IV Administration Research Articles

In vivo Pharmacokinetic and Anticancer Studies of HH-N25, a Selective Inhibitor of Topoisomerase I, and Hormonal Signaling for Treating Breast Cancer.

PurposeBreast cancer is the most frequently diagnosed cancer globally, and the leading cause of cancer-associated mortality among women. The efficacy of most clinical chemotherapies is often limited by poor pharmacokinetics and the development of drug resistance by tumors. In a continuing effort to explore small molecules as alternative therapies, we herein evaluated the therapeutic potential of HH-N25, a novel nitrogen-substituted anthra[1,2-c][1,2,5]thiadiazole-6,11-dione derivative.MethodsWe evaluated the in vivo pharmacokinetic properties and maximum tolerated dose (MTD) of HH-N25 in rats. We also characterized the compound for in vitro and in vivo anticancer activities and its inhibitory effects against DNA topoisomerases and hormonal signaling in breast cancer. Furthermore, we used molecular docking to analyse the ligand–receptor interactions between the compound and the targets.ResultsThe maximum serum concentration (Cmax), half-life (t1/2 beta), mean residence time (MRT), oral clearance (CL/f), and apparent volume of distribution (VD/f) of HH-N25 were 1446.67 ± 312.05 ng/mL, 4.51 ± 0.27 h, 2.56 ± 0.16 h, 8.32 ± 1.45 mL/kg/h, and 1.26 ± 0.15 mL/kg, respectively, after single-dose iv administration at 3 mg/kg body weight. HH-N25 had potent anticancer activity against a panel of human breast cancer cell lines with 50% inhibitory concentrations (IC50) ranging 0.045±0.01~4.21±0.05 µM. The drug also demonstrated marked in vivo anticancer activity at a tolerated dose and prolonged the survival duration of mice without unacceptable toxicities based on body weight changes in human tumor xenograft models. In addition, HH-N25 exhibited a dose-dependent inhibition of topoisomerase I and ligand-mediated activities of progesterone and androgen receptors.ConclusionHH-N25 represents a new molecular entity that selective suppressed TOP1 and hormonal signaling, and shows potent antitumor activities in human breast cancer cells in vitro and in vivo. HH-N25 thus represents a promising anticancer agent that warrants further preclinical and clinical exploration.

Pharmacokinetics of tulathromycin in pregnant ewes (Ovis aries) challenged with Campylobacter jejuni.

The purpose of this study was to evaluate the pharmacokinetics of tulathromycin in the plasma and maternal and fetal tissues of pregnant ewes when administered within 24 hours of a single, IV Campylobacter jejuni (C. jejuni) challenge. Twelve, pregnant ewes between 72–92 days of gestation were challenged IV with C. jejuni IA3902 and then treated with 1.1 ml/45.36 kg of tulathromycin subcutaneously 18 hours post-challenge. Ewes were bled at predetermined time points and euthanized either at a predetermined time point or following the observation of vaginal bleeding or abortion. Following euthanasia, tissues were collected for bacterial culture, pharmacokinetics and histologic examination. The maximum (geometric) mean tulathromycin plasma concentration was estimated at 0.302 μg/mL, with a peak level observed at around 1.2 hours. The apparent systemic clearance of tulathromycin was estimated at 16.6 L/h (or 0.28 L/kg/h) with an elimination half-life estimated at approximately 22 hours. The mean tissue concentrations were highest in the uterus (2.464 μg/g) and placentome (0.484 μg/g), and were lowest in fetal liver (0.11 μg/g) and fetal lung (0.03 μg/g). Compared to previous reports, results of this study demonstrate that prior IV administration of C. jejuni appeared to substantially alter the pharmacokinetics of tulathromycin, reducing both the peak plasma concentrations and elimination half-life. However, additional controlled trials are required to confirm those observations.

Effects of calcium supplementation, incomplete milking, and vitamin D3 injection on serum total calcium concentration during the first 24 hours after parturition in dairy cows fed an anionic diet during late gestation.

To evaluate various strategies for prevention of subclinical hypocalcemia (SH) during the first 24 hours after parturition in dairy cows. 165 multiparous German Holstein cows from 1 herd. All cows were fed a ration with a moderate dietary cation-anion difference (approx 0 mEq/100 g of dry matter; anionic diet) for the last 2 to 3 weeks of gestation. In the first part of a 2-part study, cows were randomly assigned to 1 of 4 treatment groups (no calcium supplementation [n = 30], oral administration of a calcium bolus alone [34] or in combination with IV administration of 500 mL of a calcium solution [34] or incomplete milking during the first 24 hours after parturition [34]). In part 2, cows in their fifth or greater parity were randomly assigned to receive vitamin D3 (20,000 U/kg, IM; n = 15) 7 days before the predicted calving date or a control group (18). A calcium bolus was orally administered within 30 minutes after parturition to all cows of part 2. Serum total calcium (Cat) concentration was measured immediately after parturition and every 2 hours thereafter for 24 hours and compared among treatment groups. Subclinical hypocalcemia was defined as a Cat concentration < 2.00 mmol/L. In part 1, the mean ± SD Cat concentration during the 24 hours after parturition for the IV-treated group (2.28 ± 0.42 mmol/L) was greater than that for the other 3 groups, each of which had a mean Cat concentration < 2.00 mmol/L. In part 2, the mean Cat concentration for the vitamin D3-treated cows was greater than that for control cows and remained above 2.00 mmol/L for the duration of the observation period. Intramuscular administration of vitamin D3 or IV administration of a calcium solution in combination with oral administration of a calcium bolus might alleviate SH during the first 24 hours after parturition in dairy cows fed an anionic diet during late gestation.

