Administration Of Single Dose Research Articles

Fixed dose ketamine for prehospital management of hyperactive delirium with severe agitation

IntroductionPatients exhibiting signs of hyperactive delirium with severe agitation (HDSA) may require sedating medications for stabilization and safe transport to the hospital. Determining the patient's weight and calculating the correct weight-based dose may be challenging in an emergency. A fixed dose ketamine protocol is an alternative to the traditional weight-based administration, which may also reduce dosing errors. The objective of this study was to evaluate the frequency and characteristics of adverse events following pre-hospital ketamine administration for HDSA. MethodsEmergency Medical Services (EMS) records from four agencies were searched for prehospital ketamine administration. Cases were included if a 250 mg dose of ketamine was administered on standing order to an adult patient for clinical signs consistent with HDSA. Protocols allowed for a second 250 mg dose of ketamine if the first dose was not effective. Both the 250 mg initial dose and the total prehospital dose were analyzed for weight based dosing and adverse events. ResultsReview of 132 cases revealed 60 cases that met inclusion criteria. Patients' median weight was 80 kg (range: 50-176 kg). No patients were intubated by EMS, one only requiring suction, three required respiratory support via bag valve mask (BVM). Six (10%) patients were intubated in the emergency department (ED) including the three (5%) supported by EMS via BVM, three (5%) others who were sedated further in the ED prior to requiring intubation. All six patients who were intubated were discharged from the hospital with a Cerebral Performance Category (CPC) 1 score. The weight-based dosing equivalent for the 250 mg initial dose (OR: 2.62, CI: 0.67–10.22) and the total prehospital dose, inclusive of the 12 patients that were administered a second dose, (OR: 0.74, CI: 0.27, 2.03), were not associated with the need for intubation. ConclusionThe 250 mg fixed dose of ketamine was not >5 mg/kg weight-based dose equivalent for all patients in this study. Although a second 250 mg dose of ketamine was permitted under standing orders, only 12 (20%) of the patients were administered a second dose, none experienced an adverse event. This indicates that the 250 mg initial dose was effective for 80% of the patients. Four patients with prehospital adverse events likely related to the administration of ketamine were found. One required suction, three (5%) requiring BVM respiratory support by EMS were subsequently intubated upon arrival in the ED. All 60 patients were discharged from the hospital alive. Further research is needed to determine an optimal single administration dose for ketamine in patients exhibiting signs of HDSA, if employing a standardized fixed dose medication protocol streamlines administration, and if the fixed dose medication reduces the occurrence of dosage errors.

Comprehensive assessment of dental implant procedures: a comparative study on different antibiotic prophylaxis regimens

Relevance. The administration of antibiotics in implantology is indicated to prevent suppurative inflammation conditions. Two regimens are commonly used: a single preoperative dose or prolonged postoperative antibiotic administration. Due to ethical constraints, certain parameters of antibiotic efficacy cannot be directly evaluated within clinical trials. These include the status of the implant-mandibular segment microbiome and the histological parameters of the tissue's inflammatory response at the implant site.Materials and methods. This study employed a miniature pig model comprising 10 males. The cohort was equally divided into two groups of five animals each. Group 1 received a single preoperative dose of amoxicillin/clavulanic acid 2 ml per 20 kg body weight. Group 2 received the same initial dose prior to implantation, followed by a daily postoperative dose of amoxicillin/clavulanic acid at 1 ml per 20 kg body weight for five days. Each animal received six dental implants. An implant site microbiological test was performed pre-surgery, on Day 1, 3, 7 and 14 post-surgery. Core needle biopsies for histological examination of the tissues were performed on the same postoperative days.Results. Microbiological testing revealed that Group 2 exhibited lower levels of Streptococcus spp. on Day 3 (p = 0.04) and Porphyromonas spp. on Day 7 (p = 0.04). Group 1 demonstrated reduced levels of Fusobacterium spp. on Day 1 (p = 0.02) and Porphyromonas spp. both pre-surgery (p = 0.04) and on Day 1 (p = 0.012). Comparative analysis of histological assays from the implant sites indicated identical tissue inflammatory responses, regardless of the antibiotic prophylaxis regimen.Conclusion. Both the single-dose and the prolonged antibiotic prophylaxis regimens, using amoxicillin/clavulanic acid for dental implantation, demonstrated similar histological patterns of tissue inflammation at the implant site, along with comparable microbiota profiles within the implant site. The oral mucosa exhibited an increased population of Staphylococcus spp. and Streptococcus spp., which might contribute to the development of resistant strains, as well as Candida spp., potentially increasing the risk of candidiasis infection onset.

Sustained release local anesthetics for pain management: relevance and formulation approaches.

