The Experts below are selected from a list of 2151 Experts worldwide ranked by ideXlab platform
Neeraj Gupta - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacology of Ixazomib: The First Oral Proteasome Inhibitor
Clinical Pharmacokinetics, 2019Co-Authors: Neeraj Gupta, Richard Labotka, R. Donald Harvey, Michael J. Hanley, Karthik VenkatakrishnanAbstract:Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome, and preferentially binds to and inhibits the β5 chymotrypsin-like proteolytic site. Ixazomib absorption is rapid, with a median time to reach maximum plasma concentration of approximately 1 h post-dose. Ixazomib pharmacokinetics (PK) are adequately described by a three-compartment model (terminal half-life of 9.5 days) with first-order linear absorption (oral bioavailability of 58%). Plasma exposures of Ixazomib increase in a dose-proportional manner. A high-fat meal decreases both the rate and extent of Ixazomib absorption, supporting administration on an empty stomach. Population PK analyses demonstrated that no dose adjustment is required based on age, body size/weight, race, sex, mild-to-moderate renal impairment, or mild hepatic impairment. Results from dedicated studies indicate that a reduced starting dose (from 4 to 3 mg) is appropriate for patients with severe renal impairment, end-stage renal disease requiring dialysis, or moderate-to-severe hepatic impairment. Non-cytochrome P450 (CYP)-mediated metabolism appears to be the major clearance mechanism for Ixazomib. Drug–drug interaction studies have shown no meaningful effects of strong inhibitors of CYP3A on Ixazomib PK; however, the strong inducer rifampin caused a clinically relevant reduction in Ixazomib exposure, supporting the recommendation to avoid concomitant administration of Ixazomib with strong CYP3A inducers. Exposure–response analyses of data from the phase III TOURMALINE-MM1 registrational study demonstrate a favorable benefit–risk profile for the approved dose and regimen of weekly Ixazomib 4 mg on days 1, 8, and 15 of each 28-day cycle.
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All-oral Ixazomib, cyclophosphamide, and dexamethasone for transplant-ineligible patients with newly diagnosed multiple myeloma.
European journal of cancer (Oxford England : 1990), 2018Co-Authors: Meletios A Dimopoulos, Richard Labotka, Neeraj Gupta, Markus Hansson, Sebastian Grosicki, Wiesław Wiktor Jędrzejczak, Hareth Nahi, Astrid Gruber, Catriona Byrne, Zhaoyang TengAbstract:Abstract Background Novel efficacious treatments with long-term tolerability are needed for transplant-ineligible, newly diagnosed multiple myeloma (NDMM) patients. This phase 2 study evaluated the safety and efficacy of all-oral Ixazomib-cyclophosphamide-dexamethasone (ICd) followed by single-agent Ixazomib maintenance. Patients and methods Patients were randomised (1:1) to receive 4.0 mg of Ixazomib, 300 (Arm A) or 400 (Arm B) mg/m2 of cyclophosphamide (days 1, 8, and 15), and 40 mg of dexamethasone (days 1, 8, 15, and 22) as induction (up to 13 × 28-day cycles), followed by single-agent Ixazomib maintenance (28-day cycles) until progressive disease, death, or unacceptable toxicity. Primary end-point was complete response (CR) + very good partial response (VGPR) rate for ICd induction. Results Seventy patients were enrolled (n = 36 Arm A; n = 34 Arm B); median age was 73 years (range, 61–87). At data cut-off, 66% of patients had completed 13 induction cycles followed by Ixazomib maintenance. Median overall treatment duration was 19 cycles (range, 1–29); 21% of patients discontinued treatment during induction and 3% during maintenance due to adverse events (AEs). During induction, among 67 response-evaluable patients, CR+VGPR rate was 25%, and overall response rate (ORR) was 73%. Including the maintenance phase, CR+VGPR rate was 33%, and ORR was 76%. Median progression-free survival was 23.5 months (median follow-up: 26.1 months). The most common all-grade AE was neutropenia (31%). Grade ≥3 AEs were reported by 73% of patients. Five on-study deaths occurred (not treatment-related). Conclusions ICd treatment followed by Ixazomib maintenance is tolerable and active in elderly, transplant-ineligible NDMM patients. Trial registration number NCT02046070.
