Therapeutic Exposure Research Articles

LGG-39. REAL-LIFE STUDY OF THE EFFICACY AND TOLERANCE OF TRAMETINIB IN THE TREATMENT OF LOW-GRADE GLIOMAS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1

Abstract BACKGROUND Low grade gliomas (LGG) are the most common brain tumors in children. Targeted therapies such as the MEK-inhibitor trametinib have revolutionized the management of pediatric LGGs. NF1 mutations generate misregulations in the RAS/MAP kinase pathway, but data on trametinib in type 1 neurofibromatosis (NF1)-related LGG are scarce. Efficacy and safety of trametinib in NF1 patients with LGG need to be further investigated. METHODS This retrospective study included patients with NF1 <18 years from two French centers having received trametinib for a relapsing/progressive LGG between March 2020 and July 2022. Treatment efficacy was assessed according to RAPNO criteria, and toxicities and therapeutic exposure were assessed using real-life data collected retrospectively up to July 2023. RESULTS The study enrolled 11 patients, the median age at LGG diagnosis was 3 (1-9) years. All patients previously received a median number of 2 (1-4) lines of chemotherapy. Median age at treatment initiation was 9 (4-13) years. Median duration of trametinib treatment was 9.3 (5.8-24) months. Progression-free survival was 91% at 6 months and 61% at 2 years. Median time to best response was 2.7 (1.1-9) months, including 5 stable diseases, 4 minor responses, and 2 partial responses. Median duration of response was 8.6 (3.7-36.2) months. Adverse events (AEs) occurred in all patients, and 64% of the patient had grade 3 AEs. Skin toxicities and paronychia were the most frequent AEs. Treatment interruption occurred in 55% of the patients, and 3 patients permanently discontinued trametinib due to treatment-related toxicities. Real therapeutic exposure was significantly shorter than theoretically expected (19.6% treatment reduction). CONCLUSION Trametinib showed promising efficacy in NF1 children with relapsing/progressive LGG. Trametinib toxicity remains challenging. Further prospective clinical trials stratified according to molecular alterations are needed to support these preliminary results.

Postdiscontinuation Antibiotic Exposure in Hospitalized Infants at Risk for Late-onset Sepsis in the Neonatal Intensive Care Unit.

In the neonatal intensive care unit, infants are at risk for late-onset sepsis. When blood cultures are negative, antibiotic stewardship efforts encourage stopping antibiotics, yet the duration of therapeutic exposure after the last dose is unknown. This retrospective cohort study of simulated antibiotic exposures used published population pharmacokinetic models within drug-specific neonatal intensive care unit cohorts of preterm and term infants, postnatal age 7-60 days and exposed to cefepime, piperacillin-tazobactam or tobramycin. Monte Carlo simulations (NONMEM 7.3) were used to predict steady-state exposures after a 72-hour antibiotic course per Neofax dosing. Exposure was assessed relative to drug-specific minimum inhibitory concentration (MIC) targets between 1 and 16 mcg/mL for Pseudomonas and Enterobacteriaceae species. Postdiscontinuation antibiotic exposure (PDAE) was defined as the time from the last dose to when antibiotic concentration decreased below a specific MIC. Piperacillin-tazobactam, cefepime and tobramycin cohorts included infants with median gestation age 29, 32 and 32 weeks and postnatal age 17, 19 and 15 days, respectively. The mean PDAE was 19-68 hours, depending on the specific antibiotic/MIC combination. PDAE was longer for infants <28 days old and preterm (vs. term) infants. Cefepime exhibited the longest mean PDAE of 68 hours for Enterobacteriaceae MIC 1. Piperacillin mean PDAE was 25 hours for Enterobacteriaceae MIC 8. Tobramycin had a short mean PDAE of 19 hours. Piperacillin and cefepime exposures remained therapeutic long after the expected 8- to 12-hour dosing interval. PDAE is an important consideration for antibiotic stewardship among hospitalized infants, particularly premature infants and those within 1 month postbirth.

Novel Small-Molecule ROCK2 Inhibitor GNS-3595 Attenuates Pulmonary Fibrosis in Preclinical Studies.

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease that leads to respiratory decline caused by scarring and thickening of lung tissues. Multiple pathways contribute to the fibrotic process in this disease, such as inflammation, epithelial-to-mesenchymal transition, and oxidative stress. The Rho-associated coiled-coil forming protein kinase (ROCK) signaling pathway is a key regulator of profibrotic signaling, as it affects the organization of actin-myosin and the remodeling of the extracellular matrix. ROCK1/2, a downstream effector of RhoA, is overexpressed in patients with IPF and is a promising target for IPF therapy. However, because of the hypotensive side effects of ROCK1/2 inhibitors, selective ROCK2 compounds are being explored. In this study, we report the discovery of GNS-3595, a potent and selective ROCK2 inhibitor that has ∼80-fold selectivity over ROCK1 at physiological concentrations of ATP. GNS-3595 effectively inhibited ROCK2-mediated phosphorylation of myosin light chain and reduced the expression of fibrosis-related proteins (e.g., collagen, fibronectin, and α-smooth muscle actin) in various invitro cellular models. GNS-3595 also prevented transforming growth factor β-induced fibroblast-to-myofibroblast transition. In addition, in a bleomycin-induced mouse model of pulmonary fibrosis, therapeutic exposure to GNS-3595, suppressed lung fibrosis, stabilized body weight loss, and prevented fibrosis-induced lung weight gain. Transcriptome and protein expression analysis from lung tissues showed that GNS-3595 can revert the fibrosis-related gene expression induced by bleomycin. These results indicate that GNS-3595 is a highly potent, selective, and orally active ROCK2 inhibitor with promising therapeutic efficacy against pulmonary fibrosis.

