored until trial completion at 2 years post-SBRT using Common Terminology Criteria for Adverse Events version 5.0. Escalation was halted if 2 dose limiting toxicities occurred, defined as any persistent (>4 days) grade 3 toxicity occurring within the first 3 weeks after SBRT or any grade ≥3 genitourinary (GU) or grade 4 gastrointestinal toxicity thereafter. Between August 2018 and January 2023, 9 patients underwent salvage SBRT and were observed for a median of 22 months (Q1-Q3, 20-43 months). No grade 3 to 5 adverse events related to study treatment were observed; thus, no dose limiting toxicities occurred during the observation period. Escalation was halted by amendment given excellent biochemical control in DL1 and DL2 in the setting of a high incidence of clinically significant late grade 2 GU toxicity. Therefore, the MTD was considered 42.5 Gy in 5 fractions (DL2). One- and 2-year biochemical progression-free survival were 100% and 86%, representing a single patient in the trial cohort with biochemical failure (prostate-specific antigen [PSA] nadir + 2.0) at 20 months posttreatment. The MTD of salvage SBRT for the treatment of intraprostatic radiorecurrence after brachytherapy was 42.5 Gy in 5 fractions producing an 86% 2-year biochemical progression-free survival rate, with 1 poststudy failure at 20 months. The most frequent clinically significant toxicity was late grade 2 GU toxicity.

Impact of <i>Amritikarana</i> Procedure on Safety Aspect of <i>Somanathi Tamra Bhasma</i>

Somanathi Tamra Bhasma is a unique method of preparation of Tamra Bhasma. In the classics, it is mentioned that if Tamra Bhasma has been used without Amritikarana in therapeutics, it produces ill effects. Hence it should be recommended after Amritikarana process only. Actual impact of this procedure in the preparation of Somanathi Tamra Bhasma has not evaluated till date. This is the first attempt towards preparing Somanathi Tamra Bhasma with Amritikarana (STBA) and evaluate its safety. Three batches of STBA were prepared as per the classical guidelines. In acute toxicity, STBA was administered at a maximal dose of 2000 mg/kg to overnight fasted rats and observed closely for behavioural changes, signs of toxicity and mortality if any, continuously for the first six hours and thereafter periodically up to 14 days. In the repeated dose 90-days oral toxicity evaluation, the test drug was administered daily at the doses of 67.5, 337.5 and 675 mg/kg along with Pippali Churna and honey as an adjuvant to rats for 90 days in divided dose followed by a 30-day recovery period. Animals were sacrificed on the 91st day and haematological, serum biochemical parameters and histopathology of organs were studied. In acute toxicity, STBA at the dose of 2000 mg/kg did not produce any observable toxic effects or mortality. STBA did not produce any significant changes in haematological, biochemical and histopathological parameters at TED and TED x 5 dose levels but mild fatty and inflammatory changes were observed in liver at TED x 10 dose level. These changes were returned to normal at recovery groups. Based on these observations, it can be concluded that STBA is safe at therapeutic dose levels when used judiciously along with specified adjuvants.

Ketoconazole as second-line treatment for Cushing's disease after transsphenoidal surgery: systematic review and meta-analysis.

The first-line treatment for Cushing's disease is transsphenoidal surgery for pituitary tumor resection. Ketoconazole has been used as a second-line drug despite limited data on its safety and efficacy for this purpose. The objective of this meta-analysis was to analyze hypercortisolism control in patients who used ketoconazole as a second-line treatment after transsphenoidal surgery, in addition to other clinical and laboratory criteria that could be related to therapeutic response. We searched for articles that evaluated ketoconazole use in Cushing's disease after transsphenoidal surgery. The search strategies were applied to MEDLINE, EMBASE, and SciELO. Independent reviewers assessed study eligibility and quality and extracted data on hypercortisolism control and related variables such as therapeutic dose, time, and urinary cortisol levels. After applying the exclusion criteria, 10 articles (one prospective and nine retrospective studies, totaling 270 patients) were included for complete data analysis. We found no publication bias regarding reported biochemical control or no biochemical control (p = 0.06 and p = 0.42 respectively). Of 270 patients, biochemical control of hypercortisolism occurred in 151 (63%, 95% CI 50-74%) and no biochemical control occurred in 61 (20%, 95% CI 10-35%). According to the meta-regression, neither the final dose, treatment duration, nor initial serum cortisol levels were associated with biochemical control of hypercortisolism. Ketoconazole can be considered a safe and efficacious option for Cushing's disease treatment after pituitary surgery. https://www.crd.york.ac.uk/prospero/#searchadvanced, (CRD42022308041).