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Biotransformation of [ 14 C]-Ixazomib in patients with advanced solid tumors: characterization of metabolite profiles in plasma, urine, and feces
Cancer chemotherapy and pharmacology, 2018Co-Authors: Sandeepraj Pusalkar, Karthik Venkatakrishnan, Neeraj Gupta, Michael J. Hanley, Mihaela Plesescu, Cindy Q. Xia, Xiaoquan Zhang, Swapan K. ChowdhuryAbstract:This metabolite profiling and identification analysis (part of a phase I absorption, distribution, metabolism, and excretion study) aimed to define biotransformation pathways and evaluate associated inter-individual variability in four patients with advanced solid tumors who received [14C]-Ixazomib. After administration of a single 4.1-mg oral dose of [14C]-Ixazomib (total radioactivity [TRA] ~ 500 nCi), plasma (at selected timepoints), urine, and fecal samples were collected before dosing and continuously over 0–168-h postdose, followed by intermittent collections on days 14, 21, 28, and 35. TRA analysis and metabolite profiling were performed using accelerator mass spectrometry. Radiolabeled metabolites were identified using liquid chromatography/tandem mass spectrometry. Metabolite profiles were similar in plasma, urine, and feces samples across the four patients analyzed. All metabolites identified were de-boronated. In AUC0–816 h time-proportional pooled plasma, Ixazomib (54.2% of plasma TRA) and metabolites M1 (18.9%), M3 (10.6%), and M2 (7.91%), were the primary components identified. M1 was the major metabolite, contributing to 31.1% of the 76.2% of the total dose excreted in urine and feces over 0–35-day postdose. As none of the identified metabolites had a boronic acid moiety, they are unlikely to be pharmacologically active. Hydrolytic metabolism in conjunction with oxidative deboronation appears to be the principal process in the in vivo biotransformation pathways of Ixazomib. The inference of formation-rate-limited clearance of Ixazomib metabolites and the inferred lack of pharmacologic activity of identified circulating metabolites provides justification for use of parent drug concentrations/systemic exposure in clinical pharmacology analyses.
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Model-Informed Drug Development for Ixazomib, an Oral Proteasome Inhibitor.
Clinical pharmacology and therapeutics, 2018Co-Authors: Neeraj Gupta, Richard Labotka, Paul Matthias Diderichsen, Michael J. Hanley, Deborah Berg, Huyuan Yang, Zhaoyang Teng, Chirag Patel, Guohui LiuAbstract:Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor Ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of Ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of Ixazomib.
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A phase I study to assess the mass balance, excretion, and pharmacokinetics of [14C]-Ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors
Investigational new drugs, 2017Co-Authors: Neeraj Gupta, Michael J. Hanley, Bingxia Wang, Steven Zhang, Sandeepraj Pusalkar, Mihaela Plesescu, Swapan K. Chowdhury, Cindy Q. Xia, Xiaoquan Zhang, Karthik VenkatakrishnanAbstract:This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of Ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-Ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled Ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of Ixazomib. During Part B of the study, patients received non-radiolabeled Ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, Ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that Ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material. Trial ID: ClinicalTrials.gov # NCT01953783.