Effects of cardiac radiation on sleep and psychological distress in adult survivors of pediatric Hodgkin lymphoma without breathing sleep disorders.

10068 Background: Adult survivors of childhood Hodgkin lymphoma (HL) are at higher risk for excessive sleepiness, fatigue, and other morbidities that affect long-term quality of life (QoL). The relationship between radiation dose to the heart delivered during treatment and self-reported sleep quality, fatigue, QoL, and psychological distress in survivors of HL has not been explored. This study examines clusters of cardiac dosimetry and sleep quality and associated symptoms of insomnia, fatigue, QoL, and psychological distress in a subset of adult survivors of pediatric HL without breathing sleep disorders. Methods: Survivors completed standardized surveys of sleep quality (Pittsburg Sleep Quality Index, PSQI), insomnia (Insomnia Severity Index), fatigue (FACIT-F), QoL (SF36 short survey), and psychological distress (BS18). Two consecutive nights of in-home polysomnography were completed with at least 4 hours of recorded sleep in one night. Analyses were conducted on 95 survivors (mean[SD] age=36[7.2] years, 55 female) who demonstrated at least average sleep efficiency (&gt;85%) and demonstrated no evidence of sleep apnea (Apnea-Hypopnea Index &lt;5, or AHI &gt;5 and &lt;15 with no daytime sleepiness as defined by the American Society of Sleep Medicine). Radiation dose to the heart was estimated using dose reconstruction methods for therapeutic radiation exposure developed by the MD Anderson Cancer Center. Radiation/Sleep clusters were found using a silhouette analysis and K-means algorithm. Linear regression associations between clusters and outcomes were adjusted by age and body mass index. Statistical analyses were computed in the statsmodels toolbox for Python3. Results: Sleep and radiation were not correlated (ρ=0.03, p=0.67). Considering good sleep as PSQI&lt;5, three main Radiation/Sleep clusters were found indicating a low-radiation/middling-sleep group (22%; RT = 251[250.7] cGy, PSQI = 7[2.7]), a high- radiation/better-sleep group (46%; RT = 2012[406.8] cGy, PSQI = 4[1.5]), and a high- radiation/worst-sleep group (32%; RT = 2072[472.3] cGy, PSQI = 11[2.5]). Survivors in high-radiation/worst-sleep group demonstrated worse fatigue ( β=-12.3, p=0.001) and insomnia ( β=9.52, p&lt;0.001). This group was associated with poor Mental Health ( β=-2.1, p&lt;0.001) but not Physical Health QoL ( β=-0.4, p=0.154). This latter group also indicated more psychological distress (depression β=11.6, p=0.001, somatization β=11.8, p&lt;0.001), but not anxiety ( β=4.6, p=0.241). Conclusions: Our results highlight the burden of symptoms associated with higher radiation dosimetry in the heart including poor sleep quality, insomnia, fatigue, and increased psychological distress. Understanding the mechanisms of sleep quality and fatigue in HL survivors is warranted as some survivors demonstrate poor sleep quality and fatigue due to factors other than clinical sleep disorders.

A machine learning personalized treatment rule to optimize assignment to psychotherapies for grief among veterans

BackgroundComplex grief patterns are associated with significant suffering, functional impairments, health and mental health problems, and increased healthcare use. This burden may be even more pronounced among veterans. Behavioral Activation and Therapeutic Exposure (BATE-G) and Cognitive Therapy for Grief (CT-G) are two evidence-based interventions for grief. The goal of this study was to use a precision medicine approach to develop a personalized treatment rule to optimize assignment among these psychotherapies. MethodsWe analyzed data (N = 155) from a randomized clinical trial comparing BATE-G and CT-G. Outcome weighted learning was used to estimate an optimal personalized treatment rule. Baseline characteristics including demographics, social support, variables related to the death, and psychopathology dimensions were used as prescriptive factors of treatment assignment. ResultsThe estimated rule assigned 72 veterans to CT-G and 56 to BATE-G. Assigning participants according to this rule was estimated to lead to markedly lower mean grief level following 6 months from treatment compared to assigning everyone to either BATE-G (Vdopt – VBATE-G = −18.57 [95 % CI: −29.41, −7.72]) or CT-G (Vdopt – VBATE-G = −20.89 [95 % CI: −30.7, −11.07]) regardless of their characteristics. LimitationsParticipants were primarily male veterans, and identified with Black or White race. The estimated rule was not externally validated. ConclusionThe estimated rule used relatively simple, easily accessible, client characteristics to personalize assignment to treatment using a precision medicine approach based on machine learning and causal inference. Upon further validation, such a rule can be easily implemented in clinical practice to prescriptively maximize treatment benefits.

