scholarly journals Pharmacokinetics of zonisamide after oral single dosing and multiple‐dose escalation administration in domestic chickens ( Gallus gallus )

2021 ◽  
Author(s):  
Ricardo Matos ◽  
Brendan P. Noonan ◽  
Deanna M.W. Schaefer ◽  
James Morrisey ◽  
Curtis Dewey ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Multiple Dose ◽  
Gallus Gallus ◽  
Single Dosing

A Phase 1, Open-Label, Multi-Center, Multiple-Dose, Dose-Escalation Study of MDX-1342 in Patients with CD19-Positive Refractory/Relapsed Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3425-3425 ◽  
Author(s):  
Luis H Camacho ◽  
Robin Joyce ◽  
Jennifer R Brown ◽  
Asher Chanan-Khan ◽  
Philip C. Amrein ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Multiple Dose ◽  
Phase 1 ◽  
Human Monoclonal Antibody ◽  
Lymphocytic Leukemia ◽  
Tolerability Profile ◽  
Open Label ◽  
Dose Cohort ◽  
Median Reduction

Abstract Abstract 3425 Poster Board III-313 MDX-1342 is a fully human monoclonal antibody (HuMAb) with enhanced antibody-dependent cellular cytotoxicity (ADCC) effector function, targeting CD19-membrane receptor which is highly expressed on malignant chronic lymphocytic leukemia (CLL) cells. An open-label, multi-center, multiple-dose, dose-escalating Phase 1 study is being conducted to determine the safety and tolerability profile of MDX-1342 in subjects with CD19-positive relapsed or refractory CLL. To date, MDX-1342 has been administered intravenously (iv) weekly for 4 weeks to 12 subjects (8 Male, 4 Female) - in cohorts of 3 subjects each - at doses of 0.7, 7, 40, and 200 mg/dose. Overall, MDX-1342 has been well tolerated. No drug-related serious adverse events have been reported among the 12 subjects treated. Grade 1 and 2 infusion reactions (including rigors, chills, and wheezing) have been observed in 9 subjects. This has been adequately managed with the use of antihistamines and corticosteroids. Dose escalation continues and a maximum tolerated dose has not yet been identified. Of the 9 currently evaluable subjects, 1 has experienced a partial response (40 mg/dose cohort), 6 have stable disease and 2 have discontinued due to progressive disease. Preliminary results indicate antileukemic signals with dose-correlative reductions in both white blood counts (WBC) and circulating CD20+ cells after one 4-week cycle of weekly i.v. infusions of MDX-1342. In the 40 mg/dose cohort, the median reduction in WBC was 62% and the median reduction in circulating CD20+ cells was 74%. Additional subjects are being accrued to higher dose cohorts to more accurately characterize the safety and clinical activity of MDX-1342 and to determine if there is a consistent cumulative drop in WBC and circulating CD20+ cells as the dose increases. Disclosures Assad: Medarex, Inc.: Employment. Carrigan:Medarex, Inc: Employment.

YM150, An Oral Direct Inhibitor of Factor Xa, Demonstrated a Predictable and Dose-Proportional Pharmacokinetic/Pharmacodynamic Profile After Single and Multiple Dosing: Results From Three Studies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3323-3323 ◽  
Author(s):  
Dorien Groenendaal– van de Meent ◽  
Marten Heeringa ◽  
Takeshi Kadokura ◽  
Frank Verheggen ◽  
Gregory Strabach ◽  
...  
Keyword(s):  
Single Dose ◽  
Dose Escalation ◽  
Dose Group ◽  
Dose Range ◽  
Factor Xa ◽  
Global Development ◽  
Dose Escalation Study ◽  
Sequential Group ◽  
Repeated Dosing ◽  
Single Dosing