Michael J. Hanley - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacology of Ixazomib: The First Oral Proteasome Inhibitor
Clinical Pharmacokinetics, 2019Co-Authors: Neeraj Gupta, Richard Labotka, R. Donald Harvey, Michael J. Hanley, Karthik VenkatakrishnanAbstract:Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome, and preferentially binds to and inhibits the β5 chymotrypsin-like proteolytic site. Ixazomib absorption is rapid, with a median time to reach maximum plasma concentration of approximately 1 h post-dose. Ixazomib pharmacokinetics (PK) are adequately described by a three-compartment model (terminal half-life of 9.5 days) with first-order linear absorption (oral bioavailability of 58%). Plasma exposures of Ixazomib increase in a dose-proportional manner. A high-fat meal decreases both the rate and extent of Ixazomib absorption, supporting administration on an empty stomach. Population PK analyses demonstrated that no dose adjustment is required based on age, body size/weight, race, sex, mild-to-moderate renal impairment, or mild hepatic impairment. Results from dedicated studies indicate that a reduced starting dose (from 4 to 3 mg) is appropriate for patients with severe renal impairment, end-stage renal disease requiring dialysis, or moderate-to-severe hepatic impairment. Non-cytochrome P450 (CYP)-mediated metabolism appears to be the major clearance mechanism for Ixazomib. Drug–drug interaction studies have shown no meaningful effects of strong inhibitors of CYP3A on Ixazomib PK; however, the strong inducer rifampin caused a clinically relevant reduction in Ixazomib exposure, supporting the recommendation to avoid concomitant administration of Ixazomib with strong CYP3A inducers. Exposure–response analyses of data from the phase III TOURMALINE-MM1 registrational study demonstrate a favorable benefit–risk profile for the approved dose and regimen of weekly Ixazomib 4 mg on days 1, 8, and 15 of each 28-day cycle.
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Biotransformation of [ 14 C]-Ixazomib in patients with advanced solid tumors: characterization of metabolite profiles in plasma, urine, and feces
Cancer chemotherapy and pharmacology, 2018Co-Authors: Sandeepraj Pusalkar, Karthik Venkatakrishnan, Neeraj Gupta, Michael J. Hanley, Mihaela Plesescu, Cindy Q. Xia, Xiaoquan Zhang, Swapan K. ChowdhuryAbstract:This metabolite profiling and identification analysis (part of a phase I absorption, distribution, metabolism, and excretion study) aimed to define biotransformation pathways and evaluate associated inter-individual variability in four patients with advanced solid tumors who received [14C]-Ixazomib. After administration of a single 4.1-mg oral dose of [14C]-Ixazomib (total radioactivity [TRA] ~ 500 nCi), plasma (at selected timepoints), urine, and fecal samples were collected before dosing and continuously over 0–168-h postdose, followed by intermittent collections on days 14, 21, 28, and 35. TRA analysis and metabolite profiling were performed using accelerator mass spectrometry. Radiolabeled metabolites were identified using liquid chromatography/tandem mass spectrometry. Metabolite profiles were similar in plasma, urine, and feces samples across the four patients analyzed. All metabolites identified were de-boronated. In AUC0–816 h time-proportional pooled plasma, Ixazomib (54.2% of plasma TRA) and metabolites M1 (18.9%), M3 (10.6%), and M2 (7.91%), were the primary components identified. M1 was the major metabolite, contributing to 31.1% of the 76.2% of the total dose excreted in urine and feces over 0–35-day postdose. As none of the identified metabolites had a boronic acid moiety, they are unlikely to be pharmacologically active. Hydrolytic metabolism in conjunction with oxidative deboronation appears to be the principal process in the in vivo biotransformation pathways of Ixazomib. The inference of formation-rate-limited clearance of Ixazomib metabolites and the inferred lack of pharmacologic activity of identified circulating metabolites provides justification for use of parent drug concentrations/systemic exposure in clinical pharmacology analyses.
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Model-Informed Drug Development for Ixazomib, an Oral Proteasome Inhibitor.
Clinical pharmacology and therapeutics, 2018Co-Authors: Neeraj Gupta, Richard Labotka, Paul Matthias Diderichsen, Michael J. Hanley, Deborah Berg, Huyuan Yang, Zhaoyang Teng, Chirag Patel, Guohui LiuAbstract:Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor Ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of Ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of Ixazomib.
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A phase I study to assess the mass balance, excretion, and pharmacokinetics of [14C]-Ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors
Investigational new drugs, 2017Co-Authors: Neeraj Gupta, Michael J. Hanley, Bingxia Wang, Steven Zhang, Sandeepraj Pusalkar, Mihaela Plesescu, Swapan K. Chowdhury, Cindy Q. Xia, Xiaoquan Zhang, Karthik VenkatakrishnanAbstract:This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of Ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-Ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled Ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of Ixazomib. During Part B of the study, patients received non-radiolabeled Ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, Ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that Ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material. Trial ID: ClinicalTrials.gov # NCT01953783.