Changing for the Better: Discovery of the Highly Potent and Selective CDK9 Inhibitor VIP152 Suitable for Once Weekly Intravenous Dosing for the Treatment of Cancer

Selective inhibition of exclusively transcription-regulating positive transcription elongation factor b/CDK9 is a promising new approach in cancer therapy. Starting from atuveciclib, the first selective CDK9 inhibitor to enter clinical development, lead optimization efforts aimed at identifying intravenously (iv) applicable CDK9 inhibitors with an improved therapeutic index led to the discovery of the highly potent and selective clinical candidate VIP152. The evaluation of various scaffold hops was instrumental in the identification of VIP152, which is characterized by the underexplored benzyl sulfoximine group. VIP152 exhibited the best preclinical overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats upon once weekly iv administration. VIP152 has entered clinical trials for the treatment of cancer with promising longterm, durable monotherapy activity in double-hit diffuse large B-cell lymphoma patients.

Abstract CT143: Pembrolizumab bioavailability after subcutaneous administration: analysis from the KEYNOTE-555 Cohort A in metastatic melanoma

Abstract Background: Pembrolizumab is approved for use across multiple cancers at a dose of 200 mg or 2 mg/kg Q3W or 400 mg Q6W administered as an IV infusion. Alternative subcutaneous (SC) formulations can provide added convenience and flexibility in the clinic. KEYNOTE-555 (NCT03665597) Cohort A is an open-label, phase 1 study examining the relative bioavailability of 2 different concentrations of pembrolizumab SC formulations versus pembrolizumab IV. Methods: Patients with advanced melanoma were randomly assigned to receive (in a cross-over design) 1 dose of pembrolizumab 200 mg IV and 2 doses of pembrolizumab 285 mg SC (one of each SC formulation) during the first 3 treatment cycles; thereafter, all patients receive pembrolizumab IV for up to 2 years. Bayesian analysis of pembrolizumab serum concentration data collected from 31 patients through cycles 1, 2, and 3 in the current study and previously published pembrolizumab IV data were used to characterize the pharmacokinetics (PK) of pembrolizumab SC. Distribution and elimination parameters, time-dependent clearance, and covariate effects from the previously established pembrolizumab IV PK model were used, as these phases were expected to be similar for IV and SC administrations. Injection site reactions were evaluated by monitoring patients for local skin reactions approximately 1 hour after pembrolizumab SC or IV administration during the first 3 cycles, and through use of a pt questionnaire following monitoring. Results: The model simultaneously described pembrolizumab PK after IV and SC administrations. The SC absorption was characterized by a first-order absorption rate with lag time and bioavailability parameters. The PK of both pembrolizumab SC formulations were similar with an estimated bioavailability of 64% (95% CI, 54-74); this is consistent with the reported bioavailability of other SC monoclonal antibodies that range from 50% to 85%. Inclusion of a covariate effect of the SC formulation on bioavailability, lag time, or absorption rate was not statistically significant, indicating no significant difference between the 2 SC formulations in the absorption phase. In addition, no anti-drug antibody was observed after 3 treatment cycles. In general, pembrolizumab SC formulations were well tolerated over the first 3 cycles, with no significant injection-site reactions. Two grade 2 adverse events (AEs) of pruritus and rash were reported from the SC formulations and IV infusion, respectively; the other AEs were grade 1. Conclusions: The bioavailability of SC pembrolizumab was characterized from KEYNOTE-555 Cohort A data. SC formulations will be further assessed clinically in other tumor types. Citation Format: Conrad R. Jacobs, Bernardo Leon Rapoport, Graham Lawrence Cohen, Mallika Lala, Carolina De Miranda Silva, Pavan Vaddady, Ferdous Gheyas, Dinesh de Alwis, Vikram Sinha, Omobolaji Oyekunle Akala, Elliot Chartash, Lokesh Jain. Pembrolizumab bioavailability after subcutaneous administration: analysis from the KEYNOTE-555 Cohort A in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT143.

Continuous Intravenous Administration of Granulocyte-Colony-Stimulating Factors-A Breakthrough in the Treatment of Cancer Patients with Febrile Neutropenia.

