Pharmacodynamic Changes Research Articles

Nonclinical evaluations of deucravacitinib and Janus kinase inhibitors in homeostatic and inflammatory pathways.

Translational medicine provides insight into novel drugs and predicts unwanted effects. In well-characterized pathways (e.g., cytokine-Janus kinase [JAK]-signal transducers and activators of transcription [STAT]), a variety of in vitro assessments were used to estimate selectivity of effects on different potential targets (i.e., JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]). Several approved drugs were characterized as selective for the JAK family. These assessments are challenged by a lack of compounds that only inhibit one JAK family member. Deucravacitinib is a first-in-class, oral, selective, allosteric inhibitor of TYK2, a kinase required for IL-12, IL-23, and Type I interferon signaling. Unlike deucravacitinib, which selectively binds to the TYK2 regulatory domain, JAK1,2,3 inhibitors target the catalytic domain, contributing to nonselective targeting of JAK1,2,3. Cytokines associated with JAK1,2,3 signaling are required for both immune and nonimmune functions. A similar laboratory abnormality profile was observed in clinical trials using JAK1,2,3 inhibitors that has not been observed with deucravacitinib. In vitro testing of JAK1,2,3 inhibitors has relied upon assays of signal transduction, such as those measuring STAT phosphorylation, for estimates of potency and selectivity. These assay systems can be effective in estimating in vivo efficacy; however, they may not provide insight into downstream outcomes of receptor signaling, which may be more relevant for evaluating safety aspects. Assay systems assessing functional outcomes from cells may yield a more useful translational evaluation. Here, deucravacitinib was assessed for potency and selectivity versus three representatives of the JAK inhibitor class (tofacitinib, baricitinib, and upadacitinib) based on functional assays. JAK inhibitors had suppressive activity against JAK2-dependent hematopoietic colony-forming assays modeling thrombopoiesis, erythropoiesis, and myelopoiesis; however, deucravacitinib did not. Deucravacitinib had limited potency against NK cells, cytotoxic T cells, T-helper cells, and regulatory T cells activated by JAK1/JAK3-dependent common gamma chain cytokines. These data are consistent with the biologic role of JAK1,2,3 and pharmacodynamic changes in clinical laboratory abnormalities. Against TYK2-dependent cytokines, deucravacitinib selectively inhibited Type I interferon stimulation of monocytes and dendritic cells and was a more potent inhibitor than JAK inhibitors. IL-12 and IL-23 functional outputs were similarly potently inhibited by deucravacitinib. Results are consistent with deucravacitinib selectively inhibiting TYK2.

Pharmacotherapy of older and senile patients. Review

Drug therapy of older and senile patients has several features due to age-related changes in the pharmacokinetics and pharmacodynamics of drugs, as well as the nature of the development and course of the disease. Age-related changes in drug pharmacodynamics, and increased or decreased sensitivity to drugs of different pharmacotherapeutic groups significantly affect the drug effectiveness and safety in the body. These peculiarities must be considered when prescribing pharmacotherapy for elderly and senile patients, and adjusting doses and regimens of drug administration. Morbidity in older people is characterised by a high level of polymorbidity and polypharmacy caused by it. When prescribing medicine to older patients, it has to observe all indications and contraindications. The drug interaction problem, which can increase the side effects risk, requires special attention under the conditions of age-related polymorbidity and polypharmacy. To optimise the metabolism and functions of the body, it is advisable to include metabolic therapy drugs in the older patients' complex therapy. Adherence to the rules for prescribing medicines according to the age-related features of their action is an important prerequisite for rational pharmacotherapy of older and senile patients. _________________________________________________________________________________________ Keywords: pharmacotherapy in ageing; pharmacokinetics; drug pharmacodynamics; polymorbidity; polypharmacy

Polypharmacy and Deprescription: Role of Internists.

Polypharmacy is the concurrent use of five or more drugs per day. It is common in old age because of multimorbidity. The prevalence of polypharmacy is increasing as the number of old people is increasing worldwide. The proliferation of clinical guidelines and wider availability of preventive and curative medicines are important causes of polypharmacy. Appropriate polypharmacy is beneficial to the patients. However, polypharmacy may be inappropriate, causing adverse effects, drug interactions (DI), poor treatment efficacy, hospitalizations, and high healthcare costs. Prescribing cascade and legacy prescribing add to the burden of inappropriate polypharmacy. Inappropriate polypharmacy can be prevented or managed by medication optimization through medication review, deprescription, ensuring adherence, and patient education. Deprescription includes the removal of risky, unnecessary, and duplicate drugs, replacement with efficacious drugs, and relaxation of tight control as per life expectancy. Several deprescription tools (both explicit and implicit) exist for helping physicians to decide when to deprescribe or to add medicines, especially in old age. Care should be taken during deprescription to prevent unjustified omission, reduction to subtherapeutic dose, and onset of withdrawal features. Age and disease-related changes in pharmacokinetics and pharmacodynamics of drugs should be considered during the optimization of pharmacotherapy.