Abstract Abstract 3323 Background: YM150 is a potent oral direct factor Xa (FXa) inhibitor that is rapidly and extensively metabolized into YM-222714 after oral administration. YM-222714 predominantly determines the antithrombotic effect of YM150. Three studies were undertaken to assess the pharmacokinetic/pharmacodynamic (PK/PD) profiles of YM150 and YM-222714 in healthy male subjects (aged 18–55 yrs) after single and multiple doses over a wide dose range. Methods: Study 1a was a sequential-group, double-blind (DB), randomized, placebo-controlled, single-dose escalation study (3, 10, 20 and 30 mg; n=6 per dose group, except for 30 mg, where n=5). Study 1b was an open-label, randomized, 2-period crossover study to explore the effect of food on PK (n=10). Study 2 was a sequential-group, DB, randomized, placebo-controlled, multiple-dose escalation study (3, 10, 20 and 30 mg twice daily; n=6 per dose group); subjects received a single dose of YM150 (Day 1) followed by a washout period (48 h) and, thereafter, repeated dosing (Days 3–10). Study 3 was a sequential-group, DB, randomized, placebo-controlled, multiple-dose escalation study (60, 120, 180, 240, 360, 480 and 720 mg once daily; n=12 per dose group, except for 720 mg, where n=6); subjects received a single dose of YM150 (Day 1) followed by a washout period (48 h) and, thereafter, repeated dosing (Days 3–9). In all studies, blood samples were collected for PK/PD analysis up to 48, 72 or 96 hrs post-dose for 3–120, 180–480 and 720 mg dosages, respectively. All doses were tested separately in each study. Data are presented as arithmetic means. Results: YM-222714 maximum concentration (Cmax) and area under the curve (AUC)inf generally increased proportionally with dose in all studies. After single dosing across the studies (3–720 mg), YM-222714 Cmax and AUCinf ranged from 103–13,550 ng/mL and 404–14,0793 ng·h/mL, respectively; at steady state (SS), similar ranges were observed (Cmax: 116–18,680 ng/mL; AUCtau: 630–16,6009 ng·h/mL). The time to maximum concentration (tmax) of YM-222714 was 0.75–1.08 h after single dosing and at SS in Studies 1 and 2; in Study 3, tmax slightly increased with dose (range for 60–720 mg; single dose, 0.92–2.10 h; SS, 1.00–2.20 h). YM-222714 elimination half-life (t1/2) was 14.3–20.0 h after single dosing and 14.3–20.5 h at SS. YM150 plasma concentrations were generally below the lower limit of quantification in Studies 1 and 2. In Study 3, YM150 Cmax and AUCinf increased proportionally with dose after single dosing (4.5–65.4 ng/mL and 197–590 ng·h/mL), with a t1/2 range of 12.5–17.9 h; consistent with this, YM150 Cmax and AUCtau also increased proportionally with dose at SS (6.8–90.0 ng/mL and 43.7–723 ng·h/mL), with a t1/2 of 16.2–22.3 h. Administration of YM150 10 mg in fed vs fasted state led to an increase in YM-222714 tmax (1.7 vs 0.8 h) and decrease in Cmax (253 vs 310 ng/mL); other parameters were similar in both states. Small amounts of YM150 (<0.65%) were excreted unchanged in urine after single dosing and at SS; 20–40% and 25–39% of dose was excreted as YM-222714 after single dosing and at SS, respectively. Across the studies, renal clearance (CLR) ranged from 1.60–2.91 L/h after single dosing; a similar range was observed at SS (1.37–2.57 L/h). Across studies (YM150 3–720 mg) maximum prothrombin time (PTmax; INR) increased with dose and was similar under single dosing (1.42–14.1) and at SS (1.48–14.3), as was maximum activated partial thromboplastin time (aPTTmax; single dose, 37.0–81.6 s; SS, 38.0–92.4 s). A dose-dependent decrease in FXa activity was observed that was similar after single dosing and at SS (60–720 mg; 58.0–28.1% and 50.7–22.3%, respectively). Treatment with YM150 was generally safe and well tolerated across all studies. Conclusions: YM150 is rapidly and extensively converted to YM-222714 after oral administration. YM-222714 demonstrated a predictable, dose-proportional PK profile that was similar under single dosing and SS conditions, including a linear increase in Cmax and AUC, consistent t1/2 and no dose effect on CLR; no relevant food effect was observed, with administration of YM150 in fasted or fed state, having minimal effects on YM-222714 PK. Additionally, YM150 exhibited dose-dependent antithrombotic activity, as shown by increasing PT and aPTT and decreasing FXa activity with dose. Disclosures: Groenendaal – van de Meent: Astellas Pharma Global Development Europe: Employment. Heeringa:Astellas Pharma Global Development Europe: Employment. Kadokura:Astellas Pharma Inc.: Employment. Verheggen:Astellas Pharma Global Development Europe: Employment. Heinzerling:Astellas Pharma Global Development Europe: Employment.

scholarly journals Single- and multiple-dose escalation study to assess pharmacokinetics, pharmacodynamics and safety of oral esaxerenone in healthy Japanese subjects

2018 ◽  
Vol 84 (8) ◽  
pp. 1821-1829 ◽  
Author(s):  
Manabu Kato ◽  
Hidetoshi Furuie ◽  
Takako Shimizu ◽  
Atsuhiro Miyazaki ◽  
Fumiaki Kobayashi ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Multiple Dose ◽  
Dose Escalation Study ◽  
Japanese Subjects

A phase I multiple-dose escalation study to assess the safety, tolerability, and pharmacokinetics of VEGF-receptor inhibitor telatinib (EOC315) in Chinese patients with advanced solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3061-3061
Author(s):  
Hongming Pan ◽  
Tianshu Liu ◽  
Jason Tsai ◽  
Yapeng Zhao
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Multiple Dose ◽  
Left Ventricular Systolic Dysfunction ◽  
Single Agent ◽  
Left Ventricular ◽  
Chinese Patients ◽  
Vegf Receptor ◽  
Advanced Solid Tumors