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dose and schedule selection of the oral proteasome inhibitor Ixazomib in relapsed refractory multiple myeloma clinical and model based analyses
Targeted Oncology, 2017Co-Authors: Neeraj Gupta, Shaji Kumar, Michael J. Hanley, Huyuan Yang, Paul G. Richardson, Steven Zhang, Rachael Liu, Tomas Skacel, Karthik VenkatakrishnanAbstract:The oral proteasome inhibitor Ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. The objective of this study was to quantitatively characterize the benefit–risk profile of Ixazomib in relapsed/refractory MM in support of the approved dose and schedule. We report early-phase study data and exposure–response analyses of TOURMALINE-MM1 data that support the selection of the recommended Ixazomib dose and schedule. Single-agent Ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of Ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly Ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure–response analyses from TOURMALINE-MM1, Ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between Ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher Ixazomib exposure was associated with lower lenalidomide relative dose intensity. These analyses support a favorable benefit–risk profile for weekly Ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537
Karthik Venkatakrishnan - One of the best experts on this subject based on the ideXlab platform.
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Clinical Pharmacology of Ixazomib: The First Oral Proteasome Inhibitor
Clinical Pharmacokinetics, 2019Co-Authors: Neeraj Gupta, Richard Labotka, R. Donald Harvey, Michael J. Hanley, Karthik VenkatakrishnanAbstract:Ixazomib, the first oral proteasome inhibitor, is approved in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Ixazomib is a selective, potent, and reversible inhibitor of the 20S proteasome, and preferentially binds to and inhibits the β5 chymotrypsin-like proteolytic site. Ixazomib absorption is rapid, with a median time to reach maximum plasma concentration of approximately 1 h post-dose. Ixazomib pharmacokinetics (PK) are adequately described by a three-compartment model (terminal half-life of 9.5 days) with first-order linear absorption (oral bioavailability of 58%). Plasma exposures of Ixazomib increase in a dose-proportional manner. A high-fat meal decreases both the rate and extent of Ixazomib absorption, supporting administration on an empty stomach. Population PK analyses demonstrated that no dose adjustment is required based on age, body size/weight, race, sex, mild-to-moderate renal impairment, or mild hepatic impairment. Results from dedicated studies indicate that a reduced starting dose (from 4 to 3 mg) is appropriate for patients with severe renal impairment, end-stage renal disease requiring dialysis, or moderate-to-severe hepatic impairment. Non-cytochrome P450 (CYP)-mediated metabolism appears to be the major clearance mechanism for Ixazomib. Drug–drug interaction studies have shown no meaningful effects of strong inhibitors of CYP3A on Ixazomib PK; however, the strong inducer rifampin caused a clinically relevant reduction in Ixazomib exposure, supporting the recommendation to avoid concomitant administration of Ixazomib with strong CYP3A inducers. Exposure–response analyses of data from the phase III TOURMALINE-MM1 registrational study demonstrate a favorable benefit–risk profile for the approved dose and regimen of weekly Ixazomib 4 mg on days 1, 8, and 15 of each 28-day cycle.
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Biotransformation of [ 14 C]-Ixazomib in patients with advanced solid tumors: characterization of metabolite profiles in plasma, urine, and feces
Cancer chemotherapy and pharmacology, 2018Co-Authors: Sandeepraj Pusalkar, Karthik Venkatakrishnan, Neeraj Gupta, Michael J. Hanley, Mihaela Plesescu, Cindy Q. Xia, Xiaoquan Zhang, Swapan K. ChowdhuryAbstract:This metabolite profiling and identification analysis (part of a phase I absorption, distribution, metabolism, and excretion study) aimed to define biotransformation pathways and evaluate associated inter-individual variability in four patients with advanced solid tumors who received [14C]-Ixazomib. After administration of a single 4.1-mg oral dose of [14C]-Ixazomib (total radioactivity [TRA] ~ 500 nCi), plasma (at selected timepoints), urine, and fecal samples were collected before dosing and continuously over 0–168-h postdose, followed by intermittent collections on days 14, 21, 28, and 35. TRA analysis and metabolite profiling were performed using accelerator mass spectrometry. Radiolabeled metabolites were identified using liquid chromatography/tandem mass spectrometry. Metabolite profiles were similar in plasma, urine, and feces samples across the four patients analyzed. All metabolites identified were de-boronated. In AUC0–816 h time-proportional pooled plasma, Ixazomib (54.2% of plasma TRA) and metabolites M1 (18.9%), M3 (10.6%), and M2 (7.91%), were the primary components identified. M1 was the major metabolite, contributing to 31.1% of the 76.2% of the total dose excreted in urine and feces over 0–35-day postdose. As none of the identified metabolites had a boronic acid moiety, they are unlikely to be pharmacologically active. Hydrolytic metabolism in conjunction with oxidative deboronation appears to be the principal process in the in vivo biotransformation pathways of Ixazomib. The inference of formation-rate-limited clearance of Ixazomib metabolites and the inferred lack of pharmacologic activity of identified circulating metabolites provides justification for use of parent drug concentrations/systemic exposure in clinical pharmacology analyses.