This review attempted to ascertain the rationale for the formulation of sustained-release local anesthetics and summarize the various formulation approaches designed to date to achieve sustained and localized local analgesic effects. The incidence of pain, which is the concern of patients as well as health care professionals, is increasing due to accidents, surgical procedures, and other diseases. Local anesthetics can be used for the management of moderate to severe acute and chronic pain. They also allow regional analgesia, in situations where the cause and source of the pain are limited to a particular site or region, without the need for loss of consciousness or systemic administration of other analgesics thereby decreasing the risk of potential toxicities. Though they have an interesting antipain efficacy, the short duration of action of local anesthetics makes the need for their multiple injections or opioid adjuvants mandatory. To overcome this problem, different formulations are being designed that help achieve prolonged analgesia with a single dose of administration. Combination with adjuvants, liposomal formulations, lipid-based nanoparticles, thermo-responsive nanogels, microspheres, microcapsules, complexation with multivalent counterions and HP-β-CD, lipid-based nanoparticles, and bio-adhesive films, and polymeric matrices are among the approaches. Further safety studies are required to ensure the safe and effective utilization of sustained-release local anesthetics. Moreover, the release kinetics of the various formulations should be adequately established.

Abstract LB022: Preclinical anti-tumorigenic evaluation of AXL targeting antibody-drug-conjugate in an adenoid cystic carcinoma cell line xenograft model

Abstract Adenoid cystic carcinoma (ACC) is a rare type of salivary gland cancer. Despite the many advances made in helping understand the disease behavior and characteristics, the prevailing challenge in managing patients with ACC is the lack of clinically approved systemic therapy drugs to successfully treat those with advanced recurrent or metastatic disease. There are multiple promising candidate agents being evaluated preclinically and in early phase clinical trials, yet an effective drug with consistent overall response remains to be identified. AXL is a member of the TAM family of tyrosine kinase receptors, and its overexpression and activation is generally associated with poor prognosis and chemoresistance in many cancer types. Previous reports show AXL is significantly upregulated in a subset of ACC tumors. Here, we evaluate the tumor growth inhibition effects of a newly developed antibody-drug-conjugate targeting AXL (ADCT-601) in a xenograft ACC cell line model. MDA-ACC-01 cells express high levels of cell surface AXL as confirmed by biochemical analysis. The tumor growth inhibition of MDA-ACC-01 cell xenograft was tested in a single-dose drug administration study. Immunodeficient mice bearing ACC tumors were either injected with vehicle (n=7) or with ADCT-601 at 0.5 (n=9) or 1.0 mg/kg (n=7). ADCT-601 treatment with either 0.5 mg/kg or 1.0 mg/kg resulted in complete response (CR) for all tumor implants. To reaffirm the drug’s efficacy, we challenged the vehicle-treated tumor, prior to exceeding the tumor volume endpoint, with a single-dose of ADCT-601 at 1.0 mg/kg. Strikingly, by day 6 post-treatment, tumor volume began to shrink and eventually resulted in CR except in all but one case. These results demonstrate ADCT-601 is an effective drug with significant anti-tumor activity in our preclinical models and is worthy of additional investigation to determine its translational potential. Citation Format: Joseph O. Humtsoe, Anita Pothukuchi, Hyunseok Kang, Patrick Ha. Preclinical anti-tumorigenic evaluation of AXL targeting antibody-drug-conjugate in an adenoid cystic carcinoma cell line xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB022.

Single intravenous dose ondansetron induces QT prolongation in adult emergency department patients: a prospective observational study

BackgroundOndansetron is one of the most commonly used drugs in the emergency department (ED) for treating nausea and vomiting, particularly in intravenous (IV) form. Nevertheless, it has been shown to prolong QT interval and increase the risk of ventricular dysrhythmias. This study evaluated the associations between single IV ondansetron dosage and subsequent QTc prolongation in the ED.MethodsIn this prospective observational study, a total number of 106 patients presenting to the ED in a 3-month period with nausea and vomiting treated with IV ondansetron were enrolled. QT and QTc intervals were measured at baseline (QT0 and QTc0), and 60 min (QT60 and QTc60) following a single-dose administration of ondansetron at 4 or 8 mg doses. To evaluate the predictive ability of these variables, we employed receiver operating characteristic (ROC) curve analyses.ResultsThe predictive models for QTc prolongation 1-hour post-ondansetron administration showed the following: at baseline, the area under curve of 0.70 for QT, 0.71 for QTc, and 0.64 for dosage. Conversely, a QTc0 = 375 msec indicated a QTc60 > 480 msec with a specificity of 97%. Additionally, a QTc0 of 400 msec had a sensitivity of 100% in predicting a QTc60 < 480 msec, while a QTc0 > 460 msec predicted a QTc60 > 480 msec with a specificity of 98%. Moreover, 8 mg doses were associated with higher rates of QTc60 prolongation, while 4 mg doses favored maintaining QTc60 within normal limits.ConclusionsOur study demonstrates the predictive capacity of QT0, QTc0, and ondansetron dosage in forecasting QTc60 prolongation (> 480 msec) post-ondansetron administration. These findings advocate for their incorporation into clinical protocols to enhance safety monitoring in adult ED patients.

Single-dose nonsteroidal anti-inflammatory drugs in horses have no impact on concentrations of cytokines or growth factors in autologous protein solution and platelet-rich plasma.

