Design, Synthesis, Anticonvulsant Activity, Preclinical Study and Pharmacokinetic Performance of N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin- 2-yl] methyl}, 2-[(2-isopropyl-5-methyl) 1-cyclo Hexylidene] Hydrazinecarboxamide

2019 ◽  
Vol 19 (1) ◽  
pp. 31-45
Author(s):  
Meena K. Yadav ◽  
Laxmi Tripathi
Keyword(s):  
Anticonvulsant Activity ◽  
Computational Study ◽  
Plasma Concentrations ◽  
Elimination Rate ◽  
Area Under The Curve ◽  
Preclinical Study ◽  
In Vivo Studies ◽  
Maximum Plasma ◽  
Seizure Models

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

scholarly journals Antimalarial herbal drugs: a review of their interactions with conventional antimalarial drugs

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Earnest Oghenesuvwe Erhirhie ◽  
Chidozie Ikegbune ◽  
Anthony Ifeanyi Okeke ◽  
Chukwunonso Chukwudike Onwuzuligbo ◽  
Ngozi Ukamaka Madubuogwu ◽  
...  
Keyword(s):  
Medicinal Plant ◽  
Synergistic Effects ◽  
Plasma Concentrations ◽  
Antimalarial Drugs ◽  
Herbal Remedies ◽  
In Vivo Studies ◽  
Herbal Drugs ◽  
Plant Interactions ◽  
Mice Model

AbstractDevelopment of resistance by malaria parasites to conventional antimalarial drugs has rejuvenated the exploration of herbal medicine as alternatives. Also, the increasing rate of the use of herbal antimalarial remedies in combination with conventional antimalarial drugs (both synthetic and semi-synthetic) has inspired researchers to validate their herb-drug interaction effects. This review evaluated the interaction outcomes between herbal antimalarial drugs in combination with conventional antimalarial drugs. With the aid of electronic databases, Pubmed and Google scholar, articles related to this subject were sourced from English peer reviewed scientific journals published from 2003 to 2020. Search terms used include “antimalarial-herbal drugs interaction”, “antimalarial medicinal plant interactions with conventional antimalarial drugs”, “drug-herbal interactions, “antimalarial drugs and medicinal plants”. Synergistic, antagonistic and none effects were reported among 30 studies reviewed. Among 18 in vivo studies on P. berghei and P. yoelii nigerense infected mice model, 14 showed synergism, 3 showed antagonism and 1 involving three plants showed both effects. Among 9 in-vivo studies involving normal animal (non-infected), 2 showed antagonism, 2 showed synergism and 5 showed none-effects. Two (2) studies on human volunteers and one (1) in vitro quantitative study showed that Garcinia kola reduced plasma concentrations of quinine and halofantrine. Generally, majority of herbal antimalarial drugs showed synergistic effects with CAMDs. Vernonia amygdalina was the most studied plant compared to others. Consequently, herbal remedies that produced synergistic effects with conventional antimalarial drugs may be prospects for standardization and development of antimalarial-medicinal plant combination therapy that could curtail malaria resistance to conventional antimalarial therapies.

scholarly journals Physiologically Based Pharmacokinetic Modelling of Cabozantinib to Simulate Enterohepatic Recirculation, Drug–Drug Interaction with Rifampin and Liver Impairment

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 778
Author(s):  
Bettina Gerner ◽  
Oliver Scherf-Clavel
Keyword(s):  
Hepatic Impairment ◽  
Kinase Inhibitor ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Enterohepatic Recirculation ◽  
Maximum Plasma ◽  
Good Precision ◽  
Physiologically Based Pharmacokinetic ◽  
Starting Point ◽  
Physiologically Based

Cabozantinib (CAB) is a receptor tyrosine kinase inhibitor approved for the treatment of several cancer types. Enterohepatic recirculation (EHC) of the substance is assumed but has not been further investigated yet. CAB is mainly metabolized via CYP3A4 and is susceptible for drug–drug interactions (DDI). The goal of this work was to develop a physiologically based pharmacokinetic (PBPK) model to investigate EHC, to simulate DDI with Rifampin and to simulate subjects with hepatic impairment. The model was established using PK-Sim® and six human clinical studies. The inclusion of an EHC process into the model led to the most accurate description of the pharmacokinetic behavior of CAB. The model was able to predict plasma concentrations with low bias and good precision. Ninety-seven percent of all simulated plasma concentrations fell within 2-fold of the corresponding concentration observed. Maximum plasma concentration (Cmax) and area under the curve (AUC) were predicted correctly (predicted/observed ratio of 0.9–1.2 for AUC and 0.8–1.1 for Cmax). DDI with Rifampin led to a reduction in predicted AUC by 77%. Several physiological parameters were adapted to simulate hepatic impairment correctly. This is the first CAB model used to simulate DDI with Rifampin and hepatic impairment including EHC, which can serve as a starting point for further simulations with regard to special populations.

