Single Intravenous Administration Research Articles

Effectiveness of tranexamic acid on intra- and postoperative bleeding in Bimaxillary osteotomies: a retrospective study.

Perioperative bleeding is a serious concern during orthognathic surgery. Tranexamic acid (TXA), a synthetic lysine analog with antifibrinolytic properties, reduces blood loss across various surgical fields. This study aimed to investigate the effectiveness of preoperative TXA administration in reducing intraoperative and postoperative blood loss following combined Le Fort I and sagittal split ramus osteotomies at our hospital. This single-center, retrospective cohort study included patients who underwent combined Le Fort I and sagittal split ramus osteotomies between November 2017 and October 2022. The primary outcome was the volume of intraoperative blood loss. Among 1,329 eligible patients, 87 were included in the analysis (32 in the TXA group and 55 in the control group, where no TXA was administered). The median (interquartile range) intraoperative blood loss was 200.0 (157.5-237.5) mL in the TXA group and 260.0 (180.0-350.0) mL in the control group, showing a significant difference between the groups (p = 0.0365). However, postoperative blood drainage within 24h and 24-48h did not differ significantly between the two groups. A single intravenous administration of TXA was associated with a decrease in intraoperative bleeding without severe adverse events during combined Le Fort I and sagittal split ramus osteotomies. However, postoperative blood loss, nausea, vomiting, and autologous blood transfusion were not significantly associated with this administration.

Pharmacokinetic Pattern of Menbutone in Calves after Single Intravenous and Intramuscular Administration.

Menbutone is a choleretic agent currently used in Europe to treat digestive disorders in livestock and dogs. Pharmacokinetic parameters were established in 4-month Holstein calves after intravenous (IV) and intramuscular (IM) administration. The drug was administered to 12 animals (10 mg/kg) for both IV and IM routes following a crossover design. Plasma samples were collected at various time points over 24 h and analyzed by reverse-phase high-performance liquid chromatography with a photodiode-array detector, following a method validated according to European Medicines Agency guidelines. Pharmacokinetic parameters were calculated using compartmental and non-compartmental methods. Menbutone followed a two-compartment open model after IV injection, with a total clearance (Cl) of 71.9 ± 13.5 mL/h/kg, an elimination half-life (t½β) of 4.53 ± 2.45 h, and a volume of distribution at steady-state (Vss) of 310.4 ± 106.4 mL/kg. Non-compartmental elimination half-life (t½λ) was 4.2 ± 1.1 h. After IM administration, drug pharmacokinetics was best described by a one-compartment open model. The peak plasma concentration (Cmax) was 15.1 ± 4.3 µg/mL; the time to reach Cmax (tmax), 1.66 ± 0.55 h; and the mean absorption time (MAT), 2.50 ± 1.42 h. Absorption was high, with a fraction of the dose absorbed (F) of 83.5 ± 22.4%. Menbutone was rapidly eliminated from plasma for both routes of administration, with a fast and high IM bioavailability.

Physiologically based pharmacokinetic models for systemic disposition of protein therapeutics in rabbits.

Physiologically based pharmacokinetic (PBPK) modelling is an important tool to predict drug disposition in the body. Rabbits play a pivotal role as a highly valued small animal model, particularly in the field of ocular therapeutics, where they serve as a crucial link between preclinical research and clinical applications. In this context, we have developed PBPK models designed specifically for rabbits, with a focus on accurately predicting the pharmacokinetic profiles of protein therapeutics following intravenous administration. Our goal was to comprehend the influence of key physiological factors on systemic disposition of antibodies and their functional derivatives. For the development of the systemic PBPK models, rabbit physiological factors such as gene expression, body weight, neonatal fragment crystallizable receptor (FcRn) binding, target binding, target concentrations, and target turnover rate were meticulously considered. Additionally, key protein parameters, encompassing hydrodynamic radius, binding kinetic constants (KD, koff), internal degradation of the protein-target complex, and renal clearance, were represented in the models. Our final rabbit models demonstrated a robust correlation between predicted and observed serum concentration-time profiles after single intravenous administration in rabbits, covering IgG, Fab, F(ab)2, Fc, and Fc fusion proteins from various publications. These pharmacokinetic simulations offer a promising platform for translating preclinical findings to clinical settings. The presented rabbit intravenous PBPK models lay an important foundation for more specific applications of protein therapeutics in ocular drug development.