Versatile tissue‐injectable hydrogels capable of the extended hydrolytic release of bioactive protein therapeutics

AbstractHydrogels are extensively employed in healthcare due to their adaptable structures, high water content, and biocompatibility, with FDA‐approved applications ranging from spinal cord regeneration to local therapeutic delivery. However, clinical hydrogels encounter challenges related to inconsistent therapeutic exposure, unmodifiable release windows, and difficulties in subsurface polymer insertion. Addressing these issues, we engineered injectable, biocompatible hydrogels as a local therapeutic depot, utilizing poly(ethylene glycol) (PEG)‐based hydrogels functionalized with bioorthogonal SPAAC handles for network polymerization and functionalization. Our hydrogel solutions polymerize in situ in a temperature‐sensitive manner, persist in tissue, and facilitate the delivery of bioactive therapeutics in subsurface locations. Demonstrating the efficacy of our approach, recombinant anti‐CD47 monoclonal antibodies, when incorporated into subsurface‐injected hydrogel solutions, exhibited cytotoxic activity against infiltrative high‐grade glioma xenografts in the rodent brain. To enhance the gel's versatility, recombinant protein cargos can undergo site‐specific modification with hydrolysable “azidoester” adapters, allowing for user‐defined release profiles from the hydrogel. Hydrogel‐generated gradients of murine CXCL10, linked to intratumorally injected hydrogel solutions via azidoester linkers, resulted in significant recruitment of CD8+ T‐cells and the attenuation of tumor growth in a “cold” syngeneic melanoma model. This study highlights a highly customizable, hydrogel‐based delivery system for local protein therapeutic administration to meet diverse clinical needs.

Neurological adverse effects of isoxazoline exposure in cats and dogs.

Isoxazolines are rarely reported to be associated with neurological adverse events in cats and dogs, but information about the onset and duration of neurological signs is lacking in the summary of product characteristics of these medicines. The Veterinary Poisons Information Service and the Dutch Poisons Information Center databases were searched using the Veterinary Dictionary for Drug-Related Affairs terms for ataxia, muscle tremor, convulsions or hyperesthesia in cats and dogs exposed to isoxazolines. There were 22 cases with and 57 cases without outcome information, mostly involving fluralaner or sarolaner. In both groups, muscle tremors and convulsions were the most common signs. In dogs, neurological signs occurred with oral therapeutic dose and overdosage. In cats, most fluralaner cases involved therapeutic topical exposure, and all sarolaner cases involved oral exposure. In all cases with outcome information, the animals recovered. Cases discussed with poison centres tend to involve more severe signs. The true incidence of neurological adverse effects from isoxazolines remains unclear.The delay between the administration and onset of signs can be long, and the association may be missed. A lack of timing information in the summary of product characteristics could also contribute to missed attribution of adverse effects.

Effect of loperamide on heart rhythm: Randomized, double-blind, controlled study in healthy adults

BackgroundExcessively high doses of loperamide (of up to 792 mg/day) have recently been associated with reports of cardiac events. However, no data currently demonstrate a direct effect of high doses of loperamide on the occurrence of cardiovascular abnormalities. ObjectivesThis study aimed to assess the effects of loperamide on QT/corrected QT (QTc) intervals, electrocardiogram (ECG) morphology, and overall safety and tolerability at therapeutic and supratherapeutic exposures in healthy adults. MethodsThis randomized, double-blind, 4-way-crossover study enrolled 65 healthy adults to receive loperamide 8 mg (therapeutic dose), loperamide 48 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), and placebo. Least square (LS) mean difference in change from baseline in Fridericia-corrected QT (ΔQTcF) intervals between loperamide (8 mg and 48 mg) and placebo with the 2-sided 90% CI was calculated for each time point. A noninferiority criterion of mean difference in ΔQTcF of 10 ms evaluated whether loperamide was noninferior to placebo. Treatment safety was assessed throughout the study. ResultsMost participants were female (66.2%) and white (95.4%). The age was 36.4 years (SD 9.77). The highest upper limit of the 2-sided 90% CI for LS mean difference in ΔQTcF between loperamide and placebo was 3.39 ms for the therapeutic dose and 9.28 ms for the supratherapeutic dose of loperamide, which were below the 10 ms threshold, thereby demonstrating noninferiority of loperamide to placebo. There were no statistically significant morphologic ECG changes after loperamide administration. There were no deaths, serious adverse events, or severe treatment-emergent adverse events. ConclusionSingle-dose loperamide at therapeutic (8 mg) and supratherapeutic (48 mg) doses do not show evidence of QTc prolongation of clinical concern in healthy participants. No new safety findings were identified.