To determine the effects of a single dose of the NSAIDs phenylbutazone, firocoxib, flunixin meglumine, and ketoprofen on concentrations of growth factors and cytokines in autologous protein solution (APS) and platelet-rich plasma (PRP). 6 adult university-owned horses. For the first phase, 6 horses were randomized to receive ketoprofen (1,000 mg) or flunixin meglumine (500 mg) IV. Blood was obtained and processed for APS (Pro-Stride) and PRP (Restigen) before and 6 hours after administration of NSAIDs. Horses underwent a 2-week washout period, after which the protocol was repeated using a crossover design. For the second phase, following at least a 2-week washout period, the study protocol was repeated with phenylbutazone (1 g) or firocoxib (57 mg) administered orally. Plasma was collected 6 hours after administration for evaluation of drug concentrations, and APS and PRP were analyzed for concentrations of drug, platelets, leukocytes, and several growth factors and cytokines (PDGF, fibroblast growth factor, TGF-β1, IL-1β, IL-10, IL-6, IL-8, and tumor necrosis factor-α) before and 6 hours after administration of NSAIDs using immunoassays. There were no significant differences in concentrations of cytokines or growth factors before or after administration of any NSAID. There were significant differences in concentrations of leukocytes and platelets based on both product and time. NSAID concentrations in plasma were not significantly different from concentrations in APS and PRP. These results help guide clinicians on the appropriate use of these NSAIDs in conjunction with the processing of APS and PRP, which is unlikely to significantly alter the final product after single-dose administration.

Effectiveness of Single Intravenous Dexamethasone in Prolongation of Spinal Anesthesia for Postoperative Analgesia in Elective Cesarean Section: A Systematic Review of Randomized Controlled Trials.

The analgesic effectiveness of a single perioperative dose of dexamethasone is not clearly defined. The administration of systemic medication like dexamethasone, opioids, and non-steroidal anti-inflammatory drugs has a positive effect on the prolongation of postoperative analgesia after cesarean section under spinal anesthesia. A single-dose administration of dexamethasone with moderate to high dose reduces postoperative pain, reduces opioid consumption, and prolongs spinal anesthesia after cesarean delivery. The aim of this systematic review was to investigate the effectiveness of single intravenous dexamethasone in prolongation of spinal anesthesia for postoperative analgesia in elective cesarean section. We conducted a search on PubMed, Google Scholar, the Cochrane Library, Hinari, and review articles on the effectiveness of intravenous dexamethasone for extending spinal anesthesia during elective cesarean sections, until June 2023. The searches were conducted by using keyword (IV dexamethasone OR/AND analgesia OR postoperative pain AND cesarean section OR child birth AND prolongation of spinal anesthesia). The articles included describe the analgesic efficacy of dexamethasone for prolongation of spinal anesthesia during cesarean section. A total of 25,384 papers were found using different searching methodologies from different electronic databases. The EndNote reference manager was used to remove duplicates, and 438 articles were selected for screening. Of those, 57 were included for critical evaluation, and 49 were removed with justification. The effectiveness of IV dexamethasone on the prolongation of spinal anesthesia and postoperative analgesia in women undergoing cesarean delivery is the subject of eight RCT studies on 628 parturients that are presented in the chosen journal articles from various countries. Intravenous dexamethasone administration immediately after clamping of the umbilical cord prolongs the duration of spinal block in patients undergoing cesarean sections and has a significant impact on reduction of postoperative pain severity, opioid consumption, and other pain requirements. When high-dose dexamethasone is administered intravenously, it can overcome complications that may arise after severe pain and increase patient satisfaction by extending the duration of postoperative analgesia and sensory block.

Effect of Benidipine Alone and in Combination With Bosentan and Sildenafil in Amelioration of Pulmonary Arterial Hypertension in Experimental Model in Rats.

Pulmonary arterial hypertension (PAH) is a persistent condition affecting the pulmonary arteries' endothelium. Benidipine, a calcium channel blocker, possesses vasodilatory, anti-inflammatory activity, reduces oxidative stress, and inhibits the activity of Transforming growth factor-β (TGF-β) and α-smooth muscle actin (α-SMA). The present study was designed to investigate the effect of benidipine alone and in combination with bosentan and sildenafil on monocrotaline (MCT)-induced pulmonary hypertension in a rat model. PAH was induced by a single-dose administration of MCT in rats. Animals were randomized into different groups and treated with benidipine alone and in combination with bosentan or sildenafil. Various parameters such as hemodynamic parameters, Fulton's index and oxidative stress parameters were performed. Additionally, histopathology of lung and right ventricular of heart tissue, immunohistochemistry, expression of α-SMA, endothelial nitric oxide synthase (eNOS), TGF-β, and RT-PCR, and an in vitro study using human umbilical vein endothelial cells (HUVECs) was also carried out. Treatment of benidipine and its combination exhibited better prevention in the elevated right ventricular systolic pressure, right ventricular hypertrophy, rise in oxidative stress, and increase in expression of α-SMA and TGF-β receptor 1 compared with MCT control group rats. In HUVECs, the expression of α-SMA was increased, whereas that of eNOS decreased after TGF-β exposure and was substantially reversed after pretreatment with benidipine. We concluded that benidipine and its combination with bosentan and sildenafil exhibit beneficial effects in MCT-induced PAH through the eNOS/TGF-β/α-SMA signaling pathway.