scholarly journals FORMULATION, IN VITRO, AND IN VIVO EVALUATION OF TASTE-MASKED ORAL DISINTEGRATING TABLETS OF FEXOFENADINE HYDROCHLORIDE USING SEMISYNTHETIC AND NATURAL SUPERDISINTEGRANTS

2021 ◽  
pp. 99-108
Author(s):  
NAGADANI SWARNALATHA ◽  
VIDYAVATHI MARAVAJHALA
Keyword(s):  
Desirability Function ◽  
Research Work ◽  
In Vivo Studies ◽  
Taste Masking ◽  
Wet Granulation ◽  
Maximum Plasma ◽  
In Vivo Evaluation ◽  
Eudragit Epo

Objective: The aim of the present research work was to prepare and evaluate taste-masked oral disintegrating tablets (ODT) of Fexofenadine hydrochloride. Methods: In the present work, Eudragit EPO, a taste masking agent and Karaya gum (GK) (natural), Sodium starch glycolate, and Croscarmellose sodium (CCS) (semi-synthetic) super disintegrants in three ratios (3, 6,9%) were used. Taste masked granules were prepared by different ratios of the drug: Eudragit EPO (1:1, 1:1.5, 1:2) by wet granulation method. The optimized taste-masked granules (1:2) were selected by sensory evaluation test to prepare 9 Fexofenadine ODT (FH1-FH9) formulations. These were evaluated for different parameters. Then desirability function (DF) was calculated for all formulations using disintegration time (DT), time taken for the tablet to release 90% of the drug (t 90%), and % drug dissolved in 10 min (Q10) as significant parameters. Results: The best formulation (FH6) showed the highest DF value due to less DT and 100% in vitro drug release within 15 min. Thus, FH6 formulation containing 9% CCS was selected as the best among the prepared formulations to which in vivo studies were performed on rabbits to find maximum plasma concentration (Cmax), time taken to reach maximum concentration (tmax), area under the curve (AUC), rate of elimination (Kel), absorption rate (Ka) and half-life(t1/2) and compared with Fexofenadine (Allegra) marketed tablets. Total bioavailability was increased for the test formulation compared to the reference formulation. Conclusion: Fexofenadine was successfully prepared as ODT with increased AUC and decreased tmax to which stability studies were conducted which were found to be stable.

scholarly journals Pharmacokinetic Profile of μSMIN Plus™, a new Micronized Diosmin Formulation, after Oral Administration in Rats

2015 ◽  
Vol 10 (9) ◽  
pp. 1934578X1501000 ◽  
Author(s):  
Rosario Russo ◽  
Angelo Mancinelli ◽  
Michele Ciccone ◽  
Fabio Terruzzi ◽  
Claudio Pisano ◽  
...  
Keyword(s):  
Oral Administration ◽  
Plasma Concentrations ◽  
Compartmental Analysis ◽  
Pharmacokinetic Profile ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Sprague Dawley ◽  
Time Curve ◽  
Maximum Plasma Drug Concentration

Diosmin is a naturally occurring flavonoid present in citrus fruits and other plants belonging to the Rutaceae family. It is used for the treatment of chronic venous insufficiency (CVI) for its pheblotonic and vaso-active properties, safety and tolerability as well. The aim of the current in vivo study was to investigate the pharmacokinetic profile of a branded micronized diosmin (μSMIN Plus™) compared with plain micronized diosmin in male Sprague-Dawley rats. After oral administration by gastric gavage, blood samples were collected via jugular vein catheters at regular time intervals from baseline up to 24 hours. Plasma concentrations were assessed by LC/MS. For each animal, the following pharmacokinetic parameters were calculated using a non-compartmental analysis: maximum plasma drug concentration (Cmax), time to reach Cmax (Tmax), area under the plasma concentration-time curve (AUC0-last), elimination half-life (t1/2), and relative oral bioavailability (%F). The results of the current study clearly showed an improvement in the pharmacokinetic parameters in animals treated with μSMIN Plus™ compared with animals treated with micronized diosmin. In particular, μSMIN Plus™ showed a 4-fold increased bioavailability compared with micronized diosmin. In conclusion, the results from the current study provided a preliminary pharmacokinetic profile for μSMIN Plus™, which may represent a new tool for CVI management.