Phase 1 Safety and Pharmacokinetics Study of TAVO101, an Anti-Human Thymic Stromal Lymphopoietin Antibody for the Treatment of Allergic Inflammatory Conditions.

TAVO101 is a humanized anti-human thymic stromal lymphopoietin (TSLP) monoclonal antibody under clinical development for the treatment of atopic dermatitis (AD) and other allergic inflammatory conditions. The crystallizable fragment region of the antibody was engineered for half-life extension and attenuated effector functions. This Phase 1, double-blinded, randomized, placebo-controlled study assessed the safety, tolerability, pharmacokinetics, and immunogenicity of TAVO101 in healthy adult subjects in seven ascending dose cohorts. Subjects received a single intravenous administration of TAVO101 or placebo with a 195-day follow-up. TAVO101 was safe and well tolerated. The incidences and severities of treatment-emergent adverse events were mostly mild and comparable between the active and placebo groups, with no trends of dose relationship. There were no severe adverse events, deaths, or treatment-related withdrawals. TAVO101 exhibited a linear pharmacokinetic profile, low clearance, and a median elimination half-life of 67 days in healthy subjects. All TAVO101-treated subjects tested negative for anti-drug antibodies. To support development in AD, TAVO101 was studied in an oxazolone-induced AD model in hTSLP transgenic mice and demonstrated efficacy. This long-acting anti-TSLP antibody has the potential for stronger and sustained allergic inflammatory disease control. The results from this study warranted further clinical development of TAVO101 in patients.

Experimental pharmacokinetics of a new antiparkinsonian drug ADK-1113

The pharmacokinetics of a new antiparkinsonian drug ADK-1113 after single intravenous and intragastric administrations in mice at doses of 10 and 20 mg/kg was studied. The absolute bioavailability was 10.1–16.3 % that indicates on potential possibility of preparing a dosage form for oral administration.

Luteolin-7-O-β-d-Glucuronide Attenuated Cerebral Ischemia/Reperfusion Injury: Involvement of the Blood-Brain Barrier.

Ischemic stroke is a common cerebrovascular disease with high mortality, high morbidity, and high disability. Cerebral ischemia/reperfusion injury seriously affects the quality of life of patients. Luteolin-7-O-β-d-glucuronide (LGU) is a major active flavonoid compound extracted from Ixeris sonchifolia (Bge.) Hance, a Chinese medicinal herb mainly used for the treatment of coronary heart disease, angina pectoris, cerebral infarction, etc. In the present study, the protective effect of LGU on cerebral ischemia/reperfusion injury was investigated in an oxygen-glucose deprivation/reoxygenation (OGD/R) neuronal model and a transient middle cerebral artery occlusion (tMCAO) rat model. In in vitro experiments, LGU was found to improve the OGD/R-induced decrease in neuronal viability effectively by the MTT assay. In in vivo experiments, neurological deficit scores, infarction volume rates, and brain water content rates were improved after a single intravenous administration of LGU. These findings suggest that LGU has significant protective effects on cerebral ischemia/reperfusion injury in vitro and in vivo. To further explore the potential mechanism of LGU on cerebral ischemia/reperfusion injury, we performed a series of tests. The results showed that a single administration of LGU decreased the content of EB and S100B and ameliorated the abnormal expression of tight junction proteins ZO-1 and occludin and metalloproteinase MMP-9 in the ischemic cerebral cortex of the tMCAO 24-h injury model. In addition, LGU also improved the tight junction structure between endothelial cells and the degree of basement membrane degradation and reduced the content of TNF-α and IL-1β in the brain tissue. Thereby, LGU attenuated cerebral ischemia/reperfusion injury by improving the permeability of the blood-brain barrier. The present study provides new insights into the therapeutic potential of LGU in cerebral ischemia.

Safety, tolerability, and pharmacokinetic of HY0721 in Chinese healthy subjects: A first-in-human randomized, double-blind, placebo-controlled dose escalation phase I study

