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Gerald S Falchook - One of the best experts on this subject based on the ideXlab platform.
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Effect of Food on the Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib (MLN8237) in Patients with Advanced Solid Tumors
Drugs in R&D, 2016Co-Authors: Gerald S Falchook, Razelle Kurzrock, Xiaofei Zhou, Karthik Venkatakrishnan, Devalingam Mahalingam, Jonathan W. Goldman, Jungah Jung, Claudio Dansky Ullmann, Catherine Milch, Lee S. RosenAbstract:Objective This study was conducted to characterize the effects of food on single-dose pharmacokinetics (PK) of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors. Methods Following overnight fasting for 10 h, a single 50 mg Enteric-Coated Tablet (ECT) of alisertib was administered under either fasted (alisertib with 240 mL of water) or fed (high-fat meal consumed 30 min before receiving alisertib with 240 mL of water) conditions using a two-cycle, two-way crossover design. Patients on both arms were not allowed food for 4 h post-dose. Water was allowed as desired, except for 1 h before and after alisertib administration. Results Twenty-four patients were enrolled and 14 patients were PK-evaluable (ten patients were not PK-evaluable due to insufficient data). Following a single oral dose of alisertib, median t _max was 6 h and 3 h under fed and fasted conditions, respectively. The geometric mean ratio of AUC_inf (fed- vs. fasted-state dosing) was 0.94 [90 % confidence interval (CI) 0.68–1.32]. The geometric mean C _max under fed conditions was 84 % of that under fasted conditions (90 % CI 66–106). Alisertib was generally well-tolerated; most common drug-related grade 3/4 adverse events included neutropenia (50 %), leukopenia (38 %), and thrombocytopenia (21 %). Conclusions Systemic exposures achieved following a single 50 mg dose of alisertib administered as an ECT formulation after a high-fat meal are similar to those observed in the fasted state. Alisertib 50 mg ECT can be administered without regard for food. ClinicalTrials.gov Identifier NCT00962091.
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investigational aurora a kinase inhibitor alisertib mln8237 as an Enteric Coated Tablet formulation in non hematologic malignancies phase 1 dose escalation study
Investigational New Drugs, 2014Co-Authors: Gerald S Falchook, Razelle Kurzrock, Launce Gouw, David S Hong, Kimberly A Mcgregor, Xiaofei Zhou, Hongliang Shi, Howard Fingert, Sunil SharmaAbstract:Background This phase 1b study evaluated an Enteric-Coated Tablet (ECT) formulation of the investigational Aurora A kinase inhibitor, alisertib (MLN8237). Methods Patients with advanced, non-hematologic malignancies received oral alisertib ECT for 7 d BID followed by 14 d treatment-free (21-day cycles; 3 + 3 dose escalation schema). Objectives were to assess safety, pharmacokinetics, and antitumor activity, and to define a recommended phase 2 dose (RP2D) of alisertib. Results 24 patients were treated. Median age was 57 years. Patients received a median of 2 cycles (range 1–12). The RP2D was determined as 50 mg BID for 7 d (21-day cycles). A cycle 1 dose-limiting toxicity of grade 4 febrile neutropenia was observed in 1 of 13 patients at RP2D. The most common drug-related adverse event (AE) was neutropenia (50 %). At doses ≥40 mg BID, 7 patients had drug-related AEs that were serious but largely reversible/manageable by dose reduction and supportive care, including 3 with febrile neutropenia. Pharmacokinetic data were available in 24 patients. Following administration of alisertib ECT, the plasma peak concentration of alisertib was achieved at ~3 h; systemic exposure increased with increasing dose over 10–60 mg BID. Mean t½ was ~21 h following multiple dosing. Renal clearance was negligible. Nine patients achieved stable disease (3.98*, 5.59, 1.28*, 2.56, 5.45*, 3.48, 3.15, 8.31, and 6.93* months; *censored). Conclusions Alisertib ECT was generally well tolerated in adults with advanced, non-hematologic malignancies. The RP2D is 50 mg BID for 7 d and is being evaluated in ongoing phase 2 studies.