Renal localization and actions of adrenomedullin: a natriuretic peptide

1995 ◽  
Vol 268 (4) ◽  
pp. F657-F663 ◽  
Author(s):  
M. Jougasaki ◽  
C. M. Wei ◽  
L. L. Aarhus ◽  
D. M. Heublein ◽  
S. M. Sandberg ◽  
...  
Keyword(s):  
Natriuretic Peptide ◽  
Sodium Excretion ◽  
Collecting Duct ◽  
Plasma Concentrations ◽  
In Vivo Studies ◽  
Sodium Reabsorption ◽  
Contralateral Kidney ◽  
Arterial Blood ◽  
Group I

Adrenomedullin (ADM) is a newly described 52-amino acid peptide originally isolated from extracts of human pheochromocytoma and, more recently, detected in human plasma. Based on the report that ADM mRNA and immunoreactivity are present in the kidney, the current study was designed to determine the renal distribution of ADM by immunohistochemistry and the renal biological actions of ADM. In the immunohistochemical studies, the present investigation demonstrated the localization of ADM in glomeruli, cortical distal tubules, and medullary collecting duct cells of the normal canine kidney. In the in vivo studies, ADM was administered (0.25 ng.kg-1.min-1 in group I and 1, 5, and 25 ng.kg-1.min-1 in group II) intrarenally in normal mongrel dogs with the contralateral kidney receiving only saline vehicle. Intrarenal infusion of ADM resulted in a marked diuretic and natriuretic response, whereas the contralateral kidney showed no renal effects. These significant natriuresis and diuresis in the ADM kidney were associated with increases in glomerular filtration rate and fractional sodium excretion and with a decrease in distal tubular sodium reabsorption. Intrarenal infusion of ADM also caused an increase in mean arterial blood pressure and a decrease in heart rate. Plasma concentrations of atrial natriuretic peptide, renin activity, aldosterone, and guanosine 3',5'-cyclic monophosphate were not changed during the infusion of ADM. The current study demonstrates that ADM is present in renal glomerular and tubular cells and is a potent natriuretic peptide that may play an important role in the regulation of sodium excretion.

scholarly journals Catechin Bioavailability Is Reduced in Obese Persons Without Altering Gut Microbial-Derived Valerolactones Following Consumption of a Green Tea Extract Confection

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 468-468
Author(s):  
Geoffrey Sasaki ◽  
Yael Vodovotz ◽  
Zhongtang Yu ◽  
Richard Bruno
Keyword(s):  
Green Tea ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Relative Bioavailability ◽  
Green Tea Extract ◽  
Maximum Plasma ◽  
Gut Permeability ◽  
Epicatechin Gallate ◽  
Obesity Status ◽  
Tea Extract

Abstract Objectives Green tea extract (GTE) protects against obesity in rodents by reducing gut permeability that otherwise provokes endotoxemia-mediated inflammation. However, whether obesity affects catechin bioavailability and microbial metabolism is unknown. We hypothesized that obesity will reduce catechin bioavailability by increasing microbial biotransformation of catechins. Methods Obese persons (n = 10 M/7F; 33.5 ± 0.7 kg/m2) and age-matched healthy persons (n = 10 M/9F; 21.7 ± 0.4 kg/m2) completed a pharmacokinetics (PK) trial in which a GTE confection [290 mg epigallocatechin gallate (EGCG), 87 mg epigallocatechin (EGC), 39 mg epicatechin (EC), 28 mg epicatechin gallate (ECG)] was ingested prior to collecting plasma at 0, 0.25, 0.5, 1, 2, 3, 5, 8, 10, and 12 h and urine from 0–4, 4–8, 8–12, and 12–24 h. Stool samples were collected and gut permeability was assessed prior to the 12-h PK trial. Plasma and urinary catechin/catechin-derived microbial metabolites were assessed following enzymatic hydrolysis by LC-MS. Results Regardless of health status, relative bioavailability, based on plasma area under the curve (AUC0–12 h), of GTE catechins were: EGCG > EGC > ECG > EC. However, obese persons had 24–27% lower plasma AUC0–12 h for the four catechins compared to lean persons (P < 0.05). They also had 18–36% lower maximum plasma concentrations (Cmax) of GTE catechins but 12 h plasma catechin concentrations were unaffected by obesity status (P > 0.05). 3ʹ,4ʹ-γ-valerolactone (3,4-VL) was detected in the plasma of all participants, while 3ʹ,4ʹ,5ʹ-γ-valerolactone (3,4,5-VL) was detected in 74% and 82% of lean and obese persons, respectively. Plasma AUC0–12 h for these VL metabolites did not differ by obesity status. EGC, EC, 3,4-VL, and 3,4,5-VL, but not EGCG and ECG, were primarily present in urine and urinary total VLs were increased compared with total urinary catechins. However, 24-h urinary excretion of catechins and VLs were unaffected by obesity. Conclusions Obesity reduces GTE catechin bioavailability and Cmax independent of any change in VL metabolite appearance or urinary elimination of catechins, suggesting a gut-level mechanism that limits catechin absorption. Funding Sources Supported by USDA-NIFA and the Foods for Health Discovery Theme at The Ohio State University.