Background: Febrile neutropenia (FN) remains one of the most challenging problems in medical oncology and is a very severe side effect of chemotherapy. Its late consequences, when it is recurrent or of a severe grade, are dose reduction and therapy delays. Current guidelines allow the administration of granulocyte-colony-stimulating factors (G-CSF) for profound FN (except for the case when a pegylated form of G-CSF is administrated with prophylactic intention) in addition to antibiotics and supportive care. Methods: This is a prospective study that included 96 patients with confirmed malignancy, treated with chemotherapy, who developed FN during their oncological therapy, and were hospitalized. They received standard treatment plus a dose of G-CSF of 16 µg/Kg/day IV continuous infusion. Results: The gender distribution was almost symmetrical: Male patients made up 48.96% and 51.04% were female patients, with no significance on recovery from FN (p = 1.00). The patients who received prophylactic G-CSF made up 20.21%, but this was not a predictive or prognostic factor for the recovery time from aplasia (p = 0.34). The median chemotherapy line where patients with FN were included was two and the number of previous chemotherapy cycles before FN was three. The median serological number of neutrophils (PMN) was 450/mm3 and leucocytes (WBC) 1875/mm3 at the time of FN. Ten patients possess PMN less than 100/mm3. The median time to recovery was 25.5 h for 96 included patients, with one failure in which the patient possessed grade 5 FN. Predictive factors for shorter recovery time were lower levels of C reactive protein (p < 0.001) and procalcitonin (p = 0.002) upon hospital admission and higher WBC (p = 0.006) and PMN (p < 0.001) at the time of the provoking cycle of chemotherapy for FN. The best chance for a shorter duration of FN was a short history of chemotherapy regarding the number of cycles) (p < 0.0001). Conclusions: Continuous IV administration of G-CSF could be an alternative salvage treatment for patients with profound febrile neutropenia, with a very fast recovery time for neutrophiles.

Tolerability of a single IV administration of a methylene blue challenge in patients with bipolar disorder: preliminary data from a pharmaco-MRI study

AimsTo summarise the tolerability profile following an infusion of methylene blue (MB), including subjective effects on mood and energy levels and haemodynamic changes, in patients with Bipolar Affective Disorder (BPAD).BackgroundBPAD is associated with mitochondrial dysfunction and impaired cellular energy production. MB is proposed to enhance mitochondria function via rerouting electrons and intracellular reduction of oxidative stress, and is therefore a candidate compound for use as a probe to reveal alterations in brain oxygen metabolism in vivo in patients with BPAD. Although there are reports of MB used as treatment for BPAD, the tolerability and subjective effects of a single IV dose in this population has not yet been defined.MethodUsing a single-blind, randomised, within-subject design, 7 patients with BPAD on stable pharmacological treatment and 6 healthy controls (HCs) received an infusion of 0.5mg/kg MB and a placebo glucose solution one week apart. Visual Analogue Scales (VAS) assessing ‘Mood’ and ‘Energy’ levels were completed by 11 participants, and blood pressure (BP), heart rate (HR) and any subsequent side effects were recorded before and after infusions.ResultA significant, albeit very small, effect of MB on ‘Mood’ levels relative to placebo was demonstrated, independent of groups (change relative to baseline: 5.5% ± 11 increase (placebo) vs -1.6 % ± 9.5 reduction (MB); p = 0.027). Although there was no effect of MB on energy levels in either group, there appeared to be a trend for a general group difference in ‘Energy’ levels across all trials, with lower ratings in BPAD patients (p = 0.058).There was a trend for significantly lower post-infusion HR relative to pre-infusion (-6.4 ± 8.8 bpm, p = 0.07. Diastolic BP was higher (3.0 ± 7.8mmHg, p = 0.039). These effects were independent of groups and drug. The most common side effect with MB was mild/moderate pain at infusion site (n = 10/13), resolving within median 32.5 minutes (IQR 6-102), and discoloured urine in 7/13 subjects lasting median 44.5 hours (IQR 36-59). No difference in frequency of side effects reported between groups.ConclusionAlthough limited by small sample size, this tolerability analysis demonstrates a acceptable profile of effects of MB on subjective ratings and blood pressure, in both BPAD and HCs. Common side effects of discoloured urine and pain at infusion site are in line with previous reports in the literature. We observed a small effect of MB on mood ratings which could be related to the discomfort experienced during infusion.

Identification of Novel Carbocyclic Pyrimidine Cyclic Dinucleotide STING Agonists for Antitumor Immunotherapy Using Systemic Intravenous Route.

Stimulator of Interferon Genes (STING) plays an important role in innate immunity by inducing type I interferon production upon infection with intracellular pathogens. STING activation can promote increased T-cell activation and inflammation in the tumor microenvironment, resulting in antitumor immunity. Natural and synthetic cyclic dinucleotides (CDNs) are known to activate STING, and several synthetic CDN molecules are being investigated in the clinic using an intratumoral administration route. Here, we describe the identification of STING agonist 15a, a cyclic dinucleotide structurally diversified from natural ligands with optimized properties for systemic intravenous (iv) administration. Our studies have shown that STING activation by 15a leads to an acute innate immune response as measured by cytokine secretion and adaptive immune response via activation of CD8+ cytotoxic T-cells, which ultimately provides robust antitumor efficacy.

Discovery of novel tripeptide propylene oxide proteasome inhibitors for the treatment of multiple myeloma

The ubiquitin proteasome pathway (UPP) plays a critical role in the maintenance of cell homeostasis and the development of diseases, such as cancer and neurodegenerative disease. A series of novel tripeptide propylene oxide compounds as proteasome inhibitors were designed, synthesized and biologically investigated in this manuscript. The enzymatic activities of final compounds against 20S human proteasome were investigated and structure-activity relationship (SAR) was summarized. Some potent compounds were further evaluated to inhibit the proliferation of multiple myeloma (MM) cancer cell lines RPMI8226 and U266B. The results showed that some compounds were active against MM cancer cell lines with IC50 values of less than 50 nM. The microsomal metabolic stabilities in human, rat and mice species were carried out and the results showed that compounds 30 and 31 were stable enough to be in vivo investigated. The in vivo pharmacokinetic results showed that compounds 30 and 31 had acceptable biological parameters for both ig and iv administrations. In vivo antitumor activities of compounds 30 and 31 with the doses of 100 mg/kg and 50 mg/kg BIW were performed by using RPMI8226 xenograft nude mouse model. Toxicities of compounds 30 and 31 were not observed during the experiment and dose dependent effect was obvious and the tumor volume was greatly inhibited.