The effect of prophylactic esketamine in labor and cesarian delivery on the prevention of postpartum depression (PPD): A systematic review and meta-analysis of randomized controlled trials

IntroductionPostpartum depression (PPD) is a common psychiatric illness affecting maternal health, which can lead to poor outcomes for the infant, mother and family. Since the usual pharmacological treatment has low efficacy and a delayed onset of action, new treatment options should be explored. A recent meta-analysis demonstrated positive effects of racemic ketamine on PPD, but limited evidence is available on its more potent derivative esketamine.ObjectivesTo determine the effect of esketamine administered prophylactically during labor on the risk of incidence of PPD at 1 week and 6 weeks after delivery.MethodsPubMed, Scopus and GoogleScholar databases were searched for randomized controlled trials that studied the efficacy of esketamine that screened for PPD using the Edinburgh Postpartum Depression Scale (EPDS). Risk ratio was used to determine the effect of incidence on PPD. Heterogeneity was examined with I2 statistics. A random-effects model was used, as per moderate heterogeneity (I2=59%, p-value&lt;0.05).ResultsWe included 7 RCTs with 1287 patients, 635 having received esketamine (49.3%). Patient-controlled intravenous analgesia (PCIA) or single intravenous dose during the delivery or cesarian section were the main drug delivery methods. Follow-up ranged from 4 weeks to 6 months, and EPDS cut-off scores for depression risk differed between studies, from 9 to 13 points. Dosages varied from 0.2mg/kg to 0.5mg/kg for single-dose administration and 0.1mg/kg to 1.25mg/kg for PCIA. Incidence of PPD at one week (RR: 0.459 95%CI 0.217-0.970; p&lt;0.05; figure 1A) and at 6 weeks (RR: 0.470 95%CI 0.273-0.810; p&lt;0.01; figure 1B) was significantly less common in patients who received esketamine during or after labor. Risk of bias was low in 5 studies and moderate in 2 studies. Risk of publication bias is significant.Image:ConclusionsProphylactic esketamine seems to improve EPDS scores in women at one and six weeks after birth. A more thorough analysis of the adverse effects on maternal and neonatal health are required, and long-term benefits are not fully understood. Larger multicenter studies would be a welcome addition to the issue at hand.Disclosure of InterestNone Declared

The capability of Piper betle leaves ethanolic extract to inhibit neutrophil infiltration in sepsis-induced BALB/c Mice

Background: Sepsis due to ESBL-producing Escherichia coli infection requires innovative management to prevent a higher prevalence of meropenem overuse. The antimicrobial effect of Piper betle leaves ethanolic extract has been previously proven and should be tested on sepsis-induced animal models. Objectives: This study assesses the antimicrobial effect of Piper betle leaves ethanolic extract towards the bacterial loads and its anti-inflammatory effect on neutrophil infiltration in the lung, kidney, and liver of sepsis-induced mice. Methods: After sepsis inducement, 3 mg/mL of Piper betle leaves ethanolic extract was administered orally. After the mice died, the bacterial load of the lung, kidney, and liver was measured, while neutrophil infiltration was observed using hematoxylin-eosin staining. Results: There is no significant decreasing the number of bacterial loads in the treatment group but there is a significant decrease in the number of neutrophils infiltration in the treatment group. Conclusion: Single dose administration of Piper betle leaves ethanolic extract is sufficient to inhibit neutrophil infiltration significantly.

Modeling the complexity of drug-drug interactions: A physiologically-based pharmacokinetic study of Lenvatinib with Schisantherin A/Schisandrin A

BackgroundLenvatinib's efficacy as a frontline targeted therapy for radioactive iodine-refractory thyroid carcinoma and advanced hepatocellular carcinoma owes to its inhibition of multiple tyrosine kinases. However, as a CYP3A4 substrate, lenvatinib bears susceptibility to pharmacokinetic modulation by co-administered agents. Schisantherin A (STA) and schisandrin A (SIA) — bioactive lignans abundant in the traditional Chinese medicinal Wuzhi Capsule — act as CYP3A4 inhibitors, engendering the potential for drug-drug interactions (DDIs) with lenvatinib. MethodsTo explore potential DDIs between lenvatinib and STA/SIA, we developed a physiologically-based pharmacokinetic (PBPK) model for lenvatinib and used it to construct a DDI model for lenvatinib and STA/SIA. The model was validated with clinical trial data and used to predict changes in lenvatinib exposure with combined treatment. ResultsFollowing single-dose administration, the predicted area under the plasma concentration-time curve (AUC) and maximum plasma concentrations (Cmax) of lenvatinib increased 1.00- to 1.03-fold and 1.00- to 1.01-fold, respectively, in the presence of STA/SIA. Simulations of multiple-dose regimens revealed slightly greater interactions, with lenvatinib AUC0-t and Cmax increasing up to 1.09-fold and 1.02-fold, respectively. ConclusionOur study developed the first PBPK and DDI models for lenvatinib as a victim drug. STA and SIA slightly increased lenvatinib exposure in simulations, providing clinically valuable information on the safety of concurrent use. Given the minimal pharmacokinetic changes, STA/SIA are unlikely to interact with lenvatinib through pharmacokinetic alterations synergistically but rather may enhance efficacy through inherent anti-cancer efficacy of STA/ SIA.