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phase i dose escalation study of the investigational aurora a kinase aak inhibitor mln8237 as an Enteric Coated Tablet ect formulation in patients with nonhematologic malignancies
Journal of Clinical Oncology, 2011Co-Authors: Sunil Sharma, Razelle Kurzrock, Launce Gouw, David S Hong, Xiaofei Zhou, Hongliang Shi, Howard Fingert, Kevin B Jones, Gerald S FalchookAbstract:3094 Background: The investigational drug MLN8237 is an orally available, selective AAK inhibitor with early clinical trials using a powder in capsule (PIC) formulation in a range of tumor types. T...
Xiaofei Zhou - One of the best experts on this subject based on the ideXlab platform.
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Effect of Food on the Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib (MLN8237) in Patients with Advanced Solid Tumors
Drugs in R&D, 2016Co-Authors: Gerald S Falchook, Razelle Kurzrock, Xiaofei Zhou, Karthik Venkatakrishnan, Devalingam Mahalingam, Jonathan W. Goldman, Jungah Jung, Claudio Dansky Ullmann, Catherine Milch, Lee S. RosenAbstract:Objective This study was conducted to characterize the effects of food on single-dose pharmacokinetics (PK) of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors. Methods Following overnight fasting for 10 h, a single 50 mg Enteric-Coated Tablet (ECT) of alisertib was administered under either fasted (alisertib with 240 mL of water) or fed (high-fat meal consumed 30 min before receiving alisertib with 240 mL of water) conditions using a two-cycle, two-way crossover design. Patients on both arms were not allowed food for 4 h post-dose. Water was allowed as desired, except for 1 h before and after alisertib administration. Results Twenty-four patients were enrolled and 14 patients were PK-evaluable (ten patients were not PK-evaluable due to insufficient data). Following a single oral dose of alisertib, median t _max was 6 h and 3 h under fed and fasted conditions, respectively. The geometric mean ratio of AUC_inf (fed- vs. fasted-state dosing) was 0.94 [90 % confidence interval (CI) 0.68–1.32]. The geometric mean C _max under fed conditions was 84 % of that under fasted conditions (90 % CI 66–106). Alisertib was generally well-tolerated; most common drug-related grade 3/4 adverse events included neutropenia (50 %), leukopenia (38 %), and thrombocytopenia (21 %). Conclusions Systemic exposures achieved following a single 50 mg dose of alisertib administered as an ECT formulation after a high-fat meal are similar to those observed in the fasted state. Alisertib 50 mg ECT can be administered without regard for food. ClinicalTrials.gov Identifier NCT00962091.
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investigational aurora a kinase inhibitor alisertib mln8237 as an Enteric Coated Tablet formulation in non hematologic malignancies phase 1 dose escalation study
Investigational New Drugs, 2014Co-Authors: Gerald S Falchook, Razelle Kurzrock, Launce Gouw, David S Hong, Kimberly A Mcgregor, Xiaofei Zhou, Hongliang Shi, Howard Fingert, Sunil SharmaAbstract:Background This phase 1b study evaluated an Enteric-Coated Tablet (ECT) formulation of the investigational Aurora A kinase inhibitor, alisertib (MLN8237). Methods Patients with advanced, non-hematologic malignancies received oral alisertib ECT for 7 d BID followed by 14 d treatment-free (21-day cycles; 3 + 3 dose escalation schema). Objectives were to assess safety, pharmacokinetics, and antitumor activity, and to define a recommended phase 2 dose (RP2D) of alisertib. Results 24 patients were treated. Median age was 57 years. Patients received a median of 2 cycles (range 1–12). The RP2D was determined as 50 mg BID for 7 d (21-day cycles). A cycle 1 dose-limiting toxicity of grade 4 febrile neutropenia was observed in 1 of 13 patients at RP2D. The most common drug-related adverse event (AE) was neutropenia (50 %). At doses ≥40 mg BID, 7 patients had drug-related AEs that were serious but largely reversible/manageable by dose reduction and supportive care, including 3 with febrile neutropenia. Pharmacokinetic data were available in 24 patients. Following administration of alisertib ECT, the plasma peak concentration of alisertib was achieved at ~3 h; systemic exposure increased with increasing dose over 10–60 mg BID. Mean t½ was ~21 h following multiple dosing. Renal clearance was negligible. Nine patients achieved stable disease (3.98*, 5.59, 1.28*, 2.56, 5.45*, 3.48, 3.15, 8.31, and 6.93* months; *censored). Conclusions Alisertib ECT was generally well tolerated in adults with advanced, non-hematologic malignancies. The RP2D is 50 mg BID for 7 d and is being evaluated in ongoing phase 2 studies.