Pharmacokinetics, Bioavailability, Excretion and Metabolism Studies of Akebia Saponin D in Rats: Causes of the Ultra-Low Oral Bioavailability and Metabolic Pathway.

Background: Akebia saponin D (ASD) has a variety of biological activities and great medicinal potential, but its oral bioavailability is so low as to limit its development. Its pharmacokinetic profiles and excretion and metabolism in vivo have not been fully elucidated. This study was an attempt in this area. Methods: A simple LC-MS/MS method to simultaneously quantify ASD and its metabolites M1∼M5 in rat plasma, feces, urine and bile was established with a negative ESI model using dexketoprofen as the internal standard. Meanwhile, the UPLC-HR/MS system was used to screen all possible metabolites in the urine, feces and bile of rats, as compared with blank samples collected before administration. Absolute quantitative analysis was for M0, M3, M4, and M5, while semi-quantitative analysis was for M1, M2, and Orbitrap data. Results: The AUC0-t values after intravenous administration of 10 mg/kg and intragastrical administration of 100 mg/kg ASD were 19.05 ± 8.64 and 0.047 ± 0.030 h*μg/ml respectively. The oral bioavailability was determined to be extremely low (0.025%) in rats. The exposure of M4 and M5 in the oral group was higher than that of M0 in the terminal phase of the plasma concentration time profile, and ASD was stable in the liver microsome incubation system of rats, but metabolism was relatively rapid during anaerobic incubation of intestinal contents of rats, suggesting that the low bioavailability of ASD might have been attributed to the poor gastrointestinal permeability and extensive pre-absorption degradation rather than to the potent first pass metabolism. This assertion was further verified by a series of intervention studies, where improvement of lipid solubility and intestinal permeability as well as inhibition of intestinal flora increased the relative bioavailability to different extents without being changed by P-gp inhibition. After intravenous administration, the cumulative excretion rates of ASD in the urine and bile were 14.79 ± 1.87%, and 21.76 ± 17.61% respectively, but only 0.011% in feces, suggesting that the urine and bile were the main excretion pathways and that there was a large amount of biotransformation in the gastrointestinal tract. Fifteen possible metabolites were observed in the urine, feces and bile. The main metabolites were ASD deglycosylation, demethylation, dehydroxylation, decarbonylation, decarboxylation, hydroxylation, hydroxymethylation, hydroxyethylation and hydrolysis. Conclusion: The pharmacokinetics, bioavailability, metabolism and excretion of ASD in rats were systematically evaluated for the first time in this study. It has been confirmed that the ultra-low oral bioavailability is due to poor gastrointestinal permeability, extensive pre-absorption degradation and biotransformation. ASD after iv administration is not only excreted by the urine and bile, but possibly undergoes complex metabolic elimination.

Effects of intravenous administration of recombinant Phα1β toxin in a mouse model of fibromyalgia

This study investigated the effects of intravenous (iv) administration of recombinant Phα1β toxin, pregabalin, and diclofenac by the intrathecal route using an animal model fibromyalgia (FM). The reserpine administration (0.25 mg/kg s. c) once daily for three consecutive days significantly induced hyperalgesia, immobility time, and sucrose consumption in mice on the 4th day. Reserpine caused hyperalgesia on the mechanical and thermal hyperalgesia on the 4th day was reverted by recombinant Phα1β (0.2 mg/kg iv) and pregabalin (1.25 μmol/site i. t) treatments. In contrast, diclofenac (215 nmol/site i. t) was ineffective. Recombinant Phα1β toxin, pregabalin, and diclofenac did not affect the depressive-like behavioural effect induced by reserpine on mice during the forced swim and sucrose consumption tests. The data confirmed the analgesic effect of the recombinant Phα1β toxin administered intravenously in a fibromyalgia mouse model.

Recombinant VWF fragments improve bioavailability of subcutaneous factor VIII in hemophilia A mice

AbstractConventional treatment of hemophilia A (HA) requires repetitive IV injection of coagulation factor VIII (FVIII). Subcutaneous administration of FVIII is inefficient because of binding to the extravascular matrix, in particular to phospholipids (PLs), and subsequent proteolysis. To overcome this, recombinant dimeric fragments of von Willebrand factor (VWF) containing the FVIII-stabilizing D3 domain were engineered. Two fragments, called VWF-12 and VWF-13, demonstrated high binding affinity to recombinant human FVIII (rhFVIII) and suppressed PL binding in a dose-dependent manner. High concentrations of VWF fragments did not interfere with the functional properties of full-length VWF in vitro. The HA mouse model was used to study the effects of VWF-12 or VWF-13 on the in vivo pharmacokinetics of rhFVIII, demonstrating (1) no significant impact on rhFVIII recovery or half-life after a single IV administration; (2) enhanced bioavailability (up to 18.5%) of rhFVIII after subcutaneous administration; and (3) slow absorption (peak concentration, 6 hours) and prolonged half-life (up to 2.5-fold) of rhFVIII after subcutaneous administration. Formation of anti-FVIII antibodies was not increased after administration of rhFVIII/VWF-12 subcutaneously compared with rhFVIII IV. A single subcutaneous dose of rhFVIII/VWF-12 provided protection in the HA tail-bleeding model for up to 24 hours. In summary, recombinant VWF fragments support FVIII delivery through the subcutaneous space into vascular circulation without interfering with VWF or FVIII function. Slow resorption and excretion of FVIII after subcutaneous administration highlight the potential application of VWF fragments for subcutaneous FVIII prophylaxis in HA.