BackgroundHY0721 is a novel inhibitor of sulfonylurea receptor 1–transient receptor potential melastatin 4 (SUR1-TRPM4) for the treatment of acute ischemic stroke. This study aimed to evaluate the safety, tolerability, and pharmacokinetic (PK) profiles of single and multiple intravenous administration of HY0721 in Chinese healthy subjects. MethodsThe study enrolled 48 and 30 healthy volunteers in the single-ascending dose (SAD) cohort (20, 60, 120, 240, and 320 mg) and multiple-ascending dose (MAD) cohort (60, 120, and 160 mg/bid), respectively, to receive the corresponding dosage of HY0721 or placebo. Safety monitoring included but was not limited to recording adverse events (AEs), vital signs, electrocardiograms, and laboratory tests. The blood samples were collected from subjects to determine the concentrations of HY0721 for PK evaluation. ResultsThe administration of HY0721 showed good safety and tolerability up to 320 mg in the SAD study and up to 160 mg twice daily in the MAD study. The most common AE was injection site reaction, and no AE led to discontinuation of administration or subject dropout. The exposures of HY0721 increased greater than dose proportional manner at the dosages of 20 to 320 mg in the SAD study. A linear PK profile was observed following multiple doses ranging from 60 to 160 mg twice daily, with no evidence of accumulation. Additionally, the human effective dose of HY0721 was estimated to be 120 mg. ConclusionThis study demonstrated the intravenous administration of HY0721 is safe and well-tolerated in Chinese healthy subjects and provided 60 to 160 mg b.i.d. as the recommended dosing range for further clinical trials. Trial registrationChinaDrugTrials.Org.cn; No. CTR20202604, 18 December 2020.

Single high-dose intravenous injection of Wharton’s jelly-derived mesenchymal stem cell exerts protective effects in a rat model of metabolic syndrome

BackgroundMetabolic syndrome (MetS) is a significant epidemiological problem worldwide. It is a pre-morbid, chronic and low-grade inflammatory disorder that precedes many chronic diseases. Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) could be used to treat MetS because they express high regenerative capacity, strong immunomodulatory properties and allogeneic biocompatibility. This study aims to investigate WJ-MSCs as a therapy against MetS in a rat model.MethodsTwenty-four animals were fed with high-fat high-fructose (HFHF) diet ad libitum. After 16 weeks, the animals were randomised into treatment groups (n = 8/group) and received a single intravenous administration of vehicle, that is, 3 × 106 cells/kg or 10 × 106 cells/kg of WJ-MSCs. A healthy animal group (n = 6) fed with a normal diet received the same vehicle as the control (CTRL). All animals were periodically assessed (every 4 weeks) for physical measurements, serum biochemistry, glucose tolerance test, cardiovascular function test and whole-body composition. Post-euthanasia, organs were weighed and processed for histopathology. Serum was collected for C-reactive protein and inflammatory cytokine assay.ResultsThe results between HFHF-treated groups and healthy or HFHF-CTRL did not achieve statistical significance (α = 0.05). The effects of WJ-MSCs were masked by the manifestation of different disease subclusters and continuous supplementation of HFHF diet. Based on secondary analysis, WJ-MSCs had major implications in improving cardiopulmonary morbidities. The lungs, liver and heart show significantly better histopathology in the WJ-MSC-treated groups than in the untreated CTRL group. The cells produced a dose-dependent effect (high dose lasted until week 8) in preventing further metabolic decay in MetS animals.ConclusionsThe establishment of safety and therapeutic proof-of-concept encourages further studies by improving the current therapeutic model.

Translational PK/PD and the first-in-human dose selection of a PD1/IL15: an engineered recombinant targeted cytokine for cancer immunotherapy.

Interleukin 15 (IL-15) is a potential anticancer agent and numerous engineered IL-15 agonists are currently under clinical investigation. Selective targeting of IL-15 to specific lymphocytes may enhance therapeutic effects while helping to minimize toxicities. We designed and built a heterodimeric targeted cytokine (TaCk) that consists of an anti-programmed cell death 1 receptor antibody (anti-PD-1) and an engineered IL-15. This "PD1/IL15" selectively delivers IL-15 signaling to lymphocytes expressing PD-1. We then investigated the pharmacokinetic (PK) and pharmacodynamic (PD) effects of PD1/IL15 TaCk on immune cell subsets in cynomolgus monkeys after single and repeat intravenous dose administrations. We used these results to determine the first-in-human (FIH) dose and dosing frequency for early clinical trials. The PD1/IL15 TaCk exhibited a nonlinear multiphasic PK profile, while the untargeted isotype control TaCk, containing an anti-respiratory syncytial virus antibody (RSV/IL15), showed linear and dose proportional PK. The PD1/IL15 TaCk also displayed a considerably prolonged PK (half-life range ∼1.0-4.1 days) compared to wild-type IL-15 (half-life ∼1.1h), which led to an enhanced cell expansion PD response. The PD was dose-dependent, durable, and selective for PD-1+ lymphocytes. Notably, the dose- and time-dependent PK was attributed to dynamic TMDD resulting from test article-induced lymphocyte expansion upon repeat administration. The recommended first-in-human (FIH) dose of PD1/IL15 TaCk is 0.003mg/kg, determined based on a minimum anticipated biological effect level (MABEL) approach utilizing a combination of in vitro and preclinical in vivo data. This work provides insight into the complex PK/PD relationship of PD1/IL15 TaCk in monkeys and informs the recommended starting dose and dosing frequency selection to support clinical evaluation of this novel targeted cytokine.