Recent Trends in Nanomaterial Based Electrochemical Sensors for Drug Detection: Considering Green Assessment.

An individual's therapeutic drug exposure level is directly linked to corresponding clinical effects. Rapid, sensitive, inexpensive, portable and reliable devices are needed for diagnosis related to drug exposure, treatment, and prognosis of diseases. Electrochemical sensors are useful for drug monitoring due to their high sensitivity and fast response time. Also, they can be combined with portable signal read-out devices for point-of-care applications. In recent years, nanomaterials such as carbon-based, carbon-metal nanocomposites, noble nanomaterials have been widely used to modify electrode surfaces due to their outstanding features including catalytic abilities, conductivity, chemical stability, biocompatibility for development of electrochemical sensors. This review paper presents the most recent advances about nanomaterials-based electrochemical sensors including the use of green assessment approach for detection of drugs including anticancer, antiviral, anti-inflammatory, and antibiotics covering the period from 2019 to 2023. The sensor characteristics such as analyte interactions, fabrication, sensitivity, and selectivity are also discussed. In addition, the current challenges and potential future directions of the field are highlighted.

Abstract 3954: Increased mosaic chromosomal alterations among survivors of childhood acute myeloid leukemia

Abstract Background: We previously characterized point mutations of clonal hematopoiesis (CH) including single nucleotide variants or small insertion/deletions residing in a set of cancer-related genes (e.g., DNMT3A and TET2), and found that CH point mutations occurred at a much higher prevalence in childhood cancer survivors (CCS) than in age-sex-race matched community controls. However, mosaic chromosomal alterations (mCAs), another form of CH with megabase-scale structural alterations (copy gain, copy loss and copy-neutral loss of heterozygosity), have not been examined. Methods: Detection of mCAs was performed on whole-genome sequencing (WGS, 30X) data from 5-year CCS with the Mosaic Chromosomal Alterations (MoChA) caller which utilizes phased genotypes, coverage, and B allele frequency (BAF) at heterozygous sites (HETS). We implemented the pipeline established by the TOPMed consortium to detect low mutant cell fractions (CF ≥1%). Variant filtration criteria: minor allele frequency &amp;lt;1%, the read depth of either allele &amp;lt;5, and only one variant retained in each 1Kb window. Called mCA filtration criteria: &amp;lt;100 HETS; lod score &amp;lt;5; relative coverage &amp;gt;2.9 or BAF deviation &amp;gt;0.16 and relative coverage &amp;gt;2.5. Autosomal mCAs (CF ≥1%, HETS &amp;gt;100 and length &amp;gt;1Mb) retained. Multivariable Cox models evaluated the association between mCAs and specific late-effects including all-cause mortality, obesity, myocardial infarction (MI) or cardiomyopathy (CMP); multivariable logistic models evaluated the association between mCAs and childhood cancer diagnoses. All models were adjusted for age, sex and therapeutic exposures. Results: In our evaluation of 4,330 CCS (median age at blood draw: 26.8 years) and 433 controls (33.6 years) with WGS data from the St. Jude Lifetime Cohort, the prevalence of mCAs was slightly higher among CCS than community controls (4.83% vs. 4.16%). Among CCS, mCAs were associated with therapeutic exposures (alkylating agents: odds ratio [OR]=1.48, 95% CI=1.09-2.00; antimetabolites: 1.53, 1.02-2.31; corticosteroids: 0.60, 0.40-0.91). In contrast to recent mCA studies in the general population, we observed no co-occurrence with CH point mutations, and no associations with late-effects including all-cause mortality, obesity, MI or CMP. Interestingly, mCAs were significantly associated with the primary diagnosis of acute myeloid leukemia (AML, OR=2.86, 95% CI=1.63-5.01). Furthermore, this finding was replicated in 2898 5-year survivors from the Childhood Cancer Survivor Study (OR=3.77, 95% CI=1.94-7.33). Conclusion: mCAs were not associated with age-related morbidities and mortality among CCS. However, we identified a striking association between mCAs and previous diagnoses of AML independent of treatment exposures. If validated among AML patients at the time of diagnosis, mCAs, which reflect the underlying genome instability, may serve as a diagnostic biomarker for AML. Citation Format: Xijun Zhang, Na Qin, Qian Dong, Cheng Chen, John Easton, Heather Mulder, Xiang Chen, Kyla Shelton, Cindy Im, Yutaka Yasui, Greg Armstrong, Kirsten K. Ness, Melissa M. Hudson, Paul Auer, Jinghui Zhang, Zhaoming Wang. Increased mosaic chromosomal alterations among survivors of childhood acute myeloid leukemia [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 3954.