Abstract PS13-11: Oral paclitaxel and encequidar (oPac+E) in the treatment of metastatic breast cancer (mBC): Management of gastrointestinal adverse events (GI AE). Study KX-ORAX-001

Abstract Background: There is a need for more effective and less toxic treatments for patients with mBC. Patients may prefer oral vs IV cytotoxic therapies to avoid frequent hospital visits. In addition, oral therapies allow frequent or metronomic dosing regimens which may alter the toxicity or activity profile of agents vs infrequent IV administration. oPac+E is oral paclitaxel combination with Encequidar, a specific, minimally absorbed, oral p-glycoprotein inhibitor that facilitates the absorption of oral paclitaxel. mBC patients who received oPac+E had significantly greater confirmed tumor response and longer survival with lower rates and severity of neuropathy but increased GI AE compared to IV paclitaxel (IVPac) (Study KX-ORAX-001 presented at SABCS, 2019, Abstract # GS6-01). Methods: Study KX-ORAX-001 was a phase III, randomized, study in women with mBC for whom treatment with IVPac was recommended. Patients were randomized 2:1 to receive oPac+E or IVPac. Patients continued treatment until discontinuation due to progressive disease or toxicity. oPac 205 mg/m2 was given once daily for 3 days weekly. E 12.9 mg was given 1 hour before each dose of oPac. IVPac 175 mg/m2 was infused over 3 hours every 3 weeks. The primary endpoint was efficacy defined as tumor response confirmed by BICR at two consecutive evaluations. Key secondary endpoints included PFS, OS. Safety was monitored throughout the study. Results: All IVPac patients received high-dose dexamethasone and antihistamine premedication, which have significant anti-emetic activity and may have received additional anti-emetic agents as needed. The protocol did not allow any prophylaxis for GI AE for oPac+E patients nor were they to receive predose corticosteroids, nor antihistamines. The protocol was amended after approximately 30% of patients were enrolled to allow prophylactic anti-emetic medications for patients randomized to oPac+E. Patients were also given loperamide to take at home and were instructed to initiate loperamide with the onset of diarrhea. The rates of Grade ≥2, vomiting and diarrhea for patients treated with IVPac, the patients treated with oPac+E prior to after the amendment are summarized in the table below. Prophylactic anti-emetic therapy and early use of loperamide markedly decreased the incidence of ≥Grade 2 vomiting and diarrhea although there was a greater incidence than IVPac. The most frequently prescribed anti-emetic agents for oPac+E treated patients were ondansetron (54%), metoclopramide (21%), domperidone (4%) and aprepitant (3%). For patients randomized to IVPac, the most frequently prescribed agents were ondanesteron (59%), granisetron (24%), palenosetron (7%) and aprepitant (2%). Oral administration of the oral NK1 inhibitor aprepitant appeared to be associated with increased incidence of oral paclitaxel systemic toxicity, potentially due to inhibition of metabolism of oPac by cytochrome P450 3A4. Conclusions: oPac+E was associated with greater efficacy in the treatment of mBC and lower rates and severity of peripheral neuropathy, but increased GI AE compared to IVPac 175mg/m2. GI AE in oPac+E treated patients can be managed by prophylactic use of anti-emetics, primarily 5-HT3 inhibitors and early intervention with the anti-diarrhea agent loperamide. The use of the oral NK1 inhibitor aprepitant in combination with oPac+E is not recommended.(NTC02594371) IVPacoPac+E Pre-AmendmentoPac+E Post AmendmentGrade 2Grade 3Grade 4Grade 2Grade 3Grade 4Grade 2Grade 3Grade 4Vomiting4%1%0%24%7%0%7%4%0%Diarrhea7%1%0%27%9%0%16%3%0.5% Citation Format: H S Rugo, G Umanzor, F J Barrios, R H Vasallo, M A Chivalan, S Bejarano, J R Ramirez, L Fein, R D Kowalyszyn, D L Cutler, D Kramer, J Goldfinch, H Wang, T Moore, R MF Kwan. Oral paclitaxel and encequidar (oPac+E) in the treatment of metastatic breast cancer (mBC): Management of gastrointestinal adverse events (GI AE). Study KX-ORAX-001 [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-11.