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A phase I study to assess the mass balance, excretion, and pharmacokinetics of [14C]-Ixazomib, an oral proteasome inhibitor, in patients with advanced solid tumors
Investigational new drugs, 2017Co-Authors: Neeraj Gupta, Michael J. Hanley, Bingxia Wang, Steven Zhang, Sandeepraj Pusalkar, Mihaela Plesescu, Swapan K. Chowdhury, Cindy Q. Xia, Xiaoquan Zhang, Karthik VenkatakrishnanAbstract:This two-part, phase I study evaluated the mass balance, excretion, pharmacokinetics (PK), and safety of Ixazomib in patients with advanced solid tumors. In Part A of the study, patients received a single 4.1 mg oral solution dose of [14C]-Ixazomib containing ~500 nCi total radioactivity (TRA), followed by non-radiolabeled Ixazomib (4 mg capsule) on days 14 and 21 of the 35-day PK cycle. Patients were confined to the clinic for the first 168 h post dose and returned for 24 h overnight clinic visits on days 14, 21, 28, and 35. Blood, urine, and fecal samples were collected during Part A to assess the mass balance (by accelerator mass spectrometry), excretion, and PK of Ixazomib. During Part B of the study, patients received non-radiolabeled Ixazomib (4 mg capsules) on days 1, 8, and 15 of 28-day cycles. After oral administration, Ixazomib was rapidly absorbed with a median plasma Tmax of 0.5 h and represented 70% of total drug-related material in plasma. The mean total recovery of administered TRA was 83.9%; 62.1% in urine and 21.8% in feces. Only 3.23% of the administered dose was recovered in urine as unchanged drug up to 168 h post dose, suggesting that most of the TRA in urine was attributable to metabolites. All patients experienced a treatment-emergent adverse event, which most commonly involved the gastrointestinal system. These findings suggest that Ixazomib is extensively metabolized, with urine representing the predominant route of excretion of drug-related material. Trial ID: ClinicalTrials.gov # NCT01953783.
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dose and schedule selection of the oral proteasome inhibitor Ixazomib in relapsed refractory multiple myeloma clinical and model based analyses
Targeted Oncology, 2017Co-Authors: Neeraj Gupta, Shaji Kumar, Michael J. Hanley, Huyuan Yang, Paul G. Richardson, Steven Zhang, Rachael Liu, Tomas Skacel, Karthik VenkatakrishnanAbstract:The oral proteasome inhibitor Ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. The objective of this study was to quantitatively characterize the benefit–risk profile of Ixazomib in relapsed/refractory MM in support of the approved dose and schedule. We report early-phase study data and exposure–response analyses of TOURMALINE-MM1 data that support the selection of the recommended Ixazomib dose and schedule. Single-agent Ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of Ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly Ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure–response analyses from TOURMALINE-MM1, Ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between Ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher Ixazomib exposure was associated with lower lenalidomide relative dose intensity. These analyses support a favorable benefit–risk profile for weekly Ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537
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Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses.