Abstract 6028: Preferential tumor-to-normal tissue biodistribution and single-dose efficacy with ABD147, a DLL3-targeted engineered antibody-based radiotherapeutic, in preclinical small cell lung cancer models

Abstract Targeted radiotherapies represent an emerging treatment modality for aggressive cancers with limited treatment options, such as small cell lung cancer (SCLC). ABD147 is a Delta Ligand 3 (DLL3)-targeted antibody conjugate designed to carry and deliver cytotoxic radioactive isotopes to DLL3-expressing tumor cells. DLL3 is commonly expressed on the cell surface of neuroendocrine cancer cells, including SCLC, but has limited and predominantly intracellular expression in non-malignant tissues. The ABD147 antibody specifically binds human DLL3 with high affinity and is internalized by DLL3-expressing cancer cells. To minimize radiation exposure to normal tissue, ABD147 has been engineered to clear quickly from the blood compartment. Using indium-111 to determine ABD147 pharmacokinetics and biodistribution in mice, we demonstrate rapid blood and normal tissue clearance of 111In-ABD147, as designed, following a single intravenous dose administration. However, 111In-ABD147 retains high tumor accumulation (activity concentration of up to 30% ID/g) in xenograft mouse models of SCLC despite low DLL3 surface antigen expression on tumor cells (≤ 3000 copies). 111In-ABD147 shows a favorable tumor-to-normal tissue distribution with predominant liver clearance. Following ABD147 therapeutic radioisotope delivery of actinium-225 or lutetium-177 (225Ac-ABD147, 177Lu-ABD147), we demonstrate single-dose tumor regression and dose-dependent sustained anti-tumor efficacy, corresponding to an extension of survival out to 84 days in multiple SCLC xenograft models. In summary, ABD147 can preferentially deliver radionuclides to DLL3-expressing tumor tissue while substantially reducing the systemic radioactive exposure typical of conventional IgG radioconjugates. Following promising results in preclinical models, including potent anti-tumor activity, 225Ac-ABD147 is now progressing into clinical development. Citation Format: Iva Kulic, Etienne S. Melese, Emma Cummins, Alex Mandel, Raja Viswas, Michael Abrams, Adam Judge. Preferential tumor-to-normal tissue biodistribution and single-dose efficacy with ABD147, a DLL3-targeted engineered antibody-based radiotherapeutic, in preclinical small cell lung cancer models [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 6028.

Abstract 2622: TUB-040, a novel Napi2b-targeting ADC built with ethynylphosphonamidate conjugation chemistry, demonstrates high and long-lasting anti-tumor efficacy via Topoisomerase-I inhibition and excellent tolerability predictive of a wide therapeutic window in humans

Abstract TUB-040 is a novel Antibody-Drug Conjugate (ADC) targeting Napi2b, a highly overexpressed target in ovarian cancer and lung adenocarcinoma. Napi2b is a member of the solute-carrier transporter family with eight transmembrane domains and an antibody-accessible extracellular loop, that regulates sodium-dependent phosphate homeostasis. Ethynylphosphonamidate conjugation chemistry was used to build TUB-040 with a homogenous DAR (drug-antibody-ratio) of 8 and the Topoisomerase I inhibitor Exatecan as payload, which is connected to a humanized, Fc-silenced IgG1 antibody targeting Napi2b using a cleavable linker system. In vitro, TUB-040 is characterized by sub-nanomolar affinity and specific binding to Napi2b, efficient target-mediated internalization and high cytotoxicity towards Napi2b-expressing ovarian and lung cancer cell lines as well as bystander activity against co-cultured target-negative cells. TUB-040 induces DNA damage and apoptosis in a dose-dependent fashion as well as markers of immunogenic cell death. In addition, no unspecific uptake and cytotoxicity in healthy, target-negative human cells could be detected, reducing the risk of target-independent toxicities. Pharmacokinetic analysis showed that - in contrast to maleimide-conjugated ADCs - TUB-040 is highly stable - and does not lose or transfer its linker-payload to serum proteins during blood circulation, thus enabling most efficient and continued delivery of Exatecan to the tumor. Across a variety of cell line derived xenograft (CDX) and patient derived xenograft (PDX) models of ovarian and non-small cell lung cancer, including models with low target expression, single dose administration of TUB-040 results in long-lasting tumor growth inhibition with high complete remission rates in vivo. The minimally effective dose (MED) leading to complete remission is 1 mg/kg. Preliminary repeat-dose toxicological assessment of TUB-040 in the pharmacologically relevant species cynomolgus monkey demonstrated that TUB-040 is well tolerated with no signs of lung toxicity and thrombocytopenia. Allometric scaling and PK/PD modelling predicts a human serum half-life greater 10 days and a therapeutic index in humans up to 55. Based on these results, TUB-040, designed with differentiating technology for optimal efficacy and tolerability, is ready for testing in clinical trials. Citation Format: Saskia Schmitt, Isabelle Mai, Paul Machui, Sarah Herterich, Danila Hauswald, Philipp Ochtrop, Philipp Cyprys, Izabela Kozlowska, Annabel Kitowski, Marcus Gerlach, Olivier Marcq, Pamela A. Trail, Dominik Schumacher, Marc-André Kasper, Günter Fingerle-Rowson, Björn Hock, Jonas Helma-Smets, Annette M. Vogl. TUB-040, a novel Napi2b-targeting ADC built with ethynylphosphonamidate conjugation chemistry, demonstrates high and long-lasting anti-tumor efficacy via Topoisomerase-I inhibition and excellent tolerability predictive of a wide therapeutic window in humans [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 2622.