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abstract c122 phase 1b relative bioavailability ba study of Enteric Coated Tablet ect in reference to powder in capsule pic formulation of the investigational drug alisertib mln8237 an aurora a kinase aak inhibitor in patients with advanced nonhemato
Molecular Cancer Therapeutics, 2011Co-Authors: Karthik Venkatakrishnan, Xiaofei Zhou, Howard Fingert, Jeffrey R Infante, R B Cohen, Howard A Burris, Hua Liu, Claire E DeesAbstract:Background: The investigational drug alisertib (MLN8237) is an orally available, selective AAK inhibitor. Early clinical studies used a PIC formulation; an ECT formulation was recently developed. Here we present relative BA results of ECT referenced to PIC designed to bridge transition to ECT in MLN8237 clinical development. Methods: Eligible patients were age ≥18 years with advanced solid tumors and ECOG PS 0–1. Dose-escalation cohorts received alisertib 10 mg BID (N=1), and 20 mg BID (N=1), before formal relative BA evaluation at 40 mg BID, in a 7-day schedule followed by 14 days9 rest (21-day cycles). Patients received MLN8237 40 mg BID as either ECT or PIC in a 2-cycle, 2-way cross-over design. Pharmacokinetic (PK) sampling was performed on Day 7 of cycles 1 and 2 to characterize steady-state PK of alisertib formulated as ECT or PIC for relative BA analysis. PK was also evaluated on Day 1 of ECT dosing. Results: 22 patients were included (N=1 each at 10 and 20 mg BID; N=20 at 40 mg BID); 55% were male, 90% were white, and median age was 56 years. 14 patients were evaluable for relative BA analysis. Following BID oral dosing, absorption was fast (median T max ∼2.5 hours for ECT; ∼2 hours for PIC). Relative BA of ECT referenced to PIC was 90% (90% CI: 74.4, 108.8). Steady-state C max following ECT was 82% of that from PIC (90% CI: 69.9, 95.5). Mean accumulation ratio of ECT BID was ∼2.8-fold; mean peak-to-trough ratio was ∼2.5. The range of dose-normalized exposures following ECT was within the corresponding range observed with PIC, which has previously been associated with favorable pharmacodynamic effects (Dees et al. Abstract 3010; Cervantes et al. Abstract 3031, J Clin Oncol 2010;28:15s). Conclusions: Systemic exposures following administration of ECT and PIC formulations of alisertib are generally similar, supporting transition from PIC to ECT in clinical development. Taken together with PK, pharmacodynamics, and antitumor activity from other trials, these data indicate that the ECT formulation of alisertib can provide exposures needed for clinically relevant bioactivity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C122.
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phase i dose escalation study of the investigational aurora a kinase aak inhibitor mln8237 as an Enteric Coated Tablet ect formulation in patients with nonhematologic malignancies
Journal of Clinical Oncology, 2011Co-Authors: Sunil Sharma, Razelle Kurzrock, Launce Gouw, David S Hong, Xiaofei Zhou, Hongliang Shi, Howard Fingert, Kevin B Jones, Gerald S FalchookAbstract:3094 Background: The investigational drug MLN8237 is an orally available, selective AAK inhibitor with early clinical trials using a powder in capsule (PIC) formulation in a range of tumor types. T...