Development of a quick guide for assessment of the most frequently used renal risk medication in Danish hospitals and primary care.

Due to changes in pharmacokinetics and pharmacodynamics, patients with impaired renal function suffer an increased risk of suboptimal and potentially harmful medication treatment. This necessitates careful consideration of medications affected by impaired renal function when performing medication reviews. The aim of this study was to develop a quick guide (a list of recommendations) for assessing renal risk medications in medication reviews led by hospital pharmacists. The list was based on the 100 most frequently used medications in Danish hospitals and primary care. After combining the 200 records, 29 duplicates were excluded resulting in a pool of 171 medications. Assessment by two clinical pharmacists led to the exclusion of 121 medications. Of the remaining 50 medications, seven were discussed among the two pharmacists, and two of these were also in the research group to reach a consensus. The renal risk quick guide comprised 50 medications. The most prevalent medications on the list were from Anatomical Therapeutic Chemical Classification System (ATC)-group N, C and L. Recommendations from two databases were included in the quick guide in order to provide clinical pharmacists with existing, updated evidence on medication use in impaired renal function. The next step is to test the feasibility of the quick guide in daily practice when performing medication reviews.

Central Nervous System Medications: Pharmacokinetic and Pharmacodynamic Considerations for Older Adults.

Most drugs have not been evaluated in the older population. Recognizing physiological alterations associated with changes in drug disposition and with the ultimate effect, especially in central nervous system-acting drugs, is fundamental. While considering pharmacokinetics, it should be noted that the absorption of most drugs from the gastrointestinal tract does not change in advanced age. There are only few data about the effect of age on the transdermal absorption of medications such as fentanyl. Absorption from an intramuscular injection may be similar in older adults as in younger patients. The distribution of lipophilic drugs (such as diazepam) is increased owing to a relative increase in the percentage of body fat, causing drug accumulation and prolonged drug elimination following cessation. Phase I drug biotransformation is variably decreased in aging, impacting elimination, and hepatic drug clearance has been shown to decrease in older individuals by 10-40% for most drugs studied. Lower doses of phenothiazines, butyrophenones, atypical antipsychotics, antidepressants (citalopram, mirtazapine, and tricyclic antidepressants), and benzodiazepines (such as diazepam) achieve the same extent of exposure. For renally cleared drugs with no prior metabolism (such as gabapentin), the glomerular filtration rate appropriately estimates drug clearance. Important pharmacodynamic changes in older adults include an increased sedative effect of benzodiazepines at a given drug exposure, and a higher sensitivity to mu opiate receptor agonists and to opioid adverse effects. Artificial intelligence, physiologically based pharmacokinetic modeling and simulation, and concentration-effect modeling enabling a differentiation between the pharmacokinetic and the pharmacodynamic effects of aging might help to close some of the gaps in knowledge.

Preliminary safety, antitumor activity, and pharmacodynamics of intratumoral ABO2011 (IL-12 mRNA) in patients with advanced solid tumors.