Abstract 1891: Preclinical characterization of ADRX-0706: A next-generation anti-Nectin-4 antibody-drug conjugate with improved therapeutic window

Abstract Nectin-4 is a well validated tumor target, which is highly expressed in several solid cancers such as urothelial, head-and-neck, breast, lung, pancreatic, ovarian, and cervical cancer, while expression in normal tissues is limited. A first-generation antibody-drug conjugate targeting Nectin-4, called enfortumab vedotin-ejfv (EV), was granted accelerated FDA approval in 2019 for urothelial cancers, and is currently approved for frontline therapy in cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma, providing groundbreaking improvement in patient survival. However, clinical use of EV has also revealed safety-driven limitations, which result in reduced and/or interrupted drug exposures impacting efficacy. To overcome these limitations in therapeutic window and to maximize on the potential of Nectin-4 as a tumor target beyond urothelial cancers, Adcentrx has developed ADRX-0706, a Nectin-4-targeting next-generation ADC with a drug-antibody ratio of 8. ADRX-0706 is comprised of a novel fully human IgG1k monoclonal antibody linked to an optimized tubulin inhibitor payload AP052 through a proprietary cleavable linker. ADRX-0706 has strong binding affinity and selectively induces cytotoxicity in Nectin-4-expressing tumor cells. Importantly, ADRX-0706 is designed to have improved bystander effect, which allows tumor regression even in cases of heterogeneous Nectin-4 expression. This translates to superior in vivo efficacy of ADRX-0706 over EV in multiple mouse xenograft models of other indications beyond bladder cancer. In a mouse clinical trial of patient-derived cervical cancers with a range of Nectin-4 expression levels, ADRX-0706 reaches a 73% ORR. Since peripheral neuropathy is a main platform toxicity for this payload class, ADRX-0706 is assessed in an in vitro co-culture model to evaluate its neurotoxic potential. While EV displays a 75% decrease in neurite outgrowth, ADRX-0706 strikingly has no impact at concentrations up to 1mg/ml, suggesting a lower risk of peripheral neuropathy in humans for ADRX-0706. In preclinical repeat dose toxicology study, ADRX-0706 reaches an HNSTD of 18mg/kg in NHPs well above therapeutic exposures in mouse pharmacology studies, indicating a tremendous increase in the therapeutic index compared to EV. In summary, the highly selective and potent anti-tumor activity in multiple tumor types and wide preclinical therapeutic index of ADRX-0706 support clinical evaluation of this next generation anti-Nectin-4 ADC. ADRX-0706 is currently in a phase 1a/b study (NCT06036121). Citation Format: Andrew M. Hau, Maria Shahmoradgoli, Dong Jun Lee, Wes Sisson, Anna Wang, Peter P. Challita, Erin Nye, Mario M. Kuo, Alexis Mahloch, Monica Leung, Oscar Betancourt, Alexander Chu-Kung, Maojun Guo, Hui Li, Sabine Rottmann, Pia M. Challita-Eid. Preclinical characterization of ADRX-0706: A next-generation anti-Nectin-4 antibody-drug conjugate with improved therapeutic window [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 1891.

Abstract 2097: ABT co-dose accelerated target validation with a fit-for-purpose HPK1 inhibitor tool

Abstract Target validation can be challenging when mouse efficacy studies require achieving a high therapeutic exposure of a tool compound, ideally with a low peak-to-trough (P/T) ratio to avoid Cmax-induced toxicity. Herein, we describe the daily co-administration of the CYP inhibitor aminobenzotriazole (ABT) as a well-tolerated PK enhancer for medium-term efficacy studies in mice, enabling faster decision-making in the early space with imperfect tools. Genetic studies in mice have suggested that HPK1 inhibition would lead to enhanced effector T-cell function, decreased tumor growth and enhanced αPD-L1 efficacy. However, it remains unknown whether immune activation by pharmacological inhibition of HPK1 will recapitulate the genetic deletions. We developed a fit for purpose tool compound with picomolar HPK1 potency, excellent kinome selectivity (98% &amp;gt;100x, ATP-Km corrected), dose-dependent inhibition of pSLP76, sustained IL2 elevation in PBMCs, and IL6/TNFa elevation in dendritic cells. The mouse PK for this tool was inadequate, having a low exposure (AUC 16 uM-hr at 100 mg/kg po) and a high P/T ratio of 13 that could lead to an erosion of kinome selectivity in vivo; complicating efficacy interpretation and limiting overall tolerability. However, when co-dosed with ABT (50 mg/kg po 2 h prior to the HPK1 inhibitor), improved exposure of our tool was achieved (AUC 63 uM-hr at 100 mg/kg po), 90% inhibition of pSLP76 was maintained at C(trough), and the P/T ratio was reduced to 3 to avoid Cmax-induced toxicity. The inhibitor was well-tolerated co-dosed with ABT for three weeks in mice, enabling studies sooner to probe HPK1 pharmacological inhibition in cancer immunotherapy as a monotherapy as well as in combination with a mouse anti-PD-1 antibody. Citation Format: Joey L. Methot, Joanna L. Chen, Elsie Yu, Ryan D. Otte, Haiyan Xu, Zangwei Xu, Brian Lacey, Jason Laskey, Robbie Mcleod, Dustin Smith, Alexander Pasternak. ABT co-dose accelerated target validation with a fit-for-purpose HPK1 inhibitor tool [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 2097.

Executive Summary of Clinical Practice Guideline on Immunotherapy for Inhalant Allergy.