Abstract 2110: Characterization of the correlation between BTK degradation and tumor growth inhibition of the BTK target protein degraders using PK/PD modeling

Abstract Introduction: Chimeric degradation activation compound (CDACs) are heterobifunctional molecules causing target protein degradation by simultaneously binding to the target protein as well as an E3-ubiquitin ligase. As an emerging new therapeutic modality, it is critical to understand the contribution of compound-specific parameters (e.g. drug exposure and binding potency to the target protein) and the system-specific parameters (e.g. target protein turnover) of CDACs to its in vivo effect. Method: To identify the key parameters for guiding compound optimization and to find the correlation between BTK degradation and the extent of tumor growth inhibition, a mechanistic PK/PD model was built (Phoenix WinNonlin 8.1) on a dataset generated from a BTK CDAC (Compound A). The PK/PD model was simplified mathematically compared to the full mechanistic models published previously1, since the binding affinity of Compound A to BTK was much higher than the binding affinity of CDAC to E3 ligase. This model can be linked to a tumor growth inhibition (TGI) mathematical model to find the correlation between target degradation and efficacy.Result: In mouse Rec-1 xenograft model, the BTK degradation and TGI was studied. The mice were dosed with Compound A orally at 0.3, 1, or 3 mg/kg, dose-dependent PK and BTK degradation in tumor was observed. After a single dose administration of Compound A, ~50% BTK degradation was observed in tumor at 24 h post dosing and the tumor BTK rebound to baseline at 72 hours post dosing at 3 mg/kg. The tumor BTK degradation was deeper after repeated dosing. A PK/PD model was built based on the data in this PK/PD study. The calculated BTK turnover half-life in Rec-1 model is about 16 h. In the efficacy study, Compound A was dosed orally once a day to the mice at 0.3, 1, or 3 mg/kg. The 3 mg/kg group achieved ~90% tumor growth inhibition in Rec-1 xenograft model. The PK/PD model was then linked with a mathematical model describing TGI2. A threshold level of BTK degradation in tumor to achieve tumor stasis was identified to be 96% for Rec-1 tumor model. At 90% tumor growth inhibition, average of 70% BTK was predicted to be degraded in tumor at steady state. The model was subsequently used to characterize the PK/PD relationship of BGB-16673. The efficacy of BGB-16673 was predicted using the model and it agreed with the observed value.Conclusions: The current model deepened our understanding of the PK/PD relationship of CDACs. The approach can be used to simulate different scenarios, e.g. different BTK turnover, potency or PK exposure. It can also be used in compound selection and optimization to predict repeated dose PD and efficacy from a single dose PK/PD data.1. J Pharmacokinet Pharmacodyn. 2021 Feb;48(1):149-163.2. Cancer Res. 2004 Feb 1;64(3):1094-101. Citation Format: Yue Wu, Shuran Li, Fan Wang, Nan Hu, Longbo Yin, Xiaomin Song, Jiye Zhang, Aiying Xu, Shasha Yang. Characterization of the correlation between BTK degradation and tumor growth inhibition of the BTK target protein degraders using PK/PD modeling [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 2110.

Abstract 1898: LNCB74 is a potent and safe next-generation antibody-drug-conjugate utilizing a cancer selective linker for the treatment of B7-H4 expressing cancers

Abstract The B7 family protein B7-H4 is highly expressed on a range of solid tumors including breast, ovarian, and endometrial cancers, where it may play a role in immune evasion. In non-cancerous tissues, B7-H4 expression is limited, suggesting it may be a potential target for an antibody drug conjugate (ADC). LNCB74 is a human IgG1 antibody conjugated to the potent microtubule disrupting payload monomethyl auristatin E (MMAE) with a drug-to-antibody ratio of 4 (DAR4). The ADC employs a highly selective B7-H4 antibody based upon NextCure’s expertise in B7-H4 tumor biology coupled with a glucuronidase-cleavable, site-specific linkage to an engineered cysteine in the antibody light chain via LegoChem Biosciences’ ConjuAllTM technology. This improves the safety profile and therapeutic index of the agent by a) increasing stability in circulation, b) selectively releasing payload in tumor cells, and c) reducing payload release in off-target cells. LNCB74 was further engineered with a “LALA”-mutant Fc region to minimize uptake and toxicity to immune cells. In a nonhuman primate (NHP) toxicity study, LNCB74 was well tolerated for repeat dosing and provides evidence for a superior safety profile without noticeable side effects. LNCB74 is rapidly internalized by B7-H4-expressing tumor cells, and demonstrates potent, target-specific cytotoxicity on multiple cancer cell lines. In vivo studies demonstrate a strong bystander effect following a single dose administration of LNCB74. A rapid and durable anti-tumor response has been demonstrated in multiple cell-line derived (CDX) and patient-derived xenograft (PDX) tumor models. In summary, LNCB74 is a promising ADC enabling specific targeting of B7-H4 positive cancers across a spectrum of indications. Citation Format: Daniel P. Fitzgerald, Duc N. Doan, Riley B. Peacock, Shannon M. Kahan, Suvendu Lomash, Stephen Slocum, Kwang Hwa Jung, Hwanhee Oh, Ingrid Meza, Yanira Manzanarez, Shanmugam Selvam, Dallas B. Flies, Chul-Woong Chung, Sol Langermann. LNCB74 is a potent and safe next-generation antibody-drug-conjugate utilizing a cancer selective linker for the treatment of B7-H4 expressing cancers [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 1898.