L N Cheng - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of a levonorgestrel Enteric Coated Tablet as an over the counter drug for emergency contraception a phase iv clinical trial
Human Reproduction, 2011Co-Authors: Q J Chen, Wenpei Xiang, D K Zhang, R P Wang, Y F Luo, J Z Kang, L N ChengAbstract:BACKGROUND An Enteric-Coated levonorgestrel emergency contraceptive pill (E-LNG-ECP) is an improved formulation in terms of side effects which both dissolves and is absorbed in the intestine. Our aim was to evaluate the efficacy and safety of E-LNG-ECP as an over-the-counter (OTC) drug for emergency contraception (EC) in Chinese women. METHODS A Phase IV clinical trial was conducted in five family planning clinics in China. Women seeking EC within 72 h after unprotected sexual intercourse or contraceptive failure who met the inclusion criteria were recruited. The efficacy of contraception (primary end-point was pregnancy rate) side effects (i.e. safety) and the value of E-LNG-ECP for EC were investigated. RESULTS Of 2445 women (aged 15-48 years) who took E-LNG-ECP with follow-up to determine pregnancy only five pregnancies (0.2%) occurred. The efficacy of contraception was 95.3%. In total 6.5% of women reported at least one adverse event after taking E-LNG-ECP and no serious adverse events were reported. Only four subjects (0.16%) reported vomiting. The incidence of menstrual cycle disturbance was 20.1% after taking E-LNG-ECP. Subjects who had previously taken ECPs (54.4% of these women) rated the acceptability of E-LNG-ECP at 9.36 (on a 10-point scale) higher (P<0.05) than the rating of other LNG-EC pills taken previously. CONCLUSIONS The study found that E-LNG-ECP was effective safe and well tolerated as an OTC drug. However an randomized controlled trial should be performed to compare standard LNG Tablets with E-LNG-ECP.
Razelle Kurzrock - One of the best experts on this subject based on the ideXlab platform.
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Effect of Food on the Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib (MLN8237) in Patients with Advanced Solid Tumors
Drugs in R&D, 2016Co-Authors: Gerald S Falchook, Razelle Kurzrock, Xiaofei Zhou, Karthik Venkatakrishnan, Devalingam Mahalingam, Jonathan W. Goldman, Jungah Jung, Claudio Dansky Ullmann, Catherine Milch, Lee S. RosenAbstract:Objective This study was conducted to characterize the effects of food on single-dose pharmacokinetics (PK) of the investigational Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors. Methods Following overnight fasting for 10 h, a single 50 mg Enteric-Coated Tablet (ECT) of alisertib was administered under either fasted (alisertib with 240 mL of water) or fed (high-fat meal consumed 30 min before receiving alisertib with 240 mL of water) conditions using a two-cycle, two-way crossover design. Patients on both arms were not allowed food for 4 h post-dose. Water was allowed as desired, except for 1 h before and after alisertib administration. Results Twenty-four patients were enrolled and 14 patients were PK-evaluable (ten patients were not PK-evaluable due to insufficient data). Following a single oral dose of alisertib, median t _max was 6 h and 3 h under fed and fasted conditions, respectively. The geometric mean ratio of AUC_inf (fed- vs. fasted-state dosing) was 0.94 [90 % confidence interval (CI) 0.68–1.32]. The geometric mean C _max under fed conditions was 84 % of that under fasted conditions (90 % CI 66–106). Alisertib was generally well-tolerated; most common drug-related grade 3/4 adverse events included neutropenia (50 %), leukopenia (38 %), and thrombocytopenia (21 %). Conclusions Systemic exposures achieved following a single 50 mg dose of alisertib administered as an ECT formulation after a high-fat meal are similar to those observed in the fasted state. Alisertib 50 mg ECT can be administered without regard for food. ClinicalTrials.gov Identifier NCT00962091.