e14583 Background: Interleukin (IL)-12 is a potent immunomodulatory cytokine demonstrating robust antitumor activity in multiple preclinical studies and potent immune-stimulating potential in humans. However, systemic delivery of IL-12 can result in life-threatening toxicity and therefore has shown limited efficacy at doses that can be safely administered. ABO2011 is a human IL-12 mRNA encapsulated in lipid nanoparticle and has been developed to be more effective and less toxic through the use of novel delivery technology and intratumoral injection. Methods: This phase I trial enrolled adults with advanced solid tumors who failed available standard treatments (NCT05392699). The trial was designed to primarily evaluate the safety of ABO2011 in single-dose cohorts and multiple-dose cohorts using “3+3” dose escalation approach. Patients (pts) would receive intratumoral ABO2011 at either a single dose, QW with 3 doses overall, every 3 weeks (Q3W) or QW followed by Q3W. Results: As of 09 December 2023, a total of 20 pts were enrolled and received at least one dose of ABO2011 at 4 μg single dose, 4 μg QW for 3 times, 12 μg single dose, 12 μg QW for 3 times followed by Q3W, 24 μg Q3W and 48 μg Q3W. Seventeen (85%) pts experienced treatment-related adverse events (TRAEs), and all were grade 1 or 2, including pyrexia (35%), pain (25%), and gamma-glutamyl transferase increased (25%). There were no dose-limiting toxicities or treatment-related SAEs reported and no TRAEs leading to treatment discontinuation. Of the 17 evaluable pts per RECISIT v1.1, 5 maintained stable disease, and the progression free survivals achieved 6.0 months, 5.6 months and 4.1 months for pts with colorectal cancer (6th line), non-small cell lung cancer (5th line) and pancreatic cancer (4th line), respectively. Peripheral blood IL-12 and IFN-γ levels increased and peaked at 24 hours and 48 hours after dosing, respectively, indicating expression of IL-12 and subsequent induction of IFN-γ after ABO2011 administration. Dose-dependent elevation of CXCL9, CXCL10, CXCL11 in peripheral blood was observed, consistent with the activation of downstream pathway of IFN-γ. CD8 T cells infiltration and PD-L1 expression were increased in tumor microenvironment (TME) at day 7, and further RNA sequencing analysis revealed increase of activated CD8 T cell and antigen processing and presentation after study treatment, suggesting the regulation of TME by ABO2011 and supporting the combination with PD-1(L1) inhibitor. Conclusions: Intratumoral ABO2011 was safe and well-tolerated in pts with advanced solid tumors. The pharmacodynamic changes were as expected. Promising preliminary antitumor activities of the single agent and the pharmacodynamic profiles support further investigation of ABO2011 in combination with immune checkpoint inhibitor. Clinical trial information: NCT05392699 .

CLARITY-PanTumor01: A phase 2 trial of the claudin 18.2-specific antibody-drug conjugate AZD0901 (CMG901) in patients with CLDN18.2-expressing advanced solid tumors.

TPS3163 Background: Gastric/gastroesophageal junction (G/GEJ) and pancreatic cancer are associated with poor outcomes and high unmet need. Claudin 18.2 (CLDN18.2) is highly expressed in gastric, esophageal, and pancreatic ductal adenocarcinoma (PDAC), and is a clinically validated target. AZD0901 is a potential first-in-class antibody-drug conjugate (ADC) comprising a humanized anti-CLDN18.2 IgG1 antibody conjugated via a protease-cleavable linker to monomethyl auristatin E (MMAE), a cytotoxic microtubule-disrupting agent. Interim results from the ongoing, first-in-human, Phase 1 trial of AZD0901 monotherapy in patients with G/GEJ cancer (NCT04805307) who were refractory to and/or intolerant of standard therapies demonstrated promising efficacy and a manageable safety profile. Here we describe an ongoing, Phase 2 study of AZD0901 in patients with CLDN18.2-expressing advanced solid tumors, including G/GEJ cancer and PDAC. Methods: This open-label, multicenter study (NCT06219941) comprises multiple substudies. Substudy 1 is recruiting patients with human epidermal growth factor receptor 2 (HER2)-negative, CLDN18.2-expressing G/GEJ cancer with ≤2 prior lines of therapy for unresectable or metastatic disease, who are randomized 1:1 to receive AZD0901 1.8 or 2.2 mg/kg intravenous (IV) every 3 weeks (Q3W). Substudy 2 is recruiting patients with previously untreated CLDN18.2-expressing metastatic PDAC to receive AZD0901 (up to 2.2 mg/kg IV Q3W) and either a combination of 5-fluorouracil 2400 mg/m2 IV on Days 1 and 2 Q2W, leucovorin 400 mg/m2 or l-leucovorin 200 mg/m2 IV on Days 1 and 2 Q2W, and irinotecan 150 or 180 mg/m2 or nanoliposomal irinotecan 50 mg/m2 IV on Day 1 Q2W (Arm 1), or gemcitabine 1000 mg/m2 IV on Days 1 and 8 Q3W (Arm 2), per investigator’s choice. Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent. Eligible patients are aged ≥18 years with histologically confirmed, unresectable or metastatic disease, ≥1 measurable lesion per Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, and Eastern Cooperative Oncology Group performance status 0–1. Key exclusion criteria include unstable and/or active peptic ulcer disease or digestive tract bleeding, ascites requiring drainage, central nervous system metastases, and prior exposure to an MMAE-based ADC or CLDN-18.2-targeted agents other than an anti-CLDN18.2 targeted monoclonal antibody. Primary endpoints include safety, tolerability, and objective response rate per RECIST v1.1. Secondary endpoints include overall survival, progression-free survival, duration of response, disease control rate, best change in target lesion size, pharmacokinetics, immunogenicity, and pharmacodynamics. Recruitment began in December 2023, and sites across Australia, Asia, Europe, and North America will enroll patients. Clinical trial information: NCT06219941 .