Chronic toxicity studies of Tuttha bhasma (CuSO4.5H2O) in Wistar Albino Rats

Abstract
 Tuttha Bhasma (TB) is an important metal based drug used in Ayurveda. It has widespread therapeutic uses in the treatment of metabolic disorders. Despite of its therapeutic utility there is a lack of data related to its safety. Hence the present study was undertaken to evaluate chronic toxicity of TB in Wistar albino rats. Chronic toxicity study was conducted as per AYUSH guidelines 170 and the parameters such as ponderal changes; biochemical, hematological and histopathological examinations were recorded. Based on the overall toxicity profile significant changes in the serum SGPT was noted in therapeutic and higher dose levels. We could see the serum cholesterol, SGOT, SGPT and albumin levels were significantly elevated at lower dose compared to the control group. Histopathology of kidney showed cell infiltration and sections from liver showed mild to moderate fatty changes at higher dose levels. Histopathology of jejunum revealed there was mild to moderate epithelial erosion and shortening of epithelial layer. However overall toxicity study parameters showed the test drug TB is well tolerated and no dose dependent toxicity symptoms were observed. Based on the findings we could conclude that Tuttha bhasma is much safer to use at therapeutic dose level. However, at higher dose levels there are chances of organ toxicity.

Repeated dose 90-days oral toxicity study of Tala Sindura: An Ayurvedic mercuro-arsenical formulation

Abstract BACKGROUND: Tala Sindura is one such mercuro-arsenical formulation extensively used in Ayurvedic therapeutics without any noticeable side effects. Despite this, safety concerns have been raised on such Ayurveda formulations containing heavy metals such as mercury and arsenic as an integral component. So, there is a need to generate scientific evidences on safety aspects of such formulations to prove that they are safe and non-toxic. METHODS: In current study, safety profile of Tala Sindura has been evaluated through repeated dose 90-days oral toxicity study. Test drug was administered at TED (22.5 mg/kg), TED ×5 (112.5 mg/kg), TED ×10 (225 mg/kg), and RTED ×10 (225 mg/kg) orally once in a day for 90 days along with honey (vehicle) and distilled water in a dose of 5 mL/kg body weight. Safety of Tala Sindura was assessed on the basis of hematological, biochemical, and histopathological changes in Wistar albino rats. RESULTS: Tala Sindura did not produce any significant changes in hematological, biochemical and histopathological parameters at TED and TED ×5 dose levels. Mild cell infiltration with edematous changes were observed in kidney at TED ×10 dose level; however, these changes were reversed in recovery control. CONCLUSION: From the present study, it is concluded that Tala Sindura is safe for administration at therapeutic dose level when administered for 90 days in rats.

Colchicine attenuates the electrical remodeling of post-operative atrial fibrillation through inhibited expression of immune-related hub genes and stabilization of microtubules.

Rationale: Acute inflammation is a major risk factor for post-operative atrial fibrillation (POAF), and epicardial adipose tissue (EAT) is considered as a source of inflammatory mediators. However, underlying mechanisms and pharmacological targets of POAF are poorly understood. Methods: Integrative analysis of array data from EAT and right atrial appendage (RAA) samples was conducted to identify potential hub genes. Lipopolysaccharide (LPS)-stimulated inflammatory models in mice and in induced pluripotent stem cell-derived atrial cardiomyocytes (iPSC-aCMs) were used to examine the exact mechanism underlying POAF. Electrophysiological analysis, multi-electrode array, and Ca2+ imaging was employed to explore the alterations of electrophysiology and Ca2+ homeostasis under inflammation. Flow cytometry analysis, histology and immunochemistry were performed to investigate immunological alterations. Results: We observed electrical remodeling, enhanced atrial fibrillation (AF) susceptibility, immune cell activation, inflammatory infiltration, and fibrosis in LPS-stimulated mice. LPS-stimulated iPSC-aCMs showed arrhythmias, abnormal Ca2+ signaling, reduced cell viability, disrupted microtubule network and increased α-tubulin degradation. VEGFA, EGFR, MMP9 and CCL2 were identified as hub genes simultaneously targeted in the EAT and RAA of POAF patients. Notably, treatment of colchicine in LPS-stimulated mice resulted in a U-shape dose-response curve, where greatly improved survival rates were observed only at doses between 0.10-0.40 mg/kg. At this therapeutic dose level, colchicine inhibited the expression of all the identified hub genes and effectively rescued the pathogenic phenotypes observed in LPS-stimulated mice and iPSC-aCM models. Conclusions: Acute inflammation promotes α-tubulin degradation, induces electrical remodeling, and both recruits and facilitates the infiltration of circulating myeloid cells. A certain dose of colchicine attenuates electrical remodeling and decreases the recurrence of AF.

