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1دورية أكاديمية
المؤلفون: Locatelli, Franco, Stralin, Karin Belander, Schmid, Irene, Sevilla, Julian, Smith, Owen P., van den Heuvel-eibrink, Marry M., Zecca, Marco, Zwaan, Christian M., Gaudy, Allison, Patturajan, Meera, Poon, Jennifer, Simcock, Mathew, Niemeyer, Charlotte M.
المصدر: Locatelli , F , Stralin , K B , Schmid , I , Sevilla , J , Smith , O P , van den Heuvel-eibrink , M M , Zecca , M , Zwaan , C M , Gaudy , A , Patturajan , M , Poon , J , Simcock , M & Niemeyer , C M 2024 , ' Efficacy and safety of azacitidine in pediatric patients with newly diagnosed advanced myelodysplastic syndromes before hematopoietic stem cell transplantation in the AZA-JMML-001 trial ' , Pediatric Blood & Cancer , vol. 71 , no. 5 , e30931 . ....
الوصف: Here we report efficacy, pharmacokinetics, and safety data obtained in treatment-naive, pediatric patients with newly diagnosed advanced MDS receiving azacitidine in the AZA-JMML-001 study. The primary endpoint was response rate (proportion of patients with complete response [CR], partial response [PR], or marrow CR, sustained for >= 4 weeks). Of the 10 patients enrolled, one had an unconfirmed marrow CR and none had confirmed responses after three cycles; the study was therefore closed after stage 1. Azacitidine was well tolerated. The lack of efficacy of azacitidine in pediatric patients with newly diagnosed advanced MDS highlights the need for effective new treatments in these patients.
الإتاحة: https://doi.org/10.1002/pbc.30931Test
https://pure.eur.nl/en/publications/3449a072-8f14-47e4-8dd9-0741d5539f7eTest
http://www.scopus.com/inward/record.url?scp=85186949447&partnerID=8YFLogxKTest -
2دورية أكاديمية
المؤلفون: Cheng,Yiming, Ye,Ying, Gaudy,Allison, Ghosh,Atalanta, Xue,Yongjun, Wang,Alice, Zhou,Simon, Li,Yan
مصطلحات موضوعية: Clinical Pharmacology: Advances and Applications
الوصف: Yiming Cheng,1 Ying Ye,1 Allison Gaudy,1 Atalanta Ghosh,2 Yongjun Xue,3 Alice Wang,1 Simon Zhou,1 Yan Li1 1Clinical Pharmacology & Pharmacometrics, Bristol Myers Squibb, Princeton, NJ, USA; 2Global Biometrics and Data Sciences, Bristol Myers Squibb, Princeton, NJ, USA; 3Nonclinical Research & Development, Bristol Myers Squibb, Princeton, NJ, USACorrespondence: Yan Li, Clinical Pharmacology & Pharmacometrics, Bristol Myers Squibb, 556 Morris Ave, Summit, Princeton, NJ, 07901, USA, Tel +1 908-481-6203, Email Yan.Li@bms.comIntroduction: Iberdomide, a novel cereblon modulator (CELMoD®), is currently under clinical investigation for hematology indications. To evaluate the influence of hepatic impairment on the pharmacokinetics (PK) of iberdomide and its major active metabolite M12, a phase 1, multicenter, open-label study was conducted in healthy subjects and subjects with mild, moderate, and severe hepatic impairment.Methods: Forty subjects were enrolled in the study and divided into five groups based on hepatic function. 1 mg iberdomide was administered and plasma samples were collected to evaluate the pharmacokinetics of iberdomide and M12.Results: After a single dose of iberdomide (1 mg), mean iberdomide Cmax (maximum observed concentration) and AUC (area under the concentration-time curve) exposure were generally comparable between hepatic impairment (HI) subjects (severe, moderate and mild) and their respective matched normal controls. Mean Cmax and AUC exposure of the metabolite M12 were generally comparable between mild HI and matched normal subjects. However, mean Cmax of the M12 was 30% and 65% lower and AUC was 57% and 63% lower in moderate and severe HI subjects as compared to their respective matched normal controls. However, given the relatively low M12 exposure as compared to its parent drug, the observed differences were not considered clinically meaningful.Conclusion: In summary, 1 mg single oral dose of iberdomide was generally well-tolerated. HI (mild, moderate or severe) had no ...