A phase 1, open-label, dose escalation study on the safety and tolerability of ANK-101 in advanced solid tumors.

TPS2689 Background: IL-12 is a cytokine that can stimulate both innate and adaptive tumor immunity. Clinical trials of intravenous IL-12 demonstrated anti-tumor activity limited by significant systemic toxicity, including patient deaths. ANK-101 is an anchored immunotherapy that links IL-12 to aluminum hydroxide through an alum-binding protein (ABP). The ANK-101 complex anchors IL-12 in the tumor microenvironment (TME), resulting in prolonged local retention and low levels of systemic absorption. Preclinical studies in murine tumor models showed that ANK-101 is retained at the injection site for up to 28 days, recruits and activates T and NK cells, promotes M1 myeloid cell differentiation, induces regression of both injected and un-injected tumors, and induces immunologic memory. Methods: This is a first-in-human, open-label dose escalation study of ANK-101 in advanced solid tumors with a planned sample size of 12-36 participants. The first three dose escalation cohorts include a single participant, and then study enrollment follows a standard 3+3 dose escalation design. If no dose limiting toxicity (DLT) is observed, the dose level will be escalated until ≥1/3 or ≥2/6 patients experience a DLT. An additional ten patients will be enrolled at the recommended dose for expansion (RDE). Participants will be treated with intratumoral ANK-101 every 3 weeks for 4 cycles. Imaging or clinical assessments will be performed at week 12. If there is no significant clinical deterioration or unacceptable toxicity at this visit, participants may receive four more cycles. Eligible patients must have an advanced solid malignancy refractory to standard treatment and be accessible for injection and biopsy, measurable disease by RECIST v1.1, and ECOG PS of 0-1. Key exclusion criteria include tumors close to vital structures, uncontrolled bleeding disorders, and active autoimmune disease. Primary objectives of the study are to determine the safety and tolerability of ANK-101 and identify the RDE. Secondary objectives include pharmacokinetics (PK) and immunogenicity (ADA) of ANK-101 and clinical activity as measured by ORR, DCR, DOR and PFS by RECIST v1.1. Exploratory objectives include assessment of QOL using FACT-G and profiling immune-based pharmacodynamic (PD) changes. PD assessments will include serum cytokines and circulating immune cells, and local levels of PD-L1, CD8+ T cells, and CD68+ macrophages, and changes in gene expression within the TME. This clinical trial is in progress. Clinical trial information: NCT06171750 .

WHEN LESS IS MORE: THE ROLE OF DEPRESCRIBING IN THE ELDERLY - A NARRATIVE REVIEW OF THE EVIDENCE

The aging population is associated with an increase in elderly individuals with multimorbidity and the consequent polypharmacy. While appropriate in some cases, this often leads to the prescription of potentially inappropriate medications. Older individuals are more susceptible to adverse events due to pharmacodynamic and pharmacokinetic changes resulting from physiological alterations typical of aging, which interfere with drug metabolism. The aging process is complex, associated with multimorbidity, geriatric syndromes, functional and/or cognitive deficits, and, consequently, limited life expectancy. Currently, about 40% of the elderly are polymedicated. Deprescribing is an activeprocess of reviewing all of a patient's medications, performed by a physician, based on a risk/benefit assessment. Polypharmacy is associated with an increased risk of mortality, falls, drug interactions, and hospitalizations. The deprescribing process can lead to a reduction of about 39% in chronic medication, resulting in increased therapeutic adherence to the remaining drugs. Deprescribing is a fundamental pillar of person- centred care, and the population should be aware of its importance. A classic review was conducted through bibliographic research of systematic reviews on Medline. This narrative review aimed to address polypharmacy and its prevalence in the elderly population, evaluate the benefits and risks of deprescribing, and identify barriers and facilitating factors in the deprescribing process.