Key Parameters for the Rational Design, Synthesis, and Functionalization of Biocompatible Mesoporous Silica Nanoparticles.

Over the last few years, research on silica nanoparticles has rapidly increased. Particularly on mesoporous silica nanoparticles (MSNs), as nanocarriers for the treatment of various diseases because of their physicochemical properties and biocompatibility. The use of MSNs combined with therapeutic agents can provide better encapsulation and effective delivery. MSNs as nanocarriers might also be a promising tool to lower the therapeutic dosage levels and thereby to reduce undesired side effects. Researchers have explored several routes to conjugate both imaging and therapeutic agents onto MSNs, thus expanding their potential as theranostic platforms, in order to allow for the early diagnosis and treatment of diseases. This review introduces a general overview of recent advances in the field of silica nanoparticles. In particular, the review tackles the fundamental aspects of silicate materials, including a historical presentation to new silicates and then focusing on the key parameters that govern the tailored synthesis of functional MSNs. Finally, the biomedical applications of MSNs are briefly revised, along with their biocompatibility, biodistribution and degradation. This review aims to provide the reader with the tools for a rational design of biocompatible MSNs for their application in the biomedical field. Particular attention is paid to the role that the synthesis conditions have on the physicochemical properties of the resulting MSNs, which, in turn, will determine their pharmacological behavior. Several recent examples are highlighted to stress the potential that MSNs hold as drug delivery systems, for biomedical imaging, as vaccine adjuvants and as theragnostic agents.

ABCL-022 Pharmacokinetics and Pharmacodynamics in First-MIND: A Phase Ib, Open-Label, Randomized Study of Tafasitamab ± Lenalidomide + R-CHOP in Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma

The chemo-free immunotherapy tafasitamab + lenalidomide was granted accelerated approval in the United States (2020) and conditional approval in Canada and Europe (2021) for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) in autologous stem cell transplant-ineligible adult patients. We report pharmacokinetics, pharmacodynamics, and immunogenicity in patients with newly diagnosed DLBCL after adding tafasitamab ± lenalidomide to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment. To study the pharmacokinetics, pharmacodynamics, and immunogenicity of tafasitamab. Open-label, randomized, multicenter. Fifty sites in North America and Europe. Eligible patients were ≥18 years with treatment-naïve DLBCL, IPI 2-5, and ECOG PS 0-2. Patients were randomized 1:1 to six 21-day (D) cycles (C) of either R-CHOP (R-CHO, D1; P, D1-5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafasitamab + lenalidomide (25 mg orally, D1-10) (Arm B). Tafasitamab serum concentration and the number and percentage of patients developing anti-tafasitamab antibodies were secondary endpoints. NK-cell, T-cell, and B-cell counts in peripheral blood were exploratory endpoints. Tafasitamab serum concentrations reached steady state by C3 (geometric mean trough concentrations: Arm A, 186.40-216.55 µg/mL; Arm B, 171.77-201.54 µg/mL) and steadily declined after treatment completion. Anti-tafasitamab antibodies were detected in 1/65 (1.5%) patients and decreased during treatment. Median NK-cell counts decreased from baseline at C1D8 but were at baseline or higher levels by end-of-treatment (EoT) visit (Arm A) and C1D15 (Arm B). T-cell counts decreased from baseline at C1D8 in both arms but were at baseline or higher by C1D15 (Arm A) and EoT visit (Arm B). Median B-cell counts decreased from baseline to 0 cells/µL (Arm A, C1D15; Arm B, C1D8); at 6-month follow-up after EoT visit, B-cell counts recovered to measurable levels in ~50% of patients. Tafasitamab serum concentration reached and maintained a therapeutic dose level and declined after treatment completion. No patients developed treatment-induced or treatment-boosted anti-tafasitamab antibodies. Median cell counts for NK cells, T cells, and B cells were comparable between treatment arms in all cycles. MorphoSys AG.