Allergen immunotherapy (AIT) is the therapeutic exposure to an allergen or allergens selected by clinical assessment and allergy testing to decrease allergic symptoms and induce immunologic tolerance. Inhalant AITis administered to millions of patients for allergic rhinitis (AR) and allergic asthma (AA) and is most commonly delivered as subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT). Despite its widespread use, there is variability in the initiation and delivery of safe and effective immunotherapy, and there are opportunities for evidence-based recommendations for improved patient care. The purpose of this clinical practice guideline is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the management of inhaled allergies with immunotherapy. Specific goals of the guideline are to optimize patient care, promote safe and effective therapy, reduce unjustified variations in care, and reduce risk of harm. The target patients for the guideline are any individuals aged 5 years and older with AR, with or without AA, who are either candidates for immunotherapy or treated with immunotherapy for their inhalant allergies. The target audience is all clinicians involved in the administration of immunotherapy. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group. It is not intended to be a comprehensive, general guide regarding the management of inhaled allergies with immunotherapy. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. The guideline development group made a strong recommendation that (Key Action Statement [KAS] 10) the clinician performing allergy skin testing or administering AIT must be able to diagnose and manage anaphylaxis. The guideline development group made recommendations for the following KASs: (KAS 1) Clinicians should offer or refer to a clinician who can offer immunotherapy for patients with AR with or without AA if their patients' symptoms are inadequately controlled with medical therapy, allergen avoidance, or both, or have a preference for immunomodulation. (KAS 2A) Clinicians should not initiate AIT for patients who are pregnant, have uncontrolled asthma, or are unable to tolerate injectable epinephrine. (KAS 3) Clinicians should evaluate the patient or refer the patient to a clinician who can evaluate for signs and symptoms of asthma before initiating AIT and for signs and symptoms of uncontrolled asthma before administering subsequent AIT. (KAS 4) Clinicians should educate patients who are immunotherapy candidates regarding the differences between SCIT and SLIT (aqueous and tablet) including risks, benefits, convenience, and costs. (KAS 5) Clinicians should educate patients about the potential benefits of AIT in (1) preventing new allergen sensitization, (2)reducing the risk of developing AA, and (3) altering the natural history of the disease with continued benefit after discontinuation of therapy. (KAS 6) Clinicians who administer SLIT to patients with seasonal AR should offer pre- and co-seasonal immunotherapy. (KAS 7) Clinicians prescribing AIT should limit treatment to only those clinically relevant allergens that correlate with the patient's history and are confirmed by testing. (KAS 9) Clinicians administering AIT should continue escalation or maintenance dosing when patients have local reactions to AIT. (KAS 11) Clinicians should avoid repeat allergy testing as an assessment of the efficacy of ongoing AIT unless there is a change in environmental exposures or a loss of control of symptoms. (KAS 12) For patients who are experiencing symptomatic control from AIT, clinicians should treat for a minimum duration of 3 years, with ongoing treatment duration based on patient response to treatment. The guideline development group offered the following KASs as options: (KAS 2B) Clinicians may choose not to initiate AIT for patients who use concomitant beta-blockers, have a history of anaphylaxis, have systemic immunosuppression, or have eosinophilic esophagitis (SLIT only). (KAS 8) Clinicians may treat polysensitized patients with a limited number of allergens.

Clinical Practice Guideline: Immunotherapy for Inhalant Allergy.