Supratherapeutic INR During Treatment With Nirmatrelvir/Ritonavir and Warfarin and Acute Illness With COVID-19: A Case Report

Background: Several studies have examined INR fluctuations using pharmacokinetic (PK) models or post-hoc INR values after completing nirmatrelvir/ritonavir, but further study of the effects of the drug interaction with warfarin during treatment is necessary. Case Summary: Nirmatrelvir/ritonavir is largely utilized in the outpatient setting so data regarding INR trends in hospitalized patients on warfarin is limited. However, many who receive nirmatrelvir/ritonavir outpatient experience difficulty with presenting to clinic for INR checks due to feeling acutely ill along with isolation precautions. We present the case of a patient receiving warfarin and utilizing home INR testing for monitoring. After diagnosis of coronavirus disease of 2019 (COVID-19), she was started on nirmatrelvir/ritonavir on day five after testing positive. Most recent INR prior to the start of therapy was 2.7 and had been stable on the same dose for months prior to infection. On day two of nirmatrelvir/ritonavir, her INR rose to 4.0 on home point of care INR testing. Despite reducing her dose of warfarin by 15%, her INR remained supratherapeutic the day after completing nirmatrelvir/ritonavir (4.0) and for several checks after. One month after completion of therapy, her INR returned to therapeutic levels. Practice Implications: While PK models and case series have hypothesized both potential increases or decreases in INR with the nirmatrelvir/ritonavir and warfarin interaction, COVID-19 infection itself can cause several pharmacodynamic changes which can increase INR, including decreased appetite and, in severe cases, organ dysfunction. This case provides real-world insight into the drug interaction between nirmatrelvir/ritonavir and the drug-disease state interaction between warfarin and COVID-19.

HPN328, a Trispecific T Cell-Activating Protein Construct Targeting DLL3-Expressing Solid Tumors.

Delta-like ligand 3 (DLL3) is expressed in more than 70% of small cell lung cancers (SCLCs) and other neuroendocrine-derived tumor types. SCLC is highly aggressive, and limited therapeutic options lead to poor prognosis for patients. HPN328 is a trispecific T cell-activating construct (TriTAC) consisting of three binding domains: a CD3 binder for T-cell engagement, an albumin binder for half-life extension, and a DLL3 binder for tumor cell engagement. In vitro assays, rodent models, and non-human primates were used to assess the activity of HPN328. HPN328 induces potent dose-dependent killing of DLL3-expressing SCLC cell lines in vitro, concomitant with T-cell activation and cytokine release. In an NCI-H82 xenograft model with established tumors, HPN328 treatment led to T-cell recruitment and anti-tumor activity. In an immunocompetent mouse model expressing a human CD3ε epitope, mice previously treated with HPN328 withstood tumor rechallenge, demonstrating long-term anti-tumor immunity. When repeat doses were administered to cynomolgus monkeys, HPN328 was well tolerated up to 10 mg/kg. Pharmacodynamic changes, such as transient cytokine elevation, were observed, consistent with the expected mechanism of action of T-cell engagers. HPN328 exhibited linear pharmacokinetics in the given dose range with a serum half-life of 78 to 187 hours, supporting weekly or less frequent administration of HPN328 in humans. Preclinical and nonclinical characterization suggests that HPN328 is a highly efficacious, safe, and novel therapeutic candidate. A phase 1/2 clinical trial is currently underway testing safety and efficacy in patients with DLL3-expressing malignancies.

Pharmacokinetic and pharmacodynamic changes of Ivabradine induced by hypoalbuminemia

Pharmacokinetic and pharmacodynamic changes of Ivabradine induced by hypoalbuminemia

Pharmacodynamic changes in tumor and immune cells drive iberdomide’s clinical mechanisms of activity in relapsed and refractory multiple myeloma

Iberdomide is a next-generation cereblon (CRBN)-modulating agent in the clinical development in multiple myeloma (MM). The analysis of biomarker samples from relapsed/refractory patients enrolled in CC-220-MM-001 (ClinicalTrials.gov: NCT02773030), a phase 1/2 study, shows that iberdomide treatment induces significant target substrate degradation in tumors, including in immunomodulatory agent (IMiD)-refractory patients or those with low CRBN levels. Additionally, some patients with CRBN genetic dysregulation who responded to iberdomide have a similar median progression-free survival (PFS) (10.9months) and duration of response (DOR) (9.5months) to those without CRBN dysregulation (11.2month PFS, 9.4month DOR). Iberdomide treatment promotes a cyclical pattern of immune stimulation without causing exhaustion, inducing a functional shift in Tcells toward an activated/effector memory phenotype, including in triple-class refractory patients and those receiving IMiDs as a last line of therapy. This analysis demonstrates that iberdomide's clinical mechanisms of action are driven by both its cell-autonomous effects overcoming CRBN dysregulation in MM cells, and potent immune stimulation that augments anti-tumor immunity.