scholarly journals Severe Renal Impairment Has Minimal Impact on Doravirine Pharmacokinetics

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Wendy Ankrom ◽  
Ka Lai Yee ◽  
Rosa I. Sanchez ◽  
Adedayo Adedoyin ◽  
Li Fan ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Renal Impairment ◽  
Severe Renal Impairment ◽  
Geometric Mean ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Transcriptase Inhibitor ◽  
Maximum Plasma ◽  
Minor Effect ◽  
Minimal Impact

ABSTRACT Doravirine is a novel nonnucleoside reverse transcriptase inhibitor in development for use with other antiretroviral therapies to treat human immunodeficiency virus type 1 (HIV-1) infection. Doravirine metabolism predominantly occurs via cytochrome P450 3A with <10% of elimination occurring via the renal pathway. As severe renal impairment can alter the pharmacokinetics (PK) of metabolically eliminated drugs, the effect of severe renal impairment on doravirine PK was assessed. A single dose of doravirine 100 mg was administered to subjects aged 18 to 75 years with an estimated glomerular filtration rate (eGFR) of <30 ml/min/1.73 m2 (severe renal impairment group) and healthy controls with an eGFR of ≥80 ml/min/1.73 m2, matched to the mean of the renal impairment group by age (±10 years) and weight (±10 kg). Doravirine plasma concentrations were determined at regular intervals, and safety was monitored throughout. The geometric mean ratios (90% confidence interval) for severe renal impairment/healthy subjects were 1.43 (1.00, 2.04), 1.38 (0.99, 1.92), and 0.83 (0.61, 1.15) for the plasma doravirine area under the curve from zero to infinity (AUC0–∞), plasma concentration at 24 h postdose (C24), and maximum plasma concentration (Cmax), respectively. Doravirine was generally well tolerated in both groups. Based on the overall efficacy, safety, and PK profile of doravirine, the minor effect of severe renal impairment on doravirine PK observed in this study is not considered clinically meaningful. (This study has been registered at ClinicalTrials.gov under identifier NCT02641067.)

Fludarabine Pharmacokinetics in Nonmyeloablative Hematopoietic Cell Transplantation (HCT): Association with Engraftment and Neurotoxicty.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3673-3673 ◽  
Author(s):  
Pamala A. Jacobson ◽  
John Rogosheske ◽  
Kathleen Green ◽  
Claudio Brunstein ◽  
Juliet Barker ◽  
...  
Keyword(s):  
Hematopoietic Cell Transplantation ◽  
Total Bilirubin ◽  
Clinical Status ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Hepatic Function ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Poor Renal Function