Targeted oncology, 2017Co-Authors: Neeraj Gupta, Shaji Kumar, Michael J. Hanley, Huyuan Yang, Paul G. Richardson, Steven Zhang, Rachael Liu, Tomas Skacel, Karthik VenkatakrishnanAbstract:The oral proteasome inhibitor Ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. The objective of this study was to quantitatively characterize the benefit–risk profile of Ixazomib in relapsed/refractory MM in support of the approved dose and schedule. We report early-phase study data and exposure–response analyses of TOURMALINE-MM1 data that support the selection of the recommended Ixazomib dose and schedule. Single-agent Ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of Ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly Ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure–response analyses from TOURMALINE-MM1, Ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between Ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher Ixazomib exposure was associated with lower lenalidomide relative dose intensity. These analyses support a favorable benefit–risk profile for weekly Ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537
Huyuan Yang - One of the best experts on this subject based on the ideXlab platform.
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Model-Informed Drug Development for Ixazomib, an Oral Proteasome Inhibitor.
Clinical pharmacology and therapeutics, 2018Co-Authors: Neeraj Gupta, Richard Labotka, Paul Matthias Diderichsen, Michael J. Hanley, Deborah Berg, Huyuan Yang, Zhaoyang Teng, Chirag Patel, Guohui LiuAbstract:Model-informed drug development (MIDD) was central to the development of the oral proteasome inhibitor Ixazomib, facilitating internal decisions (switch from body surface area (BSA)-based to fixed dosing, inclusive phase III trials, portfolio prioritization of Ixazomib-based combinations, phase III dose for maintenance treatment), regulatory review (model-informed QT analysis, benefit-risk of 4 mg dose), and product labeling (absolute bioavailability and intrinsic/extrinsic factors). This review discusses the impact of MIDD in enabling patient-centric therapeutic optimization during the development of Ixazomib.
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dose and schedule selection of the oral proteasome inhibitor Ixazomib in relapsed refractory multiple myeloma clinical and model based analyses
Targeted Oncology, 2017Co-Authors: Neeraj Gupta, Shaji Kumar, Michael J. Hanley, Huyuan Yang, Paul G. Richardson, Steven Zhang, Rachael Liu, Tomas Skacel, Karthik VenkatakrishnanAbstract:The oral proteasome inhibitor Ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. The objective of this study was to quantitatively characterize the benefit–risk profile of Ixazomib in relapsed/refractory MM in support of the approved dose and schedule. We report early-phase study data and exposure–response analyses of TOURMALINE-MM1 data that support the selection of the recommended Ixazomib dose and schedule. Single-agent Ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of Ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly Ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure–response analyses from TOURMALINE-MM1, Ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between Ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher Ixazomib exposure was associated with lower lenalidomide relative dose intensity. These analyses support a favorable benefit–risk profile for weekly Ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537
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Dose and Schedule Selection of the Oral Proteasome Inhibitor Ixazomib in Relapsed/Refractory Multiple Myeloma: Clinical and Model-Based Analyses.
Targeted oncology, 2017Co-Authors: Neeraj Gupta, Shaji Kumar, Michael J. Hanley, Huyuan Yang, Paul G. Richardson, Steven Zhang, Rachael Liu, Tomas Skacel, Karthik VenkatakrishnanAbstract:The oral proteasome inhibitor Ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. The objective of this study was to quantitatively characterize the benefit–risk profile of Ixazomib in relapsed/refractory MM in support of the approved dose and schedule. We report early-phase study data and exposure–response analyses of TOURMALINE-MM1 data that support the selection of the recommended Ixazomib dose and schedule. Single-agent Ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of Ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly Ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure–response analyses from TOURMALINE-MM1, Ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between Ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher Ixazomib exposure was associated with lower lenalidomide relative dose intensity. These analyses support a favorable benefit–risk profile for weekly Ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537
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a pharmacokinetics and safety phase 1 1b study of oral Ixazomib in patients with multiple myeloma and severe renal impairment or end stage renal disease requiring haemodialysis
British Journal of Haematology, 2016Co-Authors: Neeraj Gupta, Michael J. Hanley, Huyuan Yang, Ai Min Hui, Donald R Harvey, Ashraf Badros, Brea Lipe, Vishal Kukreti, Jesus G Berdeja, Mark G QianAbstract:Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single-dose pharmacokinetics (PK) of the oral proteasome inhibitor, Ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end-stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of Ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of Ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total Ixazomib concentrations were similar in pre- and post-dialyser samples collected from ESRD patients; therefore, Ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced Ixazomib dose of 3 mg in patients with severe RI/ESRD.