An NGS-based assay for accurate detection and quantification of immune gene expression in mouse tumor models.

Tumor microenvironment (TME) is a complex dynamic system with many tumor-interacting components including tumor-infiltrating leukocytes (TILs), cancer associated fibroblasts, blood vessels, and other stromal constituents. It intrinsically affects tumor development and pharmacology of oncology therapeutics, particularly immune-oncology (IO) treatments. Accurate measurement of TME is therefore of great importance for understanding the tumor immunity, identifying IO treatment mechanisms, developing predictive biomarkers, and ultimately, improving the treatment of cancer. Here, we introduce a mouse-IO NGS-based (NGSmIO) assay for accurately detecting and quantifying the mRNA expression of 1080 TME related genes in mouse tumor models. The NGSmIO panel was shown to be superior to the commonly used microarray approach by hosting 300 more relevant genes to better characterize various lineage of immune cells, exhibits improved mRNA and protein expression correlation to flow cytometry, shows stronger correlation with mRNA expression than RNAseq with 10x higher sequencing depth, and demonstrates higher sensitivity in measuring low-expressed genes. We describe two studies; firstly, detecting the pharmacodynamic change of interferon-γ expression levels upon anti-PD-1: anti-CD4 combination treatment in MC38 and Hepa 1-6 tumors; and secondly, benchmarking baseline TILs in 14 syngeneic tumors using transcript level expression of lineage specific genes, which demonstrate effective and robust applications of the NGSmIO panel.

A Phase II, Open-Label, Randomized Trial of Durvalumab With Olaparib or Cediranib in Patients With Mismatch Repair—Proficient Colorectal or Pancreatic Cancer

BackgroundThe use of immunotherapy in mismatch repair proficient colorectal cancer (pMMR-CRC) or pancreatic adenocarcinoma (PDAC) is associated with limited efficacy. DAPPER (NCT03851614) is a phase 2, basket study randomizing patients with pMMR CRC or PDAC to durvalumab with olaparib (durvalumab + olaparib) or durvalumab with cediranib (durvalumab + cediranib). MethodsPDAC or pMMR-CRC patients were randomized to either durvalumab+olaparib (arm A), or durvalumab + cediranib (arm B). Co-primary endpoints included pharmacodynamic immune changes in the tumor microenvironment (TME) and safety. Objective response rate, progression-free survival (PFS) and overall survival (OS) were determined. Paired tumor samples were analyzed by multiplexed immunohistochemistry and RNA-sequencing. ResultsA total of 31 metastatic pMMR-CRC patients were randomized to arm A (n = 16) or B (n = 15). In 28 evaluable patients, 3 patients had stable disease (SD) (2 patients treated with durvalumab + olaparib and 1 patient treated with durvalumab + cediranib) while 25 had progressive disease (PD). Among patients with PDAC (n = 19), 9 patients were randomized to arm A and 10 patients were randomized to arm B. In 18 evaluable patients, 1 patient had a partial response (unconfirmed) with durvalumab + cediranib, 1 patient had SD with durvalumab + olaparib while 16 had PD. Safety profile was manageable and no grade 4-5 treatment-related adverse events were observed in either arm A or B. No significant changes were observed for CD3+/CD8+ immune infiltration in on-treatment biopsies as compared to baseline for pMMR-CRC and PDAC independent of treatment arms. Increased tumor-infiltrating lymphocytes at baseline, low baseline CD68+ cells and different immune gene expression signatures at baseline were associated with outcomes. ConclusionsIn patients with pMMR-CRC or PDAC, durvalumab + olaparib and durvalumab + cediranib showed limited antitumor activity. Different immune components of the TME were associated with treatment outcomes.

Review of drug-drug interactions in patients with prostate cancer.