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3دورية أكاديمية
المؤلفون: Wong, Sandy W., Bar, Noffar, Victoria Mateos, María, Ribas, Paz, Hansson, Markus, Paris, Laura, Hofmeister, Craig, Rodriguez-Otero, Paula, Aranzazu Bermúdez, Maria, Santoro, Armando, Yee, Andrew J., Creignou, Maria, Encinas, Cristina, Cerchione, Claudio, de la Rubia, Javier, Oriol, Albert, Ferstl, Barbara, Besemer, Britta, Chen, Jinjie, Chung, Alexander, Boss, Isaac W., Gaudy, Allison, LI, Shaoyi, Hsu, Kevin, Godwin, Colin, Burgess, Michael R., San-Miguel, Jesús, Jose Costa, Luciano
المصدر: HemaSphere ; volume 7, issue S3, page e1220745 ; ISSN 2572-9241
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4دورية أكاديمية
المؤلفون: Gaudy, Allison, Laille, Eric, Bailey, Rochelle, Zhou, Simon, Skikne, Barry, Beach, C.L.
المصدر: Clinical Pharmacology & Therapeutics ; volume 114, issue 4, page 845-852 ; ISSN 0009-9236 1532-6535
الوصف: Oral azacitidine (oral‐AZA) maintenance is approved for adults with acute myeloid leukemia (AML) in remission post‐intensive chemotherapy, not proceeding to hematopoietic stem cell transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model to characterize oral‐AZA concentration–time profiles in patients with AML, myelodysplastic syndrome, or chronic myelomonocytic leukemia. PopPK‐estimated exposure parameters were used to evaluate exposure–response relationships in the phase III QUAZAR AML‐001 study. The PopPK dataset comprised 286 patients with 1,933 evaluable oral‐AZA concentration records. The final PopPK model was a one‐compartment model with first‐order absorption incorporating an absorption lag time and first‐order elimination. Regression analyses identified two oral‐AZA exposure parameters (area under the plasma concentration–time curve at steady state (AUC ss ); maximum plasma concentration ( C max )) as statistically significant predictors for relapse‐free survival (hazard ratio (HR) = 0.521, P < 0.001; HR = 0.630, P = 0.013; respectively), and AUC ss as a significant predictor for overall survival (HR = 0.673, P = 0.042). The probability of grade ≥ 3 neutropenia was significantly increased with increases in AUC ss (odds ratio (OR) = 5.71, 95% confidence interval (CI) = 2.73–12.62, P < 0.001), cumulative AUC through cycles 1 to 6 (OR = 2.71, 95% CI = 1.76–4.44, P < 0.001), and C max at steady‐state (OR = 2.38, 95% CI = 1.23–4.76, P = 0.012). A decreasing trend was identified between AUC ss and relapse‐related schedule extensions, vs. an increasing trend between AUC ss and event‐related dose reductions. As the majority (56.8%) of patients required no dose modifications, and the proportions requiring schedule extension (19.4%) or dose reduction (22.9%) were almost equal, oral‐AZA 300 mg once daily for 14 days is the optimal dosing schedule balancing survival benefit and safety risk.
الإتاحة: https://doi.org/10.1002/cpt.2982Test
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5دورية أكاديمية
المؤلفون: Boss, Isaac, Thompson, Ethan, Gaudy, Allison, Vu, Thi Minh Diem, Godwin, Colin, Burgess, Michael, Wong, Sandy W., Costa, Luciano
المصدر: HemaSphere ; volume 7, issue S3, page e77796ce ; ISSN 2572-9241
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6دورية أكاديمية
المؤلفون: Wu, Fan, Liu, Liangang, Gaudy, Allison, Wang, Xiaomin, Carayannopoulos, Leon, Pourdehnad, Michael, Lamba, Manisha
المصدر: CPT: Pharmacometrics & Systems Pharmacology ; volume 12, issue 10, page 1473-1484 ; ISSN 2163-8306 2163-8306
الوصف: Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD) agent with enhanced autonomous cell‐killing activity in multiple myeloma (MM) cells, and promising immunomodulatory and antitumor activity in patients with MM. We developed a population pharmacokinetics (PKs) model for mezigdomide in healthy subjects (HSs), and quantified effects of high‐fat meal and proton pump inhibitor (PPI) on human disposition parameters. Plasma concentrations from 64 HS in two phase I clinical studies (NCT03803644 and NCT04211545) were used to develop a population PK model. The HSs received single oral doses of 0.4–3.2 mg mezigdomide with full PK profiles collected. A two‐compartment linear PK model with first‐order absorption and lag time best described mezigdomide PK profiles in HSs. The population PK parameters of absorption rate constant, lag time, central volume of distribution, clearance, peripheral volume of distribution, and intercompartmental clearance were estimated to be 1.18 h −1 (interoccasion variability [IOV]: 65%), 0.423 h (IOV: 31%), 440 L (interindividual variability [IIV]: 63%), 35.1 L/h (IIV: 40%), 243 L (IIV: 26%), and 36.8 L/h (IIV: 26%), respectively. High‐fat meal increased oral bioavailability by ~30% and PPI co‐