Abstract 6656: Revolutionizing solid tumor treatment: Viral protein-targeted CAR-T with oncolytic virus

Abstract Major challenges for CAR-T cell therapy in solid tumors include various limitations due to the issue of appropriate antigen selection, tumor heterogeneity, and the immune-suppressive tumor microenvironment (TME). To overcome these hurdles, we’ve developed a novel therapy, CLM-202 which is a combination therapy of oncolytic Newcastle disease virus (NDV) and NDV F protein-targeted CAR-T cell therapy (NDV F CAR-T). After NDV infects tumor cells, NDV envelope protein F is expressed on the tumor cell surface. NDV F CAR-T recognizes NDV F protein and kills the tumor cells. This approach can be applied to patients with various indications, regardless of the presence of the target protein. Using NDV to deliver antigens minimizes the risk of tumor recurrence due to tumor heterogeneity. Furthermore, it mitigates off-target toxicity by targeting oncolytic virus-derived proteins, not human proteins. Oncolytic NDV also triggers a potent immune response within the tumor microenvironment, thereby altering the immunosuppressive conditions of the tumor and improving CAR-T efficacy. Therefore, CLM-202 can be a multipurpose solution for solid tumors. We have developed a second-generation CAR-T cell therapy, NDV F CAR-T, which can be used in combination with an oncolytic virus known as NDV. NDV F CAR-T is designed to specifically target the F protein expressed when cells are infected by NDV. It incorporates a single-chain variable fragment (scFv) derived from an antibody that can bind specifically to the F protein of NDV-infected cells. To assess the activity of NDV F CAR-T in tumor cells against a variety of solid tumors as indications, we conducted several experiments. We initially confirmed the expression of the F protein in NDV-infected tumor cells. We also conducted cytotoxicity tests to confirm NDV F CAR-T's ability to induce death in NDV-infected tumor cell lines. Furthermore, to assess the efficacy of NDV F CAR-T in an in vivo model, we established an orthotopic mouse model. In this model, we administered NDV via intratumoral injection, followed by the single-dose administration of NDV F CAR-T to perform the efficacy test. We have confirmed that NDV infects all solid tumor cell lines representing different indications and induces the expression of the F protein in infected tumor cells. Furthermore, we have observed that NDV infection in these diverse tumor cells results in robust tumor cell-killing activity by NDV F CAR-T and the subsequent activation of CAR-T. Moreover, in an orthotopic mouse model, we have demonstrated that the administration of NDV followed by NDV F CAR-T induces potent tumor growth inhibition. In summary, our research proposes a novel therapeutic strategy, CLM-202 that utilizes NDV F CAR-T and NDV to overcome the limitations of CAR-T cell therapy in solid tumors, including tumor heterogeneity and immune-suppressive tumor microenvironments. This approach aims to effectively treat a wide range of indications. Citation Format: Soyoung Choi, Kiwan Kim, Sangeun Lee, Jeongeun Choi, Song-Jae Lee, Yong Gu Lee, Jeonghun Kim, Hoyoung Lee, Kisoon Kim, Man-Seong Park, Seong-Won Song. Revolutionizing solid tumor treatment: Viral protein-targeted CAR-T with oncolytic virus [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 6656.

Abstract 4103: Novel mRNA-encoded HPV vaccine with APC maturation signal and endolysosomal trafficking domain demonstrates superior T cell-mediated immunogenicity and efficacious tumor clearance in vivo