Population Pharmacokinetics and Absolute Oral Bioavailability of Lasalocid after Single Intravenous and Intracrop Administration in Laying Hens.

Lasalocid sodium is a polyether carboxylic ionophore agent authorized by the EU for use as a coccidiostat in broilers, turkeys, and pullets up to 16 weeks of age, except for laying hens. However, laying hens are the most common nontarget species exposed to lasalocid sodium, mainly due to cross-contamination from feed mills. This exposure may result in potential drug residue deposition in eggs, which could potentially expose consumers to the drug. The breeds commonly used for commercial egg production in Poland are Isa Brown and Green-legged Partridge hens, which have been found to significantly differ in egg-laying performance. This variability may also affect the pharmacokinetics of lasalocid. Data on lasalocid plasma pharmacokinetics in laying hens are lacking. In this study, we aimed to determine typical population pharmacokinetic parameters, absolute oral bioavailability, and how breed may influence the pharmacokinetics of lasalocid. Twenty-layer hens of the two breeds were used in this study. Lasalocid was administered orally at a single dose of either 1 mg or 5 mg/kg body weight or intravenously at a dose of 1 mg/kg body weight, in a crossover design with a three-week washout period between study periods. Blood samples were collected for 72 h, and lasalocid concentrations were measured using high-performance liquid chromatography with fluorescence detection. A population pharmacokinetic analysis was conducted using nonlinear mixed effects modeling. Standard numerical and graphical criteria were used to select the best model, and a stepwise covariate modeling approach was used to determine any influencing factors. The best model was a three-compartment mammillary model with first-order absorption, transit compartments, and linear elimination. The estimated absolute oral bioavailability was low (36%). It was found that breed significantly influenced not only absorption but also the elimination of lasalocid. This study revealed that lasalocid absorption and elimination varied between the two breeds. This variability in pharmacokinetics may result in breed-related differences in drug residue accumulation in eggs, and ultimately, the risk associated with consumer exposure to drug residues may also vary.

Analysis of Enhanced Wound Closure Potential of ADSC-Derived Secretome Compared to Aquacel Extra in Diabetic Rats

Background: Diabetes Mellitus (DM) can lead to serious complications, such as Diabetic Foot Ulcers (DFUs). Currently, Aquacel Extra is one of the standard therapies for DFUs, but its efficacy has some limitations that may be overcome by alternative treatments, such as the secretome derived from Adipose-Derived Stem Cells (ADSCs). ADSC secretome has shown promising results in promoting wound healing by enhancing cell proliferation, collagen synthesis, and migration of fibroblasts. Aims: This study aims to compare the effect of the adipose-derived stem cell (ADSC) secretome to Aquacel Extra, a hydrofiber dressing containing gel-forming agents, on wound healing in a diabetic rat model. Aquacel Extra has sodium carboxymethylcellulose fibers, which contribute to its unique properties. Objective: The objective of this study is to compare the wound healing outcome of ADSC secretome and Aquacel Extra in streptozotocin-induced diabetic rats. Methods: Sprague Dawley rats received a single intravenous administration of streptozotocin to induce diabetes mellitus (DM). A full-thickness excisional circular wound was created at the dorsum aspect of the rats two weeks after diabetic induction. Rats were randomly divided into two groups: the Aquacel Extra group, which received the hydrofiber dressing Aquacel Extra containing gel-forming agents, and the secretome group, which received the ADSC secretome on days 0, 3, and 7. The gross examination was performed on days 0, 3, 7, and 14. On day 14, the rats were euthanized, and full-thickness skin biopsies of the wounds were taken for histological and immunohistochemical analysis. Results: The secretome group demonstrated accelerated cutaneous wound healing compared to the Aquacel Extra group, as indicated by faster wound closure (p < 0.05). Hematoxylin and eosin staining revealed a thicker epidermal layer in the secretome group than in the Aquacel Extra group (p < 0.05). The mean histological score of the secretome group was higher at 10 ± 1.73 compared to the score of 8.33 ± 1.52 in the Aquacel Extra group, indicating a more mature tissue architecture. Immunohistochemical analysis showed lower expression of α-smooth muscle actin (α-sma) in the secretome group than in the Aquacel Extra group, which correlated with reduced collagen secretion and deposition in the secretome group, as indicated by Masson’s trichrome staining. Conclusion: The ADSC secretome accelerated the healing of diabetic wounds compared to Aquacel Extra. However, as this study is preliminary, future studies should be conducted similar to this study with a larger sample and wound size. In addition, the optimal dosage of ADSC secretome and the components of the secretome that promoted wound healing should be determined to fully elucidate the clinical potential of ADSC secretome.