The objective of this review is to provide an overview of common drug-drug interactions (DDIs) associated with prostate cancer treatments and outline recommendations for managing polypharmacy. A literature search of PubMed, Embase, and CINAHL was carried out to identify pharmacokinetic and pharmacodynamic changes caused by DDIs that are relevant for prostate cancer patients, DDIs between prostate cancer therapies and co-administered medications (both prescription and over-the-counter), and measures to prevent DDIs. Medication package inserts were used to identify the impact of DDI on the prostate cancer therapy and suggested interventions. No DDIs are expected for the LHRH agonists leuprolide acetate, histrelin, goserelin, or leuprolide mesylate. However, DDIs have been reported for GnRH antagonists, anti-androgens, PARP inhibitors, and taxanes. Although there are no confirmed DDIs for sipuleucel-T to date, it is not generally recommended to use sipuleucel-T concurrently with immunosuppressive medications. Interventions to prevent DDIs include the use of software that can detect clinically significant DDIs, up-to-date medication reconciliation, the inclusion of dedicated clinical pharmacists in cancer treatment teams, and patient/caregiver education. Prostate cancer patients have a high risk of potential DDIs due to numerous new anti-cancer therapies, the increased use of treatment combinations, and the likelihood of comorbid conditions also requiring drug therapy. Drug-drug interaction screening software, up-to-date medication reconciliation, inclusion of oncology pharmacists on healthcare teams, and patient/caregiver education will aid the development of treatment plans that focus on achieving an optimal risk-benefit profile whilst reducing the risk of DDIs.

Abstract PO1-20-06: Phase 2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 +/- pertuzumab in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan

Abstract Background: Therapies to effectively manage patients (pts) with metastatic HER2+ breast cancer have significantly improved over the years, but improvement is still needed in both efficacy and tolerability. BDC-1001 is an ISAC consisting of a trastuzumab biosimilar conjugated to a proprietary cell membrane impermeable TLR7/8 agonist via a non-cleavable linker, administered IV every 2 weeks. It is designed to trigger the innate immune system and generate a durable tumor-targeted adaptive immune response. Preclinical studies indicate that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, leading to complete tumor regression in a TLR- and Fc receptor-dependent manner [1]. Moreover, preclinical studies with a murine surrogate of BDC-1001 (trastuzumab-T785 ISAC) indicate improved anti-tumor activity with trastuzumab-T785 compared with trastuzumab/pertuzumab. In these preclinical studies, the combination of trastuzumab-T785 and pertuzumab demonstrated significantly enhanced efficacy in multiple HER2-expressing tumor models, including those with lower HER2 expression [1]. The addition of pertuzumab decreased the quantity of ISAC required for anti-tumor activity in the JIMT-1 HER2 IHC2+ model. Moreover, the combination of pertuzumab with the ISAC significantly increased the cytokine and chemokine concentrations in the tumor xenografts, compared with monotherapy or trastuzumab/pertuzumab, indicating enhanced myeloid activation in the tumor. These preclinical studies suggest that this combination may enhance the clinical activity of trastuzumab-based ISACs. The completed part of the BDC-1001 dose escalation trial (NCT04278144) demonstrated safety, PK and pharmacodynamic changes compatible with the ISAC mechanism of action, and a wide range of antitumor activity (incl. cases with breast cancer); resulting in a RP2D of 20 mg/kg q2w [2]. Two trials are underway, including a Phase 2 trial in other HER2+ malignancies, and a randomized Phase 2 trial with BDC-1001 alone and in combination with pertuzumab in patients with HER2-positive MBC previously treated with 2 or more prior anti-HER2 therapies, including trastuzumab deruxtecan. Methods: The Phase 2 multicenter, open-label, randomized study (BBI-20231001) is enrolling up to 66 pts with HER2-positive (ASCO/CAP guidelines 2018) MBC previously treated with 2 or more prior anti-HER2 therapies, including trastuzumab deruxtecan as one of the prior therapies. Pts must be 18 years or older, have measurable disease (RECIST v1.1), and have Eastern Cooperative Oncology Group performance status of 0 or 1. Pts will be administered BDC-1001 20 mg/kg every 2 weeks (IV q2w) and randomized 1:1 to receive BDC-1001 as a single agent or in combination with pertuzumab. The trial has a Simon 2-stage design within each arm. The primary objective is to determine the overall response rate per RECIST v1.1 of BDC-1001 alone and in combination with pertuzumab. Secondary objectives will evaluate safety, additional efficacy parameters, pharmacokinetics, and immunogenicity of BDC-1001 alone and in combination with pertuzumab. Exploratory objectives will include pharmacodynamic biomarkers in tumor tissue (baseline and on-treatment biopsies if feasible) and in peripheral blood to elucidate the mechanism of action and seek to identify biomarkers associated with BDC-1001 biological activity with or without pertuzumab. This study is expected to initiate accrual in 2H 2023. For additional information, please contact Bolt Biotherapeutics at 1-650-665-9295 or info@boltbio.com.