The increasing doses of methotrexate pharmacokinetics after intravenous administration in rats - model selection

Background/Aim. Methotrexate (MTX) plays a significant role in the treatment of various diseases, but the toxicity remains the main issue of its use, especially when administered in high doses. Considering altered pharmacokinetics of MTX as a factor strongly implicated in the large interpatient variability and unexpected toxicity in certain patients, the accurate description of MTX pharmacokinetic behaviour of both low and high doses is of the utmost importance. Therefore, the objective of this study was to determine the pharmacokinetics of MTX after intravenous (iv) administration in ascending doses of 5, 40, 80 and 160 mg/kg in rats and to select the appropriate mathematical model describing MTX pharmacokinetics. Methods. Plasma concentrations of MTX were measured using the liquid chromatography - mass spectrometry (LC/MS) method. Pharmacokinetic parameters were calculated by non-compartmental and two-compartmental integer-order analyses. Results. MTX showed linear pharmacokinetics following iv administration up to the dose of 80 mg/kg. The administration of a high dose of MTX (160 mg/kg) resulted in the similar pharmacokinetic behaviour as when applied in the twice lower dose (80 mg/kg), which can be explained by dose-dependent changes in the expression of solute carrier (SLC) and ATP binding cassette (ABC) transport proteins and intracellular metabolism. Furthermore, the classical two-compartment model could not explain the pharmacokinetics of MTX in a small percentage of experimental animals, which opens up new strategies for the use of fractional order pharmacokinetic models in MTX therapy optimisation. Conclusion. These results of pharmacokinetic analyses may be helpful in adjusting the dosage regimen of MTX, but the application of novel pharmacokinetic models, such as those based on fractional calculus, is still needed in the process of MTX therapy optimisation.

Efficacy of iv infusion of magnesium sulphate and dromperidol on the management of neuropathic and somatosensory chronic pain - a two pain center study

Introduction: Droperidol as a medicine has unique properties and it has been successfully used as analgesic, antipsychotic, antiemetic and as a sedative [1]. It is an antagonist for d2-dopamine, serotonin, histamine, and nicotinic and muscarinic cholinergic receptors. It is also a dose-dependent agonist/antagonist of GABA receptors and an agonist of a2 adrenergic receptors. Moreover, is a sodium channel blocker such as lidocaine and potentiate μ opioid receptors. Its multi-receptor action justifies its use as analgesic, antiemetic and antiphycotic medication [2]. Magnesium seems to function as an antagonist for NMDA receptors and it has been used for relief of acute and chronic pain [3, 4]. The aim of the current study is the evaluation of the efficacy of droperidol and magnesium co-administration on the patients with chronic pain. Method: All patients that attended the pain clinic for chronic pain and aged over 18 years old were included in the study. Patients with atrioventricular block any grade and patients with chronic renal failure were excluded from the study. All included patients received droperidol to the dose 2.5 mg maximum and 1 gr magnesium sulphate iv. DN4 questionnaire was used to assess the presence of neuropathic pain. VAS scale and NPS scale were used to assess the intensity of pain before and after the administration. Change in the pain scales calculated as a percentage. Results: 48 patients included in the study. 23 of them had neuropathic pain. There was a 40–50% reduction of the intensity of pain after iv administration of droperidol and magnesium. There weren’t any complications. Conclusions: The co-administration of magnesium and droperidol can relieve neuropathic and somatosensory pain. Long-term evaluation is needed.

Emulsion Formulations of Indomethacine and Xylometazoline Hydrochloride for Intranasal Delivery

Nasal administration has many advantages over nasal, parenteral or oral administration. Some drugs are ineffective when administered orally due to absorption and first pass metabolism. Therefore, if the aqueous solubility problem can be overcome, the intranasal route will be an alternative method for administration. In this study, emulsion formulation was proposed as a new approach in order to increase the duration of the indomethacin-xylometazoline hydrochloride combination in the nose. The pH value of F1 and F2 emulsions were determined 9.4 and as 5.6 respectively. The particle size of F1 and F2 formulations were found to be 136.8±24 nm and 269.5±66 nm respectively. Formulation of o/w emulsion IND and XYL may be considered as an alternative to iv and po administration. This administration of drugs may be delivery to achieve rapid onset of its pharmacological effect.

Updated Phase 1 Results of Teclistamab, a B-Cell Maturation Antigen (BCMA) x CD3 Bispecific Antibody, in Relapsed and/or Refractory Multiple Myeloma (RRMM)

Updated Phase 1 Results of Teclistamab, a B-Cell Maturation Antigen (BCMA) x CD3 Bispecific Antibody, in Relapsed and/or Refractory Multiple Myeloma (RRMM)