A simple and sensitive ultra-high performance liquid chromatography tandem mass spectrometry method for the quantitative analysis of VX-548 in monkey plasma: Method validation and application to pharmacokinetic study.

VX-548 is an orally active and highly selective NaV 1.8 inhibitor that is undergoing development for the treatment of acute pain. The aim of this study was to develop a liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the measurement of VX-548 in monkey plasma. VX-548 was extracted from the plasma using acetonitrile-mediated protein precipitation. The quantitative analysis was performed on a Thermo Vantage TSQ mass spectrometer with ibrutinib as an internal standard. Chromatography was performed on a Waters ACQUITY UPLC BEH C18 column with 0.1% aqueous formic acid and acetonitrile as mobile phase. The precursor-to-product ion transitions were m/z 474.2 > 165.0 and m/z 441.2 > 138.1 for VX-548 and internal standard, respectively. This developed method was successfully validated in the concentration range of 1-1000 ng/mL. The calibration curve showed excellent linearity with a correlation coefficient of >0.999. The precision expressed as relative standard deviation (RSD) was <8.4%, whereas the accuracy denoted as relative error (RE) ranged from -5.0% to 9.1%. The mean recovery was >84%. VX-548 was stable in monkey plasma after storage under certain conditions. The validated method was successfully applied to the pharmacokinetic study of VX-548 in monkey plasma after single oral (2 mg/kg) and intravenous (1 mg/kg) administrations.

Comparative pharmacokinetics of intravenous and subcutaneous pantoprazole in sheep and goats

Abomasal ulcers are a significant concern in intensive animal farming due to their impact on animal health and productivity. While proton pump inhibitors (PPIs) such as pantoprazole (PTZ) show promise in treating these ulcers, data on PTZ's pharmacokinetics (PK) in adult goats and sheep are limited. This study aims to fill this gap by investigating and comparing PTZ's PK in these species following single intravenous (IV) and subcutaneous (SC) administrations. Five healthy male goats and sheep were included in the study. PTZ concentrations in plasma samples were determined using a validated analytical method. Non-compartmental analysis was conducted, and statistical comparisons were made between IV and SC administrations and between species. Sheep and goats showed similar systemic exposure levels regardless of the administration route. However, sheep had a shorter t1/2 due to a higher Vd compared to goats. Cl values were comparable in both species, with low extraction ratio values. There were no significant differences in Cmax and Tmax between the two species with regards to SC administration, and complete bioavailability was observed. The MAT exceeded the t1/2 in both species, indicating a potential flip-flop phenomenon. Considering the AUC as a predictor for drug efficacy, and observing no significant differences in systemic exposure between sheep and goats for any route of administration, dosage adjustment between the two species may not be necessary. In field settings, SC administration proves more practical, providing not only complete bioavailability but also a longer half-life compared to IV. Further studies are warranted to explore the PK/PD of PTZ in small ruminants with abomasal ulcers, to fully comprehend its therapeutic efficacy in such scenarios.