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pharmacokinetics of Ixazomib an oral proteasome inhibitor in solid tumour patients with moderate or severe hepatic impairment
British Journal of Clinical Pharmacology, 2016Co-Authors: Neeraj Gupta, Karthik Venkatakrishnan, Michael J. Hanley, Raymond P. Perez, Robin E. Norris, John Nemunaitis, Huyuan Yang, Gerald Steven Falchook, Mark G Qian, Richard LabotkaAbstract:Aim The aim of the present study was to characterize the pharmacokinetics of the oral proteasome inhibitor, Ixazomib, in patients with solid tumours and moderate or severe hepatic impairment, to provide posology recommendations. Methods Eligible adults with advanced malignancies for which no further effective therapy was available received a single dose of Ixazomib on day 1 of the pharmacokinetic cycle; patients with normal hepatic function, moderate hepatic impairment or severe hepatic impairment received 4 mg, 2.3 mg or 1.5 mg, respectively. Blood samples for single-dose pharmacokinetic characterization were collected over 336 h postdose. After sampling, patients could continue to receive Ixazomib on days 1, 8 and 15 in 28-day cycles. Results Of 48 enrolled patients (13, 15 and 20 in the normal, moderate and severe groups, respectively), 43 were pharmacokinetics-evaluable. Ixazomib was rapidly absorbed (median time to reach peak concentration was 0.95–1.5 h) and highly bound to plasma proteins, with a similar mean fraction bound (~99%) across the three groups. In patients with moderate/severe hepatic impairment (combined group), the geometric least squares mean ratios (90% confidence interval) for unbound and total dose-normalized area under the plasma concentration vs. time curve from time zero to the time of the last quantifiable concentration in reference to the normal hepatic function group were 1.27 (0.75, 2.16) and 1.20 (0.79, 1.82), respectively. Seven (15%) of the 48 patients experienced a grade 3 drug-related adverse event; there were no drug-related grade 4 adverse events. Conclusions In patients with moderate/severe hepatic impairment, unbound and total systemic exposures of Ixazomib were 27% and 20% higher, respectively, vs. normal hepatic function. A reduced Ixazomib starting dose of 3 mg is recommended for patients with moderate or severe hepatic impairment.
Jesus G Berdeja - One of the best experts on this subject based on the ideXlab platform.
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Ixazomib lenalidomide dexamethasone in routine clinical practice effectiveness in relapsed refractory multiple myeloma
Future Oncology, 2021Co-Authors: Roman Hájek, Jesus G Berdeja, Andrew Spencer, Jiří Minařík, Jan Straub, Luděk Pour, Alexandra Jungova, Mario Boccadoro, Lucie Brozova, Frits Van RheeAbstract:Aim: To evaluate the effectiveness and safety of Ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patients & methods: Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed. Results: At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued Ixazomib/lenalidomide due to adverse events. Conclusion: The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1. Clinical trial registration: NCT02761187 (ClinicalTrials.gov).
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Ixazomib-lenalidomide-dexamethasone in routine clinical practice: effectiveness in relapsed/refractory multiple myeloma.
Future oncology (London England), 2021Co-Authors: Roman Hájek, Jesus G Berdeja, Andrew Spencer, Jiří Minařík, Jan Straub, Luděk Pour, Alexandra Jungova, Mario Boccadoro, Lucie Brozova, Frits Van RheeAbstract:Aim: To evaluate the effectiveness and safety of Ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patients & methods: Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed. Results: At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued Ixazomib/lenalidomide due to adverse events. Conclusion: The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1. Clinical trial registration: NCT02761187 (ClinicalTrials.gov).