Evaluation of an IgG therapeutic efficacy in a humanized immune system mouse model lacking murine Fc gamma receptors

Abstract Fc gamma receptors (FcγRs) on residual murine immune cells in humanized immune system (HIS) mice can interact with human IgG-based therapeutics and confound preclinical results. We assessed impact of murine FcγRs on anti-PD1 efficacy in HIS mice engrafted with lung adenocarcinoma cells treated with pembrolizumab or vehicle. We also present humanization results for the newly generated FcγR knockout NOG-EXL. Methods: HIS NOG (huNOG) or HIS FcγR knockout NOG mice (FcResolv™ huNOG) were made using identical protocols with CD34+ cells (3 shared donors). Reconstitution was evaluated in naïve animals and HCC827 cells were inoculated in remaining animals. From D7, mice were dosed twice weekly for 4 wks then euthanized for blood, spleen, and tumor analysis. Results: Humanization was equivalent between strains. Pembro treatment showed significant tumor growth inhibition in 1 donor in FcResolv huNOG, but not in donor-matched huNOG. Human TILs in pembro-treated mice were significantly different between the strains for all donors, with more CD8+ T cells and fewer TAMs in FcResolv huNOG compared to vehicle-treated mice, and no significant differences in huNOG. Murine TIL analysis showed differences in murine macrophage populations between strains. Conclusions: Anti-PD1-treated FcResolv huNOG mice show expected pharmacodynamic changes and donor-dependent efficacy, whereas pembro-treated huNOG mice showed neither, demonstrating the impact of murine FcγRs on antibody IgG-based therapeutics.

Evaluation of potential drug-drug interactions with medical cannabis.

Cannabis-drug interactions have caused significant concerns, mainly due to their role in the cytochrome P450 (CYP) enzyme-mediated metabolic pathway of numerous medications. A systematic review was conducted to gain an overview of the potential interactions of cannabis with different drug classes by extracting pertinent information from published study data. From the inception of the study to October 1, 2023, we performed a systematic search of PubMed, Scopus, clinicaltrials.gov, and Web of Science. We included 54 out of 464 articles, and a total of 20 drug classes were identified to have interactions with medicinal cannabis. The cannabis-drug interactions were assessed and classified according to their probability and severity. The analysis revealed that antiepileptics had the most evidence of interaction with cannabis, followed by clobazam (CLB), warfarin, and tacrolimus. Generally, cannabis-drug interactions result in pharmacokinetic (PK) or pharmacodynamic (PD) changes. Therefore, careful monitoring should be performed to detect any unusual elevations in plasma levels. In addition, dose titrations or treatment withdrawal could help mitigate the adverse effects attributed to cannabis-drug interactions. Nevertheless, novel drugs are constantly emerging, and more research is needed to further identify potential interactions with cannabis.

Kajian efek interaksi antihipertensi dengan obat antiinflamasi nonsteroid (OAINS) terhadap tekanan darah pada pasien hipertensi

Hypertension causes atherosclerosis which can cause occlusion resulting in subchondral ischemia, which causes the exchange of nutrients and gases into the articular cartilage, which is disrupted and becomes the potential initiator of degradative changes or the so-called osteoarthritis. This review aims to evaluate the effect of antihypertensive drug interactions with NSAIDs on blood pressure. This article review was conducted using a narrative review study. The inclusion criteria in this article are the pharmacodynamic interaction of antihypertensives with NSAIDs in hypertensive patients with osteoarthritis. The results obtained seven articles that meet the inclusion criteria. Hypertensive patients with osteoarthritis receive medications that must be monitored because a drug-drug interaction can decrease the effectiveness of antihypertensives. One of the most widely used drugs in antihypertensive therapy is ACEi, but NSAIDs inhibit the antihypertensive effect on prostaglandin synthesis resulting from bradykinin production. The decrease in blood pressure stimulated by bradykinin plays an essential role in vasodilatation. The interaction of ACEi and NSAIDs can cause an increase in blood pressure with a minimum expansion of 1.1 mmHg. Still, when administering NSAIDs with CCBs, a decrease in blood pressure of 2.86 mmHg is obtained because the action is not dependent on prostaglandins. Based on the results, there were pharmacodynamic changes for both antihypertensive drugs and NSAIDs due to drug interactions that affected the patient's clinical outcome in the form of blood pressure.