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investigational aurora a kinase inhibitor alisertib mln8237 as an Enteric Coated Tablet formulation in non hematologic malignancies phase 1 dose escalation study
Investigational New Drugs, 2014Co-Authors: Gerald S Falchook, Razelle Kurzrock, Launce Gouw, David S Hong, Kimberly A Mcgregor, Xiaofei Zhou, Hongliang Shi, Howard Fingert, Sunil SharmaAbstract:Background This phase 1b study evaluated an Enteric-Coated Tablet (ECT) formulation of the investigational Aurora A kinase inhibitor, alisertib (MLN8237). Methods Patients with advanced, non-hematologic malignancies received oral alisertib ECT for 7 d BID followed by 14 d treatment-free (21-day cycles; 3 + 3 dose escalation schema). Objectives were to assess safety, pharmacokinetics, and antitumor activity, and to define a recommended phase 2 dose (RP2D) of alisertib. Results 24 patients were treated. Median age was 57 years. Patients received a median of 2 cycles (range 1–12). The RP2D was determined as 50 mg BID for 7 d (21-day cycles). A cycle 1 dose-limiting toxicity of grade 4 febrile neutropenia was observed in 1 of 13 patients at RP2D. The most common drug-related adverse event (AE) was neutropenia (50 %). At doses ≥40 mg BID, 7 patients had drug-related AEs that were serious but largely reversible/manageable by dose reduction and supportive care, including 3 with febrile neutropenia. Pharmacokinetic data were available in 24 patients. Following administration of alisertib ECT, the plasma peak concentration of alisertib was achieved at ~3 h; systemic exposure increased with increasing dose over 10–60 mg BID. Mean t½ was ~21 h following multiple dosing. Renal clearance was negligible. Nine patients achieved stable disease (3.98*, 5.59, 1.28*, 2.56, 5.45*, 3.48, 3.15, 8.31, and 6.93* months; *censored). Conclusions Alisertib ECT was generally well tolerated in adults with advanced, non-hematologic malignancies. The RP2D is 50 mg BID for 7 d and is being evaluated in ongoing phase 2 studies.
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phase i dose escalation study of the investigational aurora a kinase aak inhibitor mln8237 as an Enteric Coated Tablet ect formulation in patients with nonhematologic malignancies
Journal of Clinical Oncology, 2011Co-Authors: Sunil Sharma, Razelle Kurzrock, Launce Gouw, David S Hong, Xiaofei Zhou, Hongliang Shi, Howard Fingert, Kevin B Jones, Gerald S FalchookAbstract:3094 Background: The investigational drug MLN8237 is an orally available, selective AAK inhibitor with early clinical trials using a powder in capsule (PIC) formulation in a range of tumor types. T...
Yongqing Wang - One of the best experts on this subject based on the ideXlab platform.
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stereoselective pharmacokinetics of r and s rabeprazole in human using chiral lc ms ms after administration of rabeprazole sodium Enteric Coated Tablet
Chirality, 2018Co-Authors: Luning Sun, Yiwen Shen, Yuwen Ying, Xuehui Zhang, Ping Zhao, Li Ding, Yongqing WangAbstract:Rabeprazole is an effective proton pump inhibitor to treat acid-related diseases. To achieve the simultaneous determination of rabeprazole enantiomers in human plasma, a chiral LC-MS/MS method was developed and validated. Acetonitrile including 0.1% ammonium were used as protein precipitating agent. Analytes were separated within 8 minutes on a Chiralpak IC column (4.6 mm × 150 mm, 5 μm). The mobile phase was 10 mM ammonium acetate including 0.2% acetic acid-acetonitrile (35:65, v/v). An API 4000 mass spectrometer was used as detector for the analysis, and the multiple reactions monitoring transitions of m/z 360.1 → 242.2 and 346.1 → 198.1 were opted for quantifying rabeprazole enantiomers and internal standard. Matrix effects were not apparent for each enantiomer and internal standard (esomeprazole), the calibration curves were linear over the concentration of 0.500 to 400 ng·mL-1 , the intra-run precisions were below 5.4%, the inter-run precisions were below 9.9%, and the accuracy was between -9.2% and 9.3%. There was no chiral inversion observed during sample storage, preparation procedure, and analysis, demonstrating that analytes were stable in this study. This method was applied to the stereoselective pharmacokinetic study of (R)-(+)- and (S)-(-)-rabeprazole after oral administration of 10-mg rabeprazole sodium Enteric-Coated Tablet in healthy Chinese subjects.