scholarly journals A Single Dose-Escalation Study to Evaluate the Safety and Pharmacokinetics of Orally Administered Des-Aspartate Angiotensin I in Healthy Subjects

Drugs in R&D ◽  
2016 ◽  
Vol 16 (4) ◽  
pp. 317-326 ◽  
Author(s):  
Ko-Onn Lee ◽  
Chin-Meng Khoo ◽  
Balram Chowbay ◽  
Yiong-Huak Chan ◽  
Meng-Kwoon Sim
Keyword(s):  
Single Dose ◽  
Dose Escalation ◽  
Healthy Subjects ◽  
Angiotensin I ◽  
Dose Escalation Study

scholarly journals SAFETY AND TOLERABILITY OF GLIAL GROWTH FACTOR 2 IN PATIENTS WITH CHRONIC HEART FAILURE: A PHASE I SINGLE DOSE ESCALATION STUDY

2013 ◽  
Vol 61 (10) ◽  
pp. E707 ◽  
Author(s):  
Daniel J. Lenihan ◽  
Sarah Anderson ◽  
Carrie Geisberg ◽  
Anthony Caggiano ◽  
Andrew Eisen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Single Dose ◽  
Growth Factor ◽  
Chronic Heart Failure ◽  
Phase I ◽  
Dose Escalation ◽  
Dose Escalation Study ◽  
Glial Growth Factor

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.

Fractionated dose radiolabeled anti−prostate specific membrane antigen (PSMA) radioimmunotherapy (177Lu−J591) for progressive metastatic castration−resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 205-205
Author(s):  
Jaspreet S. Batra ◽  
Beerinder S. Karir ◽  
Kavya Pinto-Chengot ◽  
Yuliya Jhanwar ◽  
Shankar Vallabhajosula ◽  
...  
Keyword(s):  
Single Dose ◽  
Phase I ◽  
Dose Escalation ◽  
Maximum Tolerated Dose ◽  
Dose Fractionation ◽  
Castration Resistant Prostate Cancer ◽  
Planar Imaging ◽  
Dose Escalation Study ◽  
Initial Portion ◽  
Before And After

205 Background: Phase I and II single dose 177Lu−J591 studies have been published. Based on the theoretical advantages of dose fractionation on safety and efficacy, we initiated a phase I dose−escalation study of fractionated−dose 177Lu−J591. Methods: Men with progressive mCRPC with normal neutrophil and platelet counts were enrolled. The initial portion was 3+3 dose−escalation, with 6 cohorts of 3−6 patients receiving 2 doses 177Lu−J591, 2 weeks apart starting with 20 mCi/m2, escalating to 45 mCi/m2. After determining maximum tolerated dose (MTD), patients enrolled in 2 expansion cohorts at recommended phase II doses (RP2D). Planar imaging of 177Lu−J591 at 6−8 days following the initial dose was performed. Pre− and post−treatment PSA was measured for all patients and the highest dose−level cohorts had CTC counts (CellSearch) measured before and after treatment. Results: 48 patients enrolled with median age 74 (55−95) ), median baseline PSA 45.38 (1.93−766.5), 37.5% with prior chemo. The RP2D’s of fractionated 177Lu−J591 were 40 mCi/m2 or 45 mCi/m2 x2 with option for GCSF. Overall PSA decline ≥ 50% in 9 (18.8%), ≥ 30% in 14 (29.2%) and any PSA decline in 26 (54.2%); at RP2D doses (n = 32), 8 (25%) with ≥ 50%, 12 (37.5%) with ≥ 30%, and 20 (62.5%) with any PSA decline. Of 25 with available CTC counts, 14 declined, 8 remained stably favorable, and 3 increased. Of 12 with unfavorable baseline CTC counts, 8 (66.7%) became favorable at follow up, 2 decreased by 30% and 88% but remained ≥ 5, and 2 increased; 1 converted from < 5 to ≥ 5. Thirty-five (72.9%) had grade 3/4 hematological toxicities; 19 (59.4%) with Gr 4 heme toxicity in RP2D cohorts, with 15 (16.9%) receiving at least 1 platelet transfusion, 6 receiving GCSF, and 0 with febrile neutropenia. Overall 4 had Gr 1 transaminitis and 14 (29.2%) had grade 1 infusion reactions (without pre−medication). Accurate targeting of 177Lu−J591 at known sites of disease seen in 84.4%. Conclusions: Fractionated 177Lu−J591 is well tolerated with predictable, reversible myelosuppression, achieving a higher cumulative dose than possible with a single dose. Both PSA and CTC count control was achieved. Clinical trial information: NCT00538668.

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