Abstract Chemotherapy related complications and risk of graft vs host disease limit HCT to younger patients with good clinical status and organ function. Non-myeloablative (NMA) transplant is now being widely used to extend access to HCT for patients not fit for conventional allografting. However, the incidence of engraftment and toxicity of this procedure can vary. Most NMA preparative therapies include fludarabine, a purine analog antimetabolite infrequently associated with neurotoxicity. In vivo, fludarabine undergoes rapid dephosphorylation to the active compound, F-ara-A which is 40 % renally eliminated and accumulates in renal dysfunction. Given that patients receiving a NMA HCT are often older or have poor renal function we hypothesized that variability in toxicities and clinical outcomes may be related to differences in exposure to F-ara-A. We evaluated the pharmacokinetics of F-ara-A in 29 subjects receiving a fludarabine based NMA HCT and the relationship between pharmacokinetics, engraftment and neurotoxicity. All received fludarabine 40 mg/m2/day IV x 5 days (infused over 1 hour) on days −6 to −2 in combination with cyclophosphamide 50 mg/kg/day IV on day −6 and TBI 200cGy single fraction day −1. Sampling was performed with the 1st and 5th dose of fludarabine. F-ara-A plasma concentrations were measured by HPLC. Patients underwent weekly neurotoxicity evaluation. The median age and weight of subjects was 54.8 years (range, 36–69) years and 79 kg (range, 54.6–134), respectively. Diagnoses were leukemia (n=13), lymphoma (n=7), myelodysplastic syndrome (n=5) and other (n=4). Subjects were transplanted with peripheral blood stem cells from related donors (n=10) and unrelated donor umbilical cord blood (n=19). Median CrCl and total bilirubin on admission was 100 ml/min (range, 49–190) and 0.5 mg/dL (range, 0.2–1.2), respectively. Median F-ara-A area under the curve (AUC0-∞) was 5261 ng hr/mL (range, 2935–7762), half life 9.6 hr (range, 3.1–26.6), clearance 14.5 L/hr (range, 9.4–25.6) and Cmax 851 ng/mL (range, 409–1146). F-ara-A plasma concentrations were slightly higher with dose 5. Correlation (r2) between AUC and age, weight, CrCl, SCr and total bilirubin were all ≤0.1. F-ara-A concentrations were detectable, 13.8 ng/mL (range, 5.7–38.2), on day 0 in all patients. Twenty five (cumulative incidence 89%, 95% CI: 77–100%) patients engrafted at a median of day 7. While neutrophil engraftment occurred in 100% with an AUC &gt;5261 ng hr/mL (n=14), the incidence was 80% (95% CI 60–100%) for those with an AUC &lt;5261 ng hr/mL (n=15)(p=.83). Engraftment was 100% in patients with an F-Ara-A concentration on day transplant ≥14 ng/mL (n=13) and 79% (95% CI 58–100%) if &lt;14 ng/mL (n=16)(p=.45). The patient with the highest AUC (7762) and a Cmax of 1050 ng/mL died of probable fludarabine-related neurotoxicity on day 47. In summary, F-ara-A accumulates slightly between dose 1 and 5 and was detectable in all patients on the day of stem cell infusion. There was a weak correlation between F-ara-A exposure and renal and hepatic function within the ranges studied. The patient with the highest AUC died from severe neurotoxicity.

A Novel T-Cell Redirecting Anti-CD19-F(ab)2/CD3scFv Bispecific Antibody Exhibits Potent Lymphoma Cytotoxicity.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2762-2762
Author(s):  
Diane L Rossi ◽  
Edmund A Rossi ◽  
Thomas M Cardillo ◽  
David M Goldenberg ◽  
Chien-Hsing Chang
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Elimination Rate ◽  
Cell Killing ◽  
Antibody Engineering ◽  
In Vivo Studies ◽  
Target Cells ◽  
Daudi Cells