Allergen immunotherapy (AIT) is the therapeutic exposure to an allergen or allergens selected by clinical assessment and allergy testing to decrease allergic symptoms and induce immunologic tolerance. Inhalant AITis administered to millions of patients for allergic rhinitis (AR) and allergic asthma (AA) and is most commonly delivered as subcutaneous immunotherapy (SCIT) or sublingual immunotherapy (SLIT). Despite its widespread use, there is variability in the initiation and delivery of safe and effective immunotherapy, and there are opportunities for evidence-based recommendations for improved patient care. The purpose of this clinical practice guideline (CPG) is to identify quality improvement opportunities and provide clinicians trustworthy, evidence-based recommendations regarding the management of inhaled allergies with immunotherapy. Specific goals of the guideline are to optimize patient care, promote safe and effective therapy, reduce unjustified variations in care, and reduce the risk of harm.The target patients for the guideline are any individuals aged 5 years and older with AR, with or without AA, who are either candidates for immunotherapy or treated with immunotherapy for their inhalant allergies. The target audience is all clinicians involved in the administration of immunotherapy. This guideline is intended to focus on evidence-based quality improvement opportunities judged most important by the guideline development group (GDG). It is not intended to be a comprehensive, general guide regarding the management of inhaled allergies with immunotherapy. The statements in this guideline are not intended to limit or restrict care provided by clinicians based on their experience and assessment of individual patients. The GDG made a strong recommendation that (Key Action Statement [KAS] 10) the clinician performing allergy skin testing or administering AIT must be able to diagnose and manage anaphylaxis. The GDG made recommendations for the following KASs: (KAS 1) Clinicians should offer or refer to a clinician who can offer immunotherapy for patients with AR with or without AA if their patients'symptoms are inadequately controlled with medical therapy, allergen avoidance, or both, or have a preference for immunomodulation. (KAS 2A) Clinicians should not initiate AIT for patients who are pregnant, have uncontrolled asthma, or are unable to tolerate injectable epinephrine. (KAS 3) Clinicians should evaluate the patient or refer the patient to a clinician who can evaluate for signs and symptoms of asthma before initiating AIT and for signs and symptoms of uncontrolled asthma before administering subsequent AIT. (KAS 4) Clinicians should educate patients who are immunotherapy candidates regarding the differences between SCIT and SLIT (aqueous and tablet) including risks, benefits, convenience, and costs. (KAS 5) Clinicians should educate patients about the potential benefits of AIT in (1) preventing new allergen sensitizations, (2) reducing the risk of developing AA, and (3) altering the natural history of the disease with continued benefit after discontinuation of therapy. (KAS 6) Clinicians who administer SLIT to patients with seasonal AR should offer pre- and co-seasonal immunotherapy. (KAS 7) Clinicians prescribing AIT should limit treatment to only those clinically relevant allergens that correlate with the patient's history and are confirmed by testing. (KAS 9) Clinicians administering AIT should continue escalation or maintenance dosing when patients have local reactions (LRs) to AIT. (KAS 11) Clinicians should avoid repeat allergy testing as an assessment of the efficacy of ongoing AIT unless there is a change in environmental exposures or a loss of control of symptoms. (KAS 12) For patients who are experiencing symptomatic control from AIT, clinicians should treat for a minimum duration of 3 years, with ongoing treatment duration based on patient response to treatment. The GDG offered the following KASs as options: (KAS 2B) Clinicians may choose not to initiate AIT for patients who use concomitant beta-blockers, have a history of anaphylaxis, have systemic immunosuppression, or have eosinophilic esophagitis (SLIT only). (KAS 8) Clinicians may treat polysensitized patients with a limited number of allergens.

Multifunctional capabilities of СО2 for providing pharmacodynamics of carboxytherapy

Background. To identify potential opportunities for carboxytherapy, it is necessary to assess the importance of various signaling mechanisms of sensitivity to СО2 and summarize the knowledge about the cellular and molecular mechanisms underlying the beneficial and safe effects of carboxytherapy. High level of СО2 activates the mechanisms that convert hypoxia into the mode of survival and physiological homeostasis. The balance between the pro-inflammatory and anti-inflammatory phases in inflammation also shifts towards homeostasis when tissue СО2 level increases, which is very important for wound and fracture healing. The physiological properties of СО2 provide oxygenation, enhancement of angiogenesis, mitochondrial biogenesis, blood flow in tissues, anti-inflammatory effect, and reduction of oxidative stress. These pro-perties of СО2 determine the potential use of carboxytherapy as a therapeutic approach in tissue hypoxia, to accelerate tissue repair and reduce inflammation. Methods. Тhe search for scientific information on the possibilities of СО2 in medicine was conducted in the PubMed and Google Scholar electronic databases. Results. Literature data on СО2 studies aimed at the mechanisms of pharmacological action of carboxytherapy were found, which have been investigated in animal models in vivo and in research with human participants. Conclusions. This review presents the scientific evidence supporting the clinical benefits of therapeutic exposure to СО2 (carboxytherapy).

Eculizumab dose tapering should take into account the nonlinearity of its pharmacokinetics.

Eculizumab is a monoclonal antibody targeting complement protein C5 used in renal diseases. As recommended dosing regimen leads to unnecessarily high concentrations in some patients, tailored dosing therapeutic drug monitoring was proposed to reduce treatment cost. The objectives of the present work were (i) to investigate the target-mediated elimination of eculizumab and (ii) whether a pharmacokinetic model integrating a nonlinear elimination allows a better prediction of eculizumab concentrations than a linear model. We analysed 377 eculizumab serum concentrations from 44 patients treated for atypical haemolytic uraemic syndrome and C3 glomerulopathy with a population pharmacokinetic approach. Critical concentrations (below which a non-log-linear decline of concentration over time is evidenced) were computed to estimate the relevance of the target-mediated elimination. Simulations of dosing regimens were then performed to predict probabilities of target attainment (i.e. trough >100 mg/L). Pharmacokinetics of eculizumab was nonlinear and followed a mixture of first-order (CL = 1.318 mL/day/kg) and Michaelis-Menten elimination (Vmax = 26.07 mg/day, Km = 24.06 mg/L). Volume of distribution (72.39 mL/kg) and clearance were weight-dependent. Critical concentrations (Vmax /CL) ranged from 144.7 to 759.7mg/L and were inversely related to body weight (P = .013). Nonlinearity was thus noticeable at therapeutic concentrations. Simulations predicted that 1200 mg of eculizumab every 21 days would allow 85% and 76% of patients to maintain a therapeutic exposure, for 50 or 90 kg body weight, respectively. Our study investigates the nonlinear elimination of eculizumab and discusses the importance of accounting for eculizumab target-mediated elimination in therapeutic drug monitoring.