Effects of ionizing radiation in the diagnostic and therapeutic range on the biophysical properties of collagen fibrils.

<h3>Background</h3> Ionizing radiation may indiscriminately and adversely affect tissues during exposure. As collagen is the most abundant protein in the human body, its exposure to ionizing radiation is inevitable. To date, there has been limited comprehensive evaluation of the biophysical properties of individual collagen fibrils exposed to clinically relevant doses of ionizing radiation. <h3>Objective</h3> To assess the effects of ionizing radiation at diagnostic and therapeutic levels on the biophysical properties of collagen at the nanoscale. <h3>Study Design</h3> <i>In vitro</i> acellular type I collagen scaffolds (rat tail origin) were irradiated at two relevant dose levels (diagnostic regime D = 50 µGy and therapeutic regime D = 70 Gy (single fraction)) in hydrated and dehydrated states. Alterations in the biophysical properties of these scaffolds were assessed using atomic force microscopy (AFM) (imaging, nanoindentation) and attenuated total reflectance Fourier-transform infrared (ATR-FTIR) spectroscopy. <h3>Results</h3> Preliminary analysis demonstrated changes in Young's modulus for all samples treated with both diagnostic and therapeutic dose levels, suggesting the presence of internal crosslinking modifications. These hypothesized changes will be further evaluated by fluorescence-lifetime imaging microscopy (FLIM) and dielectric analysis. No changes were detected in the infrared spectrum, suggesting no denaturation of the protein structure. A neural network for texture analysis is in development for AFM image processing and dose correlation quantification. <h3>Conclusion</h3> In this exploratory project, we demonstrated that diagnostic and therapeutic levels of radiation can alter Young's modulus of individual collagen fibers. Evaluation of irradiated collagen changes may prove important in managing oral diseases such as squamous cell carcinoma and radiation-induced mucositis and caries. Additional imaging and image processing studies are ongoing to further characterize the response of collagen to radiation. <b>Statement of Ethical Review</b> Ethical Review or exemption was not warranted for this study

Population pharmacokinetic model to generate mechanistic insights in bile acid homeostasis and drug-induced cholestasis

Bile acids (BA) fulfill a wide range of physiological functions, but are also involved in pathologies, such as cholestasis. Cholestasis is characterized by an intrahepatic accumulation of BAs and subsequent spillage to the systemic circulation. The aim of the present study was to develop physiologically based kinetic (PBK) models that would provide a tool to predict dose-dependent BA accumulation in humans upon treatment with a Bile Salt Export Pump (BSEP) inhibitor. We developed a PBK model describing the BA homeostasis using glycochenodeoxycholic acid as an exemplary BA. Population wide distributions of BSEP abundances were incorporated in the PBK model using Markov Chain Monte Carlo simulations, and alternatively the total amount of BAs was scaled empirically to describe interindividual differences in plasma BA levels. Next, the effects of the BSEP inhibitor bosentan on the BA levels were simulated. The PBK model developed adequately predicted the in vivo BA dynamics. Both the Markov Chain Monte Carlo simulations based on a distribution of BSEP abundances and empirical scaling of the total BA pool readily described the variations within and between data in human volunteers. Bosentan treatment disproportionally increased the maximum BA concentration in individuals with a large total BA pool or low BSEP abundance. Especially individuals having a large total BA pool size and a low BSEP abundance were predicted to be at risk for rapid saturation of BSEP and subsequent intrahepatic BA accumulation. This model provides a first estimate of personalized safe therapeutic external dose levels of compounds with BSEP-inhibitory properties.