3061 Background: Telatinib (EOC315) is a highly selective inhibitor of VEGFR/PDGFR (VEGFR 1-3, PDGFR-β, and c-Kit tyrosine kinases). This phase I study was to assess the safety, tolerability, and pharmacokinetics (PK) of Telatinib in Chinese patients with advanced solid tumors. Methods: Telatinib was administered to Chinese patients with advanced refractory solid tumors as a single agent in 3+3 dose escalation design, starting from 600mg and escalated to 900mg and 1200mg, given orally twice daily. The PK profile, safety, and tolerability were evaluated per protocol. Efficacy was evaluated with RECIST 1.1 criteria every 6 weeks. Results: A total of 15 subjects (6 colorectal cancer, 4 lung cancer, 1 head and neck cancer, 1 melanoma, 1 thymic carcinoma, 1 esophageal carcinoma,1 peritoneal carcinoma) were enrolled per protocol between July 2017 and August 2018, and 13 subjects received at least second line therapies before enrollment. Telatinib was well tolerated in the three dose arms. No dose limiting toxicities (DLTs) occurred during the dose escalation phase. CTC grade 3 AEs observed include hypertension (46.7%, 7/15), fatigue (6.7%, 1/15), transaminase elevation (6.7%, 1/15), hand-foot syndrome (6.7%, 1/15), oral mucositis (6.7%, 1/15), neutropenia (6.7%, 1/15), urobilinogen elevation (6.7%, 1/15), left ventricular systolic dysfunction/decreased ejection fraction (6.7%, 1/15). No CTC grade 4 AE were observed. There were 2 drug related SAEs (hospitalization due to high blood pressure. The PK profile of Telatinib (EOC315) at 600, 900, 1200 mg in Chinese patient cohorts is summarized in Table. For 12 evaluable patients, DCR was 58.3%. For all patients, mPFS was 15 weeks (3.3-34.3w). Conclusions: This study demonstrated the safety and tolerability of Telatinib (EOC315) in a multiple dose escalation design at 600, 900, and 1200 mg PO bid in Chinese patients with advanced refractory solid tumor. Telatinib AUC increased dose-proportionally from 600 mg to 900 mg bid, where 900 mg Telatinib bid is the maximum feasible and recommended dose for future studies in Chinese patients with advanced tumors. Clinical trial information: NCT03175497. [Table: see text]

A phase I/II dose-escalation study of fractionated and multiple dose 225Ac-J591 for progressive metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS188-TPS188
Author(s):  
Michael Sun ◽  
Jones T. Nauseef ◽  
Justin M Lebenthal ◽  
Muhammad Junaid Niaz ◽  
Sharon Singh ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Multiple Dose ◽  
Dose Escalation Study ◽  
Dose Cohort ◽  
Cell Counts ◽  
Psma Pet ◽  
Patient Reported ◽  
Pet Scans

TPS188 Background: Prostate-specific membrane antigen (PSMA)-based targeted radionuclide therapy (TRT) is a promising treatment. PSMA-targeting via large antibodies vs small molecules has different kinetics, biodistribution, and resulting clinical toxicities. Using beta-TRT, 177Lu-J591 has more heme toxicity and 177Lu-PSMA-617 more non-heme toxicity (xerostomia and nausea) [Niaz AUA 2020]. Alpha-emitters are more potent than beta radionuclides, and alpha-PSMA-TRT has efficacy even after beta-PSMA-TRT. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg [Tagawa ASCO 2020]. No maximal tolerated dose (MTD) was achieved. One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of grade 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had grade > 3 heme toxicity or grade > 2 non-heme toxicity. Preliminary results indicate 64% had any PSA decline and 41% had > 50% PSA decline (PSA50) across all doses, despite lack of selection for PSMA expression and the majority having been previously treated with 177Lu-PSMA. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function (including normal neutrophil and platelet counts), and prior receipt of AR pathway inhibitor and chemotherapy (or refuse/ineligible for chemotherapy). There is no limit to prior lines of therapy except alpha-PSMA-TRT. Phase I includes 2 separate parallel dose-escalation cohorts. In the fractionated-dose cohort, men will receive a single cycle of 225Ac-J591 administered on D1 and D15. In the multiple-dose cohort, 225Ac-J591 will be given every 6 weeks for up to 4 cycles. The phase I component is a 3+3 dose-escalation study design, with the goal of identifying MTD. Each phase II component will treat up to 27 men with PSMA+ PET scans in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup, but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment began in August 2020 (NCT04506567). Clinical trial information: NCT04506567.

scholarly journals A Phase I/II, Multiple-Dose, Dose-Escalation Study of Siltuximab, an Anti-Interleukin-6 Monoclonal Antibody, in Patients with Advanced Solid Tumors

2014 ◽  
Vol 20 (8) ◽  
pp. 2192-2204 ◽  
Author(s):  
Eric Angevin ◽  
Josep Tabernero ◽  
Elena Elez ◽  
Steven J. Cohen ◽  
Rastilav Bahleda ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Interleukin 6 ◽  
Multiple Dose ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study
Sign in / Sign up

Export Citation Format

Share Document