Residue, distribution and depletion of fluralaner in egg following a single intravenous and transdermal administration in healthy shaver hens: fluralaner residue in egg

The demand for the use of fluralaner in an extra label manner is increasing due to lack of efficacious treatment to combat mites and bed bugs in the poultry industry in the United States. Fluralaner residue data in eggs is lacking and residues might cause risks to human health. The present study aimed to determine the depletion profiles of fluralaner in eggs and estimate the drug withdrawal interval in whole eggs by adopting the US Food and Drug administration tolerance limit method with single intravenous (0.5 mg/kg) or transdermal administration (average 58.7 mg/kg) in healthy shaver hens. Hens were treated intravenously or trans-dermally with fluralaner. The eggs were collected daily for 28 days for intravenous treated and for 40 days from the transdermal route group. Fluralaner concentrations in yolk and albumen were determined by mass spectrometry. The greater percentage of fluralaner was observed in yolk when compared to the albumen for both administration routes. Non-compartmental analysis was used to calculate the pharmacokinetic parameters in yolk, albumen and whole egg. The longest apparent half-life confirmed in yolk was 3.7 days for intravenous and 14.3 days for the transdermal route. The withdrawal intervals in whole egg for fluralaner following the intravenous and transdermal administration were 7 days and 81 days, respectively, with maximum residue limits (1.3 µg/g) at 13 days and 171 days, respectively, based on the limit of quantification (0.4 µg/g) from the analytical assay reported by EMA and APVMA.

Research Note: Pharmacokinetics of bromhexine hydrochloride in broilers after single oral and intravenous administration

The current study aimed to investigate the pharmacokinetics of bromhexine hydrochloride in broilers after single intravenous (IV) and oral (PO) administration at 2.5 mg/kg body weight (BW). The trial adopted a randomized, parallel-controlled design, where 20 twelve-wk-old broilers were randomly assigned to either the PO or IV group. Blood samples were collected at predetermined time points, and plasma was further separated for analysis. The bromhexine hydrochloride concentrations in plasma samples were determined using an ultra-performance liquid chromatography-tandem quadrupole mass spectrometry (UPLC-MS/MS) method. Noncompartmental analysis (NCA) using Phoenix software was conducted to analyze the concentration versus time data of bromhexine hydrochloride in every chicken. Subsequently, the main pharmacokinetic parameters between the 2 groups were statistically analyzed using SPSS software. Results from NCA revealed that after oral administration at 2.5 mg/kg BW, bromhexine hydrochloride exhibited slow absorption, reaching an average peak concentration of 32.72 ng/mL at 1.78 h. However, incomplete absorption was observed, with an absolute bioavailability of only 20.06% ± 10.84%. Additionally, bromhexine hydrochloride displayed wide distribution, with a steady-state distribution volume (VSS) of 22.55 ± 13.45 L/kg, and slow elimination, with a clearance (Cl) of 1.52 ± 0.38 L/h/kg. Furthermore, gender effects were assessed on the pharmacokinetics of bromhexine hydrochloride in broilers, revealing better absorption in male broilers compared to females. This disparity may be attributed to the faster blood flow and richer blood volume typically found in male broilers.

Pharmacokinetics of famotidine in goats after intravenous administration.

There is currently limited pharmacokinetic data for the use of famotidine in goats for treatment and prevention of abomasal ulceration. The objective of this study was to determine the pharmacokinetic parameters after a single intravenous administration of famotidine (0.6 mg/kg). Famotidine was administered to six healthy goats and plasma samples were collected over a 24-h period. The famotidine concentration was measured using reverse phase high-performance liquid chromatography (HPLC). Non-compartmental analysis was then used to determine the pharmacokinetic parameters. The maximum plasma concentration was estimated at 5476.68 ± 1530.51 ng/mL and elimination half-life was estimated at 18.455 ± 13.26 min. The mean residence time was determined to be 19.85 ± 12.14 min with the apparent volume of distribution being estimated at 321.924 ± 221.667. The area under the curve was determined to be 54230.08 ± 24947.6 min*ng/mL. Total exposure and elimination half-life were less than what has been reported in cattle and horses. Future research evaluating the pharmacokinetics of subcutaneous administration and looking at the pharmacodynamics of famotidine in goats is needed to determine the effectiveness of famotidine on raising pH levels of the abomasum.

Abstract PO2-06-13: Promising clinical performance of 89Zirconium-labelled Girentuximab PET-CT for imaging metastatic triple negative breast cancer patients (OPALESCENCE)