PB2110: PHARMACOKINETICS AND PHARMACODYNAMICS IN FIRST-MIND: A PHASE IB, OPEN-LABEL, RANDOMIZED STUDY OF TAFASITAMAB ± LENALIDOMIDE + R-CHOP IN PATIENTS WITH NEWLY DIAGNOSED DIFFUSE LARGE B-CELL LYMPHOMA

Background: The combination of tafasitamab + lenalidomide (LEN) has been granted accelerated approval in the United States (2020) and is conditionally approved in Canada and Europe (2021) for R/R DLBCL in autologous stem-cell transplant-ineligible adult patients. A tolerable safety profile for rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) + tafasitamab ± LEN in patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) in the Phase Ib First-MIND study (NCT04134936) was previously reported, with clinically meaningful efficacy for R-CHOP + tafasitamab + LEN compared to R-CHOP + LEN (ASH 2021; #3556). Aims: To report pharmacokinetics, pharmacodynamics, and immunogenicity in patients with newly diagnosed DLBCL after adding tafasitamab ± LEN to R-CHOP as first-line treatment. Methods: Eligible patients were ≥18 years with treatment-naïve DLBCL, International Prognostic Index 2–5, and Eastern Cooperative Oncology Group performance score 0–2. Patients were randomized 1:1 to either six 21-day (D) cycles (C) of R-CHOP (R-CHO, D1; P, D1–5) + tafasitamab (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafasitamab + LEN (25 mg orally, D1–10) (Arm B). Secondary endpoints included tafasitamab serum concentration and number and percentage of patients developing anti-tafasitamab antibodies. Exploratory endpoints included natural killer (NK) cell, T-cell, and B-cell count in peripheral blood. Results: In total, 83 patients were screened; 66 were randomized (Arm A, n=33; Arm B, n=33). The data cut-off was 13 March 2021 for the safety analysis, including ≥1 month follow-up after end of treatment (EoT) visit for all patients, and 15 September 2021 for the efficacy analysis. Tafasitamab serum concentrations reached steady state by C3 (geometric mean trough concentrations: Arm A, 186.40–216.55 µg/mL; Arm B, 171.77–201.54 µg/mL) and steadily declined after treatment completion. Anti-tafasitamab antibodies were detected in 1/65 (1.5%) patients. This patient showed pre-existing anti-tafasitamab antibodies at baseline, which decreased during treatment. Median NK cell counts decreased from baseline at C1 D8, but were at baseline or higher levels by EoT visit (Arm A) and C1 D15 (Arm B; Table). T-cell counts decreased from baseline at C1 D8 in both arms but were at baseline level or higher by C1 D15 (Arm A) and EoT visit (Arm B). Median B-cell counts decreased from baseline to 0 cells/μL (Arm A, C1 D15; Arm B, C1D8); at 6-month follow-up after EoT visit, B-cell counts had recovered to measurable levels in ~50% of patients. Image:Summary/Conclusion: Tafasitamab serum concentration reached and maintained a therapeutic dose level in this first-line regimen and declined in line with known tafasitamab half-life (~16 days) after treatment completion; tafasitamab levels were comparable between the two treatment arms. No patients developed treatment-induced or treatment-boosted anti-tafasitamab antibodies. Median NK, T-cell, and B-cell counts were comparable between treatment arms in all cycles. NK and T-cell counts recovered to baseline levels by EoT; further follow up on B-cell recovery will be performed.

Pharmacokinetics (PK) and pharmacodynamics (PD) in First-MIND: A phase Ib, open-label, randomized study of tafasitamab (tafa) ± lenalidomide (LEN) in addition to R-CHOP in patients (pts) with newly diagnosed diffuse large B-cell lymphoma (DLBCL).