Abstract Abstract 2762 Background: The use of bispecific antibodies (bsAbs) to redirect effector T cells for the targeted killing of tumor cells is a very active area of antibody engineering. Various formats of such agents made recombinantly have shown considerable promise both pre-clinically and clinically. For example, one design termed Bispecific T-cell engager (BiTE) employs a single polypeptide containing 2 antigen-binding specificities (each contributed by a cognate VH and VL) linked in tandem via a flexible linker, and another design termed DART (Dual-Affinity Re-Targeting) utilizes a disulfide-stabilized diabody. Both BiTE and DART, however, exhibit fast blood clearance due to their small size (∼55 kDa). Herein, we describe, for the first time, the generation of a novel T-cell redirecting bsAb, (19)-3s, comprising an anti-CD3 scFv covalently conjugated to a stabilized anti-CD19 F(ab)2. The potential advantages of (19)-3s include bivalent binding to tumor cells, a larger size (∼130 kDa) to preclude rapid renal clearance, and potent T-cell mediated cytotoxicity. Methods and Results: The Dock-and-Lock (DNL) method was used to generate (19)-3s by combining a stabilized anti-CD19 F(ab)2 with an anti-CD3-scFv, resulting in a homogeneous covalent structure of the designed composition, as shown by SE-HPLC, ELISA, SDS-PAGE, and immunoblot analyses. Functionally, (19)-3s induced synapse formation between effector and target cells using freshly isolated human T cells mixed with Daudi Burkitt lymphoma cells. Using an E:T ratio of 2.5:1 and 1 μg/mL of (19)-3s, the cell mixture was stained with anti-CD20-APC (for Daudi) and anti-CD7-FITC (for T cells), and cobinding was measured by flow cytometry as the % of CD20+/CD7+ events. After treatment with (19)-3s, 45.5% of events were found to be CD20/CD7 dual-positive, indicating synapsed Daudi and T cells, compared with 2% measured for untreated cells. Gating of the Daudi cell population showed that >90% of Daudi cells were associated with T cells. To access the targeted T-cell killing of Daudi, isolated T cells and Daudi were mixed at an E:T ratio of 12.5:1 and treated with serial dilutions of (19)-3s. After 18-h incubation at 37°C, cytotoxicity was measured using a LDH-release assay. Potent (19)-3s-mediated T-cell killing of Daudi cells was observed at <1 pM, with maximal activity at 10 pM. Similar results were seen with both Ramos and Raji NHL cell lines. In vivo studies to determine Pk and efficacy are underway. Based on DNL constructs of similar design, we expect (19)-3s to have an elimination rate longer than that of MT103, a BiTE comprising scFvs derived from anti-CD19 and anti-CD3, thus perhaps avoiding continuous infusions with this new construct. Conclusions: (19)-3s can bind T cells and NHL cells simultaneously and induce T-cell-mediated killing at pM concentrations in an ex vivo setting. The modular nature of the DNL method will allow the rapid production of a large number of related conjugates for redirected T-cell killing of various malignancies, without the need for additional recombinant engineering and protein production. We are currently evaluating the in vivo activity of (19)-3s, as a prototype, to determine if this novel bsAb format offers additional advantages. Disclosures: Rossi: Immunomedics, Inc.: Employment. Rossi:Immunomedics, Inc.: Employment; IBC Pharmaceuticals Inc.: Employment. Cardillo:Immunomedics, Inc: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership. Chang:Immunomedics, Inc.: Employment.

Results of a phase I trial of the proteasome inhibitor carfilzomib in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7077-7077
Author(s):  
Jennifer Ann Woyach ◽  
Joseph M. Flynn ◽  
Jeffrey Alan Jones ◽  
Leslie A. Andritsos ◽  
Margaret Lucas ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase I Trial ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Area Under The Curve ◽  
Lymphocytic Leukemia ◽  
Maximum Plasma ◽  
Maximal Dose

7077 Background: CLL is an incurable malignancy, and survival for patients (pts) with relapsed disease is limited. Carfilzomib (CFZ) has shown efficacy in multiple myeloma, and our group has shown significant in vitro activity in primary CLL cells. Therefore, we have undertaken a phase I trial of this agent in CLL. Methods: This is a single institution phase I trial of CFZ in pts with relapsed or refractory CLL. Primary endpoints were to determine maximal tolerated dose (MTD) and describe toxicity. Pts with CLL relapsed after at least one therapy were enrolled using a 3x3 design. CFZ was administered on the standard myeloma schedule. The first two doses were administered at 20 mg/m2 with remainder given at doses starting at 27 mg/m2 for dose level 1 with escalation to 56 mg/m2. Results: 17 pts received at least 1 dose of CFZ. 12 pts completed at least 1 cycle of therapy, with the remaining 5 experiencing PD during cycle 1. The MTD was not reached, with 3 pts accrued to each dose level to the maximal dose tested without dose limiting toxicity. Most adverse events (AE) were grade (G) 1 or 2. G3/4 AE were quickly reversible and included G3 neutropenia (4 pts), G4 neutropenia (2), G3 febrile neutropenia (1), and G3 thrombocytopenia (3). G1/2 toxicities observed in ≥ 20% of pts included anemia (10), thrombocytopenia (7), and hypocalcemia (8). Median number of cycles was 3, with 9 pts achieving stable disease after 2 cycles. Of 3 pts enrolled at maximal dose level, 2 remain on therapy after 5 and 7 months, with 1 achieving a clinical partial response. Of 5 evaluable pts, at least 50% proteasome inhibition was seen in all at 1 hour, with minimal recovery at 24 hours. PK was best characterized by a two-compartment model. Maximum plasma concentrations across all dose levels ranged from 0.81 to 8.1 uM. Across the evaluated dose range, area under the curve increased in an apparent dose-proportional manner. Conclusions: Despite relatively limited efficacy in this study, CFZ has acceptable toxicity in CLL, with no MTD identified up to 56 mg/m2. This suggests that CFZ may be better studied in CLL using a different schedule or in combination with other active agents. Clinical trial information: NCT01212380.

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