Abstract Human Papillomavirus (HPV), particularly HPV16, is a known causative agent of cancers in various anatomical sites, notably the anogenital and oropharyngeal regions. Despite the availability of prophylactic HPV vaccines for almost two decades, vaccination rates among young females, who are at a heightened risk for cervical intraepithelial neoplasia (CIN) and subsequent invasive cancer, remain suboptimal. The current standard of care for cervical cancer, involving invasive surgery and chemotherapy-based treatments, underscores the pressing need for safer and more effective therapeutics to enhance patient survival and quality of life. In this context, while several HPV16-E6/E7 targeted therapeutic vaccines are in development and clinical trials, their clinical efficacy has been limited due to inadequate antigen presentation and suboptimal immunogenicity. Addressing this, our team has developed a novel, highly immunogenic mRNA therapeutic cancer vaccine, engineered to activate a robust T cell-mediated adaptive immune response and exhibit strong anti-tumor potential. Our innovative approach includes the design of an HPV16-E6/E7 mRNA vaccine (ABO2101) that incorporates a unique antigen-expressing cassette. This cassette features endolysosomal trafficking domains and antigen presenting cell (APC) activation stimulators, enhancing both Class I and Class II antigen presentation and APC maturation, thereby amplifying antigen-specific T cell responses. In both murine and human-derived experimental models, ABO2101 has demonstrated a significantly more potent adaptive T cell response against HPV16 antigens compared to other HPV16 mRNA therapeutic vaccines. In antitumor efficacy evaluations using TC-1 tumor-bearing mice, ABO2101 single-dose administration successfully eradicated both early-stage (50 mm³) and advanced (500 mm³) tumors. This was accompanied by a marked increase in HPV16-specific CD8+ cytotoxic T lymphocytes within the tumor microenvironment. Moreover, in prophylactic and adjuvant therapy models, ABO2101 prevented tumor growth across various dosages, indicating its robust preventative capabilities. Further, the combination of ABO2101 with immune checkpoint inhibitors, including PD-1 and CTLA-4 antibodies, displayed a synergistic effect in both immune-oncology sensitive and resistant animal models, suggesting a potential for combinational clinical therapy. In conclusion, our development of ABO2101, a mRNA-based HPV16-E6/E7 therapeutic cancer vaccine inclusive of APC maturation signals, represents a groundbreaking advancement in HPV-associated cancer treatment, as supported by our compelling preclinical data. Citation Format: Liang Du, Hongya Han, Jingshu Ma, Zhenxing Yang, Jinjuan Mao, Jijun Yuan, Bo Ying. Novel mRNA-encoded HPV vaccine with APC maturation signal and endolysosomal trafficking domain demonstrates superior T cell-mediated immunogenicity and efficacious tumor clearance in vivo [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 4103.

The bioequivalence study design recommendations for immediate-release solid oral dosage forms in the international pharmaceutical regulators programme participating regulators and organisations: differences and commonalities.

Bioequivalence (BE) studies are considered the standard for demonstrating that the performance of a generic drug product in the human body is sufficiently similar to that of its comparator product. The objective of this article is to describe the recommendations from participating Bioequivalence Working Group for Generics (BEWGG) members of the International Pharmaceutical Regulators Programme (IPRP) regarding the conduct and acceptance criteria for BE studies of immediate release solid oral dosage forms. A survey was conducted among BEWGG members regarding their BE recommendations and requirements related to study subjects, study design, sample size, single or multiple dose administration, study conditions (fasting or fed), analyte to be measured, selection of product strength, drug content, handling of endogenous substances, BE acceptance criteria, and additional design aspects. All members prefer conducting single dose cross-over designed studies in healthy subjects with a minimum of 12 subjects and utilizing the parent drug data to assess BE. However, differences emerged among the members when the drug's pharmacokinetics and pharmacodynamics become more complex, such that the study design (e.g., fasting versus fed conditions) and BE acceptance criteria (e.g., highly variable drugs, narrow therapeutic index drugs) may be affected. The survey results and discussions were shared with the ICH M13 Expert Working Group (EWG) and played an important role in identifying and analyzing gaps during the harmonization process. The draft ICH M13A guideline developed by the M13 EWG was endorsed by ICH on 20 December 2022, under Step 2.

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Nlmixr2 Versus NONMEM: An Evaluation of Maximum A Posteriori Bayesian Estimates Following External Evaluation of Gentamicin and Tobramycin Population Pharmacokinetic Models.

The objective of this project is to compare the results of the same study carried out on NONMEM and nlmixr2. This analysis consists of evaluating previously published population pharmacokinetic models of gentamicin and tobramycin in our population of interest with sparse concentrations. A literature review was performed to determine the gentamicin and tobramycin models in critically ill adult patients. In parallel, gentamicin and tobramycin dosing data, information on the treatment, the patient, and the bacteria were collected retrospectively in 2 Quebec establishments. The external evaluations were previously performed using NONMEM Version 7.5. Model equations were rewritten with R, and external evaluations were performed using nlmixr2. Predictive performance was assessed based on the estimation of bias and imprecision of the prediction error for maximum a posteriori (MAP) Bayesian PK parameter and observed concentrations. Comparison between nlmixr2 and NONMEM was performed on 4 gentamicin and 3 tobramycin population pharmacokinetic models. Compared to NONMEM, for gentamicin and tobramycin clearance and central volume of distribution, nlmixr2 produced individual pharmacokinetic parameters with bias values ranging from -32.5% to 5.67% and imprecision values ranging from 6.33% to 32.5%. Despite these differences, population bias and imprecision for sparse concentrations were low and ranged from 0% to 5.3% and 0.2% to 6.5%, respectively. The external evaluations performed with both software packages resulted in the same interpretation in terms of population predictive performance for all 7 models. Nlmxir2 showed comparable predictive performance with NONMEM with sparse concentrations that are, at most, sampled twice within a single dose administration (peak and trough).