e19553 Background: The combination of tafa + LEN has accelerated approval in the United States (2020) and conditional approval in Canada and Europe (2021) for R/R DLBCL in ASCT-ineligible adult pts. A tolerable safety profile for R-CHOP + tafa ± LEN in pts with newly diagnosed DLBCL in the Phase Ib First-MIND study (NCT04134936) was previously reported, with numerically superior efficacy for R-CHOP + tafa + LEN (ASH 2021; #3556). We report PK, PD, and immunogenicity of R-CHOP + tafa ± LEN in this first line setting. Methods: Eligible pts ≥18 years with treatment-naïve DLBCL, IPI 2–5, and ECOG PS 0–2 were randomized 1:1 to either six 21-day (D) cycles (C) of R-CHOP (R-CHO, D1; P, D1–5) + tafa (12 mg/kg IV, D1, 8, 15) (Arm A) or R-CHOP + tafa + LEN (25 mg orally, D1–10) (Arm B). Secondary endpoints included tafa serum conc and number and percentage of pts developing anti-tafa Abs. Exploratory endpoints included natural killer (NK) cell, T-cell, and B-cell count in peripheral blood. Results: Data cut-off: 13 March 2021 for safety analysis, incl. ≥1 month follow-up after EoT visit for all pts; 15 September 2021 for efficacy. Tafa serum conc reached steady state by C3 (geometric mean trough conc: Arm A, 186.40–216.55 µg/mL; Arm B, 171.77–201.54 µg/mL) and steadily declined after treatment completion. Anti-tafa Abs were detected in 1/65 (1.5%) pts. This pt showed pre-existing tafa Abs at baseline, which decreased during treatment. Median NK cell count decreased from baseline at C1D8 but was at baseline or higher levels by EoT visit (Arm A) and C1D15 (Arm B; Table). T-cell count decreased from baseline at C1D8 in both arms but was at baseline level or higher by C1D15 (Arm A) and EoT visit (Arm B). Median B-cell count decreased from baseline to 0 cells/μL (Arm A, C1D15; Arm B, C1D8); at 6-month follow-up after EoT visit, B-cell count had recovered to measurable levels in ̃50% of pts. Conclusions: Tafa serum conc reached and maintained a therapeutic dose level in this first-line regimen and declined in line with known tafa half-life (̃16 days) after treatment completion; tafa levels were comparable between the two treatment arms. No pt developed treatment-induced or treatment-boosted anti-tafa Abs. Median NK-cell, T-cell, and B-cell counts were comparable between treatment arms in all cycles. Clinical trial information: NCT04134936. [Table: see text]

Application of Meta-analysis to Evaluate Relationships Among ARIA-E Rate, Amyloid Reduction Rate, and Clinical Cognitive Response in Amyloid Therapeutic Clinical Trials for Early Alzheimer's Disease.

Removal of the extracellular Aβ plaques in the brain is one of the mechanisms to treat Alzheimer's disease (AD). Separate clinical trials for several therapeutic compounds that target amyloid plaque reduction have shown noteworthy correlations among plaque removal, the Amyloid-Related Imaging Abnormalities (ARIA) rate, and clinical efficacy of the treatment. The relationships among therapeutic dose levels, the rate of amyloid removal, and the clinical efficacy deserve further investigation across therapeutic agents, particularly for clinical trials to provide insights for strategies to develop amyloid therapies in Alzheimer's disease. Published data summaries from clinical trials with amyloid therapies of aducanumab, donanemab, lecanemab, and gantenerumab are evaluated with meta-analyses. Linear mixed models for repeated measurements for visits and random study effects are applied to analyze amyloid centiloid value reduction from baseline and clinical cognition change from baseline for treatment groups according to doses and compounds for the clinical trials. Logistic regression analysis is applied to evaluate the relationship between the amyloid removal rate and the ARIA-Edema (ARIA-E) rate across different dose groups and clinical trials. The extent of amyloid removal varies among therapeutic agents and their dose levels. Across treatment groups and clinical trials, amyloid centiloid value reductions at Weeks 26 and 52 are strongly correlated with both ARIA-E rate over 78weeks and the clinical efficacy response in the Clinical Dementia-Rating Scale Sum of Boxes (CDR-SB) score change from baseline at Week 78; and the Spearman rank correlations for amyloid reduction at Week 52 are stronger as - 0.79 with the ARIA-E rate over 78weeks and 0.73 with the Week 78 CDR-SB score change from baseline. Aβ plaques removal in the brain due to amyloid therapy is strongly correlated with a better clinical response in patients with early Alzheimer's disease and a higher ARIA-E rate for the treatment groups and clinical trials in this meta-analysis. These relationships suggest that the balance between the clinical efficacy response and safety in ARIA-E rate is relevant for the choice of doses for amyloid therapies in confirmatory clinical trials.

5MO Comprehensive dose-finding strategy for single-agent RP-3500, a highly selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase

Dose-finding studies typically establish a maximum tolerated dose, a recent shift from this “more is better” approach towards long-term tolerability is of interest. The ongoing RP-3500 TRESR study (NCT04497116) used a comprehensive, non-randomized, dose-finding approach, focusing on longer-term tolerability to establish a patient (pt)-specific therapeutic dose level.