Abstract Aim: Triple Negative Breast Cancer (TNBC) is aggressive, often with a metastatic evolution and drug-resistant with limited therapeutic options. Evaluating new markers is an unmet need. Recently, the combination of anti-angiogenic and targeted hypoxia effectors agents proved to enhance therapy response. Indeed, anhydrase Carbonic-IX (CA-IX), a hypoxia-mediated breast tumor growth regulator, is important for the BC stem cells maintenance within hypoxic region and is highly overexpressed in TNBC. This pilot prospective study “OPALESCENCE” (NCT04758780) aimed at assessing PET/CT with 89Zr-labeled girentuximab (89Zr-TLX250) targeting CA-IX in 12 metastatic TNBC patients. Methods: Patients underwent FDG and 89Zr-TLX250 PET-CT and conventional imaging (CI) if needed (CT, US, mammography, brain MRI). Without any premedication or dietary preparation, patients received a single slow intravenous administration of 37±10% MBq 89Zr-TLX250 (10 mg). Day 3 or 5 post injection, a skull to mid-thigh PET/CT was acquired with 10 minutes acquisition time per bed position. The gold standard was determined by FDG PET/CT, CI and follow-up; lesion detected at least by 2 modalities was considered as true positive. Immunohistochemistry (IHC) was performed with Bond RX fully automated research stainer with CA-IX antibody (Leica, clone TH22). Staining was evaluated with semi-quantitative analysis (percentage and intensity of tumor cells expression). Human anti-chimeric antibody (HACA) were sampled but will be determined at study end. Results: Enrolment has been completed, a total of 273 lesions confirmed by gold standard as shown on table 1 were detected in 12 patients (231 by 89Zr-TLX250 and 264 by FDG PET/CT). Overall sensitivity of 89Zr-TLX250 PET/CT was 87.5%, with 100% sensitivity for breast, skin, adrenal gland and brain and 88.0%, 91.9% for nodes and bone respectively. Overall sensitivity for FDG-PET/CT was 96.7%. According to table 2, 6 patients had 100% of their lesions highlighted by 89Zr-TLX250 PET. In addition, for 2 other patients only one of the lesions was not detected by immunoPET. 89Zr-TLX250 PET therefore detected almost all of the metastatic lesions in 67% of the patients. For 8/12 patients, IHC was analysed and for 6 patients, CA-IX expression lesions was from 100% to 10% with an intensity from 3+ to 2+, whereas two patients presented no Ca-IX expression on tumour lesions. No 89Zr-TLX250 safety issue was reported. Conclusion: 89Zr-TLX250 PET/CT seems very promising because it allows the CA IX status lesions knowledge on whole body scale with a minimally invasive way, unlike the information provided by biopsies corresponding to only 1 or 2 lesions studied. Moreover, these results illustrated interest of 89Zr-TLX250 PET/CT as targeting agent for TNBC patients leading above all to a theranostic approach possibility. Study analysis (specially IHC, HACA and semi-quantitative PET/CT analysis) is ongoing and supplementary data will be presented during the congress. This is an investigator initiated trial. Investigational medicinal product was provided by Telix Pharmaceuticals. Table 1: Sensitivity of 89Zr-TLX250 PET, FDG PET, and conventional imaging (US, brain MRI and Mammography). Table 2: Number of confirmed lesions according to Gold Standard detected by 89Zr-TLX250 PET/CT (iPET), FDG PET/CT and CI for each patients. Citation Format: Caroline Rousseau, Marie Francoise Heymann, Jean Sebastien FRENEL, Elise Picot-Dilly, Maelle Le Thiec, Manon Taupin, Alexis Mouton, Emmanuelle Bourbouloux, Agnès Morel, Nadia Allam, Amélie Mallet, Mario Campone, Ludovic Ferrer, Françoise Kraeber-Bodéré. Promising clinical performance of 89Zirconium-labelled Girentuximab PET-CT for imaging metastatic triple negative breast cancer patients (OPALESCENCE) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-13.

Advancing 6-bromo-7-[11C]methylpurine to clinical use: improved regioselective radiosynthesis, non-clinical toxicity data and human dosimetry estimates