Effect of Therapeutic Radiation on Polycaprolactone/Hydroxyapatite Biomaterials in a Calvarial Model.

Bone defects caused by cancer resection often require postoperative radiotherapy. Although various synthetic polymers have been introduced as graft materials, their biological behavior after radiation exposure remains unclear. Here, we investigated how polycaprolactone/hydroxyapatite (PCL/HA) implants respond to therapeutic radiation exposure (in terms of volume and bone regeneration). Four 8mm diameter calvaria defects were surgically created on the parietal bone of 6 rabbits. PCL/HA implants made of porous, solid, and hybrid polymers were grafted by random placement in each defect. The fourth defect was left untreated. Four weeks after surgery, radiation exposure was conducted weekly for 6 weeks (total: 48Gy). Micro-computed tomography and histologic analysis were performed at 3 and 6 months, and 6 months postradiation, respectively. The total augmented volumes of all implants showed no significant differences between 3- and 6-months postradiation computed tomography images. In histologic analysis, new bone areas were 0.45±0.11mm2, 2.02±0.34mm2, and 3.60±0.77mm2 in solid, hybrid, and porous polymer grafts, respectively. Bone regeneration was limited to the periphery of the defect in the hybrid and porous polymer grafts, whereas new bone formed inside the porous implant. The total augmented volume of the defect was maintained without significant absorption even after radiation exposure. The PCL/HA implant maintained its structure despite radiation exposure. The porous PCL/HA implant demonstrated excellent bone regeneration, followed by the hybrid and solid implants. The PCL/HA implant is a promising candidate for bone defect reconstruction.

Tumor fluorescence and oxygenation monitoring during photodynamic therapy with chlorin e6 photosensitizer

BackgroundThe study is aimed at developing a method for monitoring photodynamic therapy (PDT) of a tumor using chlorin-type photosensitizers (PSs). Lack of monitoring of chlorin e6 (Cе6) photobleaching, hemoglobin oxygenation and blood flow during light exposure can limit the PDT effectiveness. Materials and methodsPhototheranostics includes spectral-fluorescence diagnostics of Ce6 distribution in the NIR range and PDT with simultaneous assessment of hemoglobin oxygenation and tumor blood flow. Fluorescence diagnostics and PDT were performed using the single laser λexc=660 ± 5 nm. ResultsCombined spectroscopic PDT monitoring method allowed simultaneous estimation of Ce6 photobleaching, hemoglobin oxygenation and tumor vascular thrombosis during PDT without interrupting the therapeutic light exposure. ConclusionThe developed method of tumor phototheranostics using chlorin-type PSs may make it possible to personalize the duration of therapeutic light exposure during PDT.

Diabetes-related complications, glycemic levels, and healthcare utilization outcomes after therapeutic inertia in type 2 diabetes mellitus

AimsTo assess diabetes-related complications, glycemic levels, and healthcare utilization 12 months after exposure to therapeutic inertia among patients with type 2 diabetes mellitus (T2D). MethodsThis retrospective cohort study analyzed data from the OneFlorida Clinical Research Consortium (electronic health records from Florida practices/clinics). The cohort included adult patients (≥18 years old) with T2D who had an HbA1c≥7.0% (53 mmol/mol) recorded from January 1, 2014-September 30, 2019. Therapeutic inertia (exposed vs. not exposed) was evaluated during the six months following HbA1c≥7.0% (53 mmol/mol). The outcomes assessed during the 12-month follow-up period included diabetes-related complications (continuous Diabetes Complications and Severity Index (DCSI)), glycemic levels (continuous follow-up HbA1c lab), and healthcare utilization counts. We analyzed data using multivariable regression models, adjusting for covariates. ResultsThe cohort included 26,881 patients with T2D (58.94% White race, 49.72% female, and mean age of 58.82 (SD=13.09)). After adjusting for covariates, therapeutic inertia exposure was associated with lower DCSI (estimate=−0.14 (SE=0.03), p < 0.001), higher follow-up HbA1c (estimate=0.14 (SE=0.04), p < 0.001), and lower rates of ambulatory visits (rate ratio=0.79, 95% CI=0.75–0.82). ConclusionsFindings communicate the clinical practice implications and public health implications for combating therapeutic inertia in diabetes care.

To homeostasis and beyond! Recent advances in the medicinal chemistry of heterobifunctional derivatives.

The field of induced proximity therapeutics has expanded dramatically over the past 3 years, and heterobifunctional derivatives continue to form a significant component of the activities in this field. Here, we review recent advances in the field from the perspective of the medicinal chemist, with a particular focus upon informative case studies, alongside a review of emerging topics such as Direct-To-Biology (D2B) methodology and utilities for heterobifunctional compounds beyond E3 ligase mediated degradation. We also include a critical evaluation of the latest thinking around the optimisation of physicochemical and pharmacokinetic attributes of these beyond Role of Five molecules, to deliver appropriate therapeutic exposure in vivo.