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Ixazomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma: long-term follow-up including Ixazomib maintenance
Leukemia, 2019Co-Authors: Shaji K. Kumar, Jacob P Laubach, Jesus G Berdeja, Ruben Niesvizky, Sagar Lonial, Mehdi Hamadani, A. Keith Stewart, Parameswaran Hari, Robert Vescio, Jonathan L. KaufmanAbstract:Triplet combinations containing a proteasome inhibitor are a standard of care in newly diagnosed multiple myeloma (NDMM). We examined the long-term efficacy and safety of the all-oral combination of weekly Ixazomib plus lenalidomide-dexamethasone (IRd), followed by single-agent Ixazomib maintenance in NDMM patients. Of 65 enrolled patients, 53 received Ixazomib 4 mg (days 1, 8, and 15) plus lenalidomide 25 mg (days 1–21) and dexamethasone 40 mg (days 1, 8, 15, and 22) for up to twelve 28-day induction cycles. Twenty-three patients discontinued induction for stem cell transplantation (SCT). In the remaining 42 patients, overall response rate was 80%, including 63% ≥very good partial response (VGPR) and 32% complete responses. At a median follow-up of 56 months, median progression-free survival (PFS) was 35.4 months in the total population. Twenty-five patients received Ixazomib maintenance; eight deepened their response (76% ≥VGPR), and median PFS was 37.2 months in this subgroup. Nine of 42 patients who did not proceed to SCT (14% of total population) had an adverse event requiring discontinuation. Ixazomib (median ≥ 96%) and lenalidomide (median 88–94%) relative dose intensities were maintained throughout treatment. Weekly IRd, followed by Ixazomib maintenance, was highly active with acceptable toxicity, enabling long-term administration with no evidence of cumulative toxicities.
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Twice-weekly Ixazomib in combination with lenalidomide-dexamethasone in patients with newly diagnosed multiple myeloma.
British journal of haematology, 2018Co-Authors: Paul G. Richardson, Craig C Hofmeister, Jesus G Berdeja, David H. Vesole, Cara A. Rosenbaum, Myo Htut, Michaela Liedtke, Ajai Chari, Stephen D. Smith, Daniel LebovicAbstract:Weekly Ixazomib with lenalidomide-dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice-weekly Ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice-weekly oral Ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9-16) for up to sixteen 21-day cycles, followed by maintenance with twice-weekly Ixazomib alone. No dose-limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression-free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug-related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug-related AEs. Thirteen patients discontinued due to AEs. Twice-weekly Ixazomib-Rd offers substantial activity with promising long-term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly Ixazomib-Rd in this setting.
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a pharmacokinetics and safety phase 1 1b study of oral Ixazomib in patients with multiple myeloma and severe renal impairment or end stage renal disease requiring haemodialysis
British Journal of Haematology, 2016Co-Authors: Neeraj Gupta, Michael J. Hanley, Huyuan Yang, Ai Min Hui, Donald R Harvey, Ashraf Badros, Brea Lipe, Vishal Kukreti, Jesus G Berdeja, Mark G QianAbstract:Renal impairment (RI) is a major complication of multiple myeloma (MM). This study aimed to characterize the single-dose pharmacokinetics (PK) of the oral proteasome inhibitor, Ixazomib, in cancer patients with normal renal function [creatinine clearance (CrCl) ≥90 ml/min; n = 20), severe RI (CrCl <30 ml/min; n = 14), or end-stage renal disease requiring haemodialysis (ESRD; n = 7). PK and adverse events (AEs) were assessed after a single 3 mg dose of Ixazomib. Ixazomib was highly bound to plasma proteins (~99%) in all renal function groups. Unbound and total systemic exposures of Ixazomib were 38% and 39% higher, respectively, in severe RI/ESRD patients versus patients with normal renal function. Total Ixazomib concentrations were similar in pre- and post-dialyser samples collected from ESRD patients; therefore, Ixazomib can be administered without regard to haemodialysis timing. Except for anaemia, the incidence of the most common AEs was generally similar across groups, but grade 3 and 4 AEs were more frequent in the severe RI/ESRD groups versus the normal group (79%/57% vs. 45%), as were serious AEs (43%/43% vs. 15%). The PK and safety results support a reduced Ixazomib dose of 3 mg in patients with severe RI/ESRD.