Background6-Bromo-7-[11C]methylpurine ([11C]BMP) is a radiotracer for positron emission tomography (PET) to measure multidrug resistance-associated protein 1 (MRP1) transport activity in different tissues. Previously reported radiosyntheses of [11C]BMP afforded a mixture of 7- and 9-[11C]methyl regioisomers. To prepare for clinical use, we here report an improved regioselective radiosynthesis of [11C]BMP, the results of a non-clinical toxicity study as well as human dosimetry estimates based on mouse PET data.Results[11C]BMP was synthesised by regioselective N7-methylation of 6-bromo-7H-purine (prepared under good manufacturing practice) with [11C]methyl triflate in presence of 2,2,6,6-tetramethylpiperidine magnesium chloride in a TRACERlab™ FX2 C synthesis module. [11C]BMP was obtained within a total synthesis time of approximately 43 min in a decay-corrected radiochemical yield of 20.5 ± 5.2%, based on starting [11C]methyl iodide, with a radiochemical purity > 99% and a molar activity at end of synthesis of 197 ± 130 GBq/μmol (n = 28). An extended single-dose toxicity study conducted in male and female Wistar rats under good laboratory practice after single intravenous (i.v.) administration of unlabelled BMP (2 mg/kg body weight) revealed no test item related adverse effects. Human dosimetry estimates, based on dynamic whole-body PET data in female C57BL/6J mice, suggested that an i.v. injected activity amount of 400 MBq of [11C]BMP will deliver an effective dose in the typical range of 11C-labelled radiotracers.Conclusions[11C]BMP can be produced in sufficient amounts and acceptable quality for clinical use. Data from the non-clinical safety evaluation showed no adverse effects and suggested that the administration of [11C]BMP will be safe and well tolerated in humans.

Safety and efficacy of multiple-dose versus single-dose MIBG therapy in patients with refractory pheochromocytoma and paraganglioma: a single-center retrospective analysis.

To investigate the incidence of adverse events (AEs) following single and multiple administrations of I-131 metaiodobenzylguanidine (MIBG) therapy for inoperable pheochromocytomas and paragangliomas (PPGLs). A single-center retrospective study was conducted on patients with inoperable PPGLs who underwent I-131 MIBG therapy between January 2000 and December 2020. A total of 28 patients with available electronic medical records were included. The treatment consisted of a single intravenous administration of 150mCi (5.55GBq) of I-131 MIBG. We evaluated the first MIBG treatment and repeated MIBG treatments performed within 200days of the previous treatment. AEs for each treatment were evaluated using CTCAE version 4.0, and the statistical analysis was conducted at a significance level of p < 0.05. Objective response based on RECIST 1.1 criteria and biochemical response based on urinary catecholamines were assessed. The study included a total of 63 administrations, consisting of 28 single administrations (SAs), including the first administration for all 28 cases, and 35 multiple administrations (MAs), which included the second or later administrations. Hematological AEs were evaluable for 23 SAs and 29 MAs. Grade 3 or higher leukopenia occurred in 9.8% of all administrations, and Grade 3 or higher lymphopenia in 23.5%; both were manageable through observation. There were no significant differences in clinical AE Grades 1-2 (p = 0.32), hematological AE Grades 1-2 (p = 0.22), or hematological AE Grades 3-4 (p = 0.12) between MAs and SAs. Statistical analysis for each type of AE revealed significant increases in leukopenia (p < 0.01) and lymphopenia (p = 0.04). No significant difference in anemia, thrombocytopenia, or neutropenia was observed between MAs and SAs. There was no significant increase in the incidence rate of Grade 3 or higher hematological AEs for any of the parameters. The objective response rate was 0% for SAs and 36% for MAs. Biochemical response rates were 18% for SAs and 67% for MAs. In I-131 MIBG therapy for PPGLs, multiple administrations significantly increased only Grade 1 or 2 lymphopenia and leukopenia compared to single administration.

Effects of Chrysin and Chrysin-7-sulfate on Ochratoxin A-Albumin Interactions and on the Plasma and Kidney Levels of the Mycotoxin in Rats.

The nephrotoxic mycotoxin ochratoxin A (OTA) is a common food contaminant. OTA binds to the Sudlow's Site I region of serum albumin with very high affinity, resulting in its slow elimination. The displacement of OTA from albumin may be beneficial due to the faster excretion of the mycotoxin, while it may also lead to the increased tissue uptake of OTA. Furthermore, it is challenging to displace the mycotoxin from albumin even with high-affinity Site I ligands. In this study, we tested the impacts of Site I and Heme site ligands on OTA-albumin interactions by applying fluorescence spectroscopic, ultracentrifugation, and modeling studies. Chrysin-7-sulfate (C7S) strongly displaced OTA from both human and rat albumins; therefore, the impacts of C7S (single intravenous administration) and the parent flavonoid chrysin (repeated peroral treatment) were examined on the plasma and kidney levels of OTA in rats. Chrysin barely influenced the concentrations of mycotoxin in plasma and kidneys. In the first few hours, C7S significantly decreased the plasma levels of OTA compared to the control animals; while after 24 h, only minor differences were noticed. Our study highlights the superior displacing ability of C7S vs OTA regarding human and rat albumins.