Alternative Approaches to Oral Tolerance Induction to Factor FVIII

A serious complication in the treatment X-linked bleeding disorder hemophilia A is the formation of inhibitory antibodies against factor VIII (FVIII), which compromise traditional replacement therapy. We previously developed an Oral immunotherapy (OTI) based on repeated uptake of a mixture of lettuce plant cells transgenic for heavy chain (HC) or C2 domain of human FVIII fused to cholera toxin B (CTB) subunit [Blood 124:1659; Plant Biotechnol J. 16:1148]. Fusion proteins were transgenically expressed in the chloroplasts. Repeated oral uptake of a mixture of freeze-dried powder of lettuce cells accomplished antigen delivery to the immune system of the small intestine by targeting of the GM1 receptor that is highly expressed on the surface of the gut epithelium, resulting in induction of regulatory T cells (Treg) that suppress inhibitor formation upon subsequent intravenous (iv) FVIII replacement therapy. An alternative to oral antigen delivery is the oral delivery of immune modulatory antibodies. Here, we compared the plant cell-based method with oral delivery of anti-CD3, which has been successful in murine models of autoimmune disease and is currently evaluated in clinical trials. Unlike in iv administration, oral anti-CD3 does not systemically deplete T cells. Hemophilia A BALB/c mice (F8 e16 gene deletion) received oral gavage of a mixture of CTB-FVIII-HC/-C2 (1.5 µg/antigen) expressing lettuce leaf cells 2x/week for 9 weeks. Starting at 4 weeks into the experiment, 1 IU/mouse of BDD-FVIII (Xyntha) was given iv, once per week for 5 weeks. Alternatively, following a published protocol that was successful in other models, 5 µg of hamster anti-murine CD3 was given by oral gavage daily for 5 straight days, followed by 5 weekly iv injections of BDD-FVIII. Control animals (no OTI) developed inhibitors with an average titer of 18 ± 3 BU/ml (n=16). Of these, 88% were high-titer (i.e &amp;gt;5 BU/ml, up to 43 BU/ml). Inhibitor formation was significantly reduced in plant cell-treated mice (10 ± 2.5 BU/ml, n=17), with 47% showing no or low-titer inhibitors (&amp;lt;5 BU/ml). Interestingly, inhibitor formation in anti-CD3 treated mice showed a unique pattern, with two distinct outcomes. One subset of animals developed inhibitors of 0-15 BU/ml (on average 2.5-fold lower than control group), while the second subset showed increased titers of 41-89 BU/ml. There were no animals with intermediate titers. In general, FVIII-specific IgG titers followed the same patterns as inhibitor responses. When the 2 approaches (plant cells and anti-CD3) were combined, 50% of mice developed &amp;lt;5 BU/ml (as compared to 36% for anti-CD3 only). However, this did not represent an improvement over giving lettuce cells only. Finally, we tested anti-CD3 Fab fragment in place of FL anti-CD3. While a daily dose of 5 µg anti-CD3 Fab/mouse was unsuccessful in suppressing inhibitor formation, a dose of 0.5 µg marginally decrease titers. In summary, oral anti-CD3 delivery was not as effective in reducing inhibitor formation as plant cells expressing CTB-FVIII antigen fusions. While FL anti-CD3 showed promise in a subset of animals, it also posed a risk of an increased response in others, which complicates development of this approach. Distinct from all other treatment groups, lettuce-fed mice showed elevated frequencies in Foxp3+ Treg, a reduction in Teff cells, and the highest increase in LAP+ Treg. Further studies on induced CD4+LAP+FoxP3- Treg cells from lettuce-fed mice showed high expression of ICOS, CD69 and Ki-67, but not CTLA-4. Among the different subsets of Treg, LAP+ T cell contained the highest proportion of IL-10 expressing cells, and oral antigen delivery induced IL-10+LAP+ Treg, which are likely key to the suppression of the immune response against FVIII. Disclosures Daniell: Takeda Pharmaceuticals: Patents &amp; Royalties. Herzog:Takeda Pharmaceuticals: Patents &amp; Royalties.

NHL Patients and Nurses in the US Prefer Subcutaneous Rituximab Injection Versus Intravenous Rituximab Infusion: A Real-World Study

Introduction: In 2017, the US FDA granted approval of a subcutaneous (SC) injection form of rituximab as an alternative means of administration for patients with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), and chronic lymphocytic leukemia (CLL). Although patients have reported a preference for SC rituximab (R-SC) over intravenous rituximab infusion (R-IV) in the clinical trial setting, patient and nurse provider preferences for R-SC vs R-IV in a real-world setting have not been studied. We report the findings of two surveys designed to assess patient and nurse treatment preferences for R-SC vs R-IV. Methods: Two descriptive, cross-sectional surveys of 70 patients and 208 oncology nurse providers were conducted via web-based questionnaires. Patients who received R-SC, and nurses who administered at least one R-IV and at least one R-SC treatment between July 1, 2017 and April 30, 2019 in US Oncology Network (USON) clinics, were eligible to participate. The surveys evaluated patients' and nurses' experience with R-SC vs R-IV, preference for SC or IV administration, convenience, and overall experience. Results: Among the 70 patients invited to participate in the patient survey, 29 (DLBCL n=12; FL n=13; CLL n=4) completed it (41% response rate). Of the respondents, the mean age was 69 years, 59% were male, 86% were Caucasian, 35% had stage IV disease, 72% had an Eastern Cooperative Oncology Group performance status of 0-1, and 69% were retired. Respondents received a mean of 4 (standard deviation [SD] 2.5) R-SC injections per patient, with the majority indicating preference for R-SC (n=20, 69%) over R-IV infusion (n=9, 31%). Among patients preferring R-SC, less time spent in the clinic (n=20, 69%) and less emotional distress (n=12, 41%) were the most common reasons for their treatment preference. A higher percentage of patients reported R-SC as being very convenient (n=18, 62%) versus R-IV (n=13, 45%). More patients required caregiver assistance during R-IV administration (n=13, 45% patients) compared with R-SC administration (n=8, 28%). Among 208 nurse providers invited to participate in the nurse provider survey, 36 completed it (17% response rate). In total, 58% (n=21) of nurse respondents preferred administering R-SC over R-IV, with time saving, convenience, and patient preference being the most common reasons. A high proportion of respondents (61%) had a positive/very positive experience with R-SC over R-IV, as a result of patient time saved, clinic/staff time saved, and quality time with patients. Most (80%) respondents reported spending 1.5 to over 2 hours of nursing time monitoring and administering R-IV for each patient, and 52% reported that 1.5 to 2 hours could be saved with each administration of R-SC as compared with R-IV. All respondents judged that chair time could be saved with each administration of R-SC compared with R-IV. Respondents reported that the time saved could be used to see more patients, complete nursing procedures, and complete administrative work, and most agreed that the quality of patient care was not impacted by the shorter administration time of R-SC. Conclusions: Although this study is limited by a small sample size, of the patients and nurses surveyed, the majority expressed a positive experience with respect to receiving and administrating R-SC over R-IV. Reduced time spent in the clinic was the main reason for R-SC preference among patients. Time saved, convenience, and patient preference contributed to the positive experience with R-SC among nurse providers. This survey-based assessment of patient and nurse preference demonstrates a majority of respondents preferring R-SC compared to R-IV. While our analysis is limited by a small sample size, it provides real-world data on patient and provider preferences of rituximab administration. Disclosures Gandhi: TG Therapeutics (Advisory board), GlaxoSmithKline (Advisory board): Membership on an entity's Board of Directors or advisory committees. Shapouri:Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Ravelo:Genentech, Inc.: Current Employment; Roche Holdings: Current equity holder in publicly-traded company. Sudharshan:Employee of McKesson. McKesson was paid consulting fees for the conduct of this study: Consultancy; McKesson Life Sciences: Current Employment. Beeks:F. Hoffmann-La Roche Ltd: Consultancy; McKesson: Current Employment. Dawson:Genentech, Inc.: Current Employment; Roche/Genentech: Current equity holder in publicly-traded company.

A Population Pharmacokinetic Model for Concizumab Based on Phase 1 and Phase 2 Trial Data

Introduction Concizumab is a high-affinity anti-tissue factor pathway inhibitor (TFPI) monoclonal antibody in clinical investigation for the subcutaneous (SC) treatment of patients with hemophilia. The data generated from phase 1 and 2 concizumab trials have been used to develop a population pharmacokinetic (PK) model with the aim of supporting dose selection for phase 3 trials. WMethods The objective of this study was to develop a model to describe the PK of concizumab across administration routes in various groups of patients with hemophilia to generate a generally applicable population PK model of concizumab. The model was developed based on available PK data from four phase 1 trials (for both intravenous [IV] and SC concizumab administration) and two phase 2 trials (for SC concizumab administration). Trial populations in the phase 1 trials included both healthy subjects and patients with hemophilia, whilst the phase 2 trials enrolled patients with hemophilia A or B with inhibitors and patients with hemophilia A without inhibitors. A structural population PK model was first developed based on phase 1 data and the final population PK model was then estimated using data from both phase 1 and phase 2 trials. Simulations were performed for phase 3 concizumab exposure using a full parametric simulation (n=10,000), including both inter-individual and intra-individual variability for the selected population. Randomly sampled body weights from a normal distribution with mean and variance corresponding to body weight distribution from phase 2 trials were used to simulate patient profiles. WResults The population PK dataset used for the model comprised 1,504 observations from 119 subjects (89 patients and 30 healthy individuals), with a mean age of 35 years (range: 18-65 years) and mean body weight of 74.4 kg (range: 47.1-130 kg). The PK model parameters were first estimated based on phase 1 data alone, and after fixing the majority in order to ensure robustness of the model only a few parameters were re-estimated based on phase 1 and 2 data combined. The PK model (Figure 1) was evaluated by standard goodness-of-fit plots and qualification assessments. Using visual predictive checks, it was shown that the model was able to reproduce the median and the 5th and 95th percentiles of the observed concizumab concentrations from phase 1 and 2 trials, and so it was deemed suitable for simulation purposes. The PK model suggested a target-mediated drug disposition following concizumab binding to TFPI at the endothelium, and subsequent elimination of the complex to account for the non-linear elimination. WConclusions The developed model accurately described the PK of concizumab delivered at a wide dose range by either SC or IV administration to both healthy subjects and patients with hemophilia A or B with and without inhibitors. The model was used for simulations to select the dosing regimen for subsequent phase 3 studies. Figure 1. Concizumab pharmacokinetic model. Structure of the final concizumab PK model for SC and IV dosing with target-mediated drug disposition via the endothelial TFPI. CL, clearance; doseiv, intravenous dose; dosesc, subcutaneous dose; IV, intravenous; ka, absorption rate constant; kcom, elimination rate constant of the concizumab-TFPI complex; kon and koff, rate constants for binding of concizumab to the endothelial TFPI; ktr, rate constant from the transit compartment; Q, inter-compartmental clearance; Rtot, amount of endothelial TFPI available for concizumab binding; SC, subcutaneous; TFPI, tissue factor pathway inhibitor; V, volume. Figure Disclosures Høyer Rose: Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Hollensen:Novo Nordisk: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Agersø:Novo Nordisk A/S: Current Employment. Viig Overgaard:Novo Nordisk A/S: Current Employment, Current equity holder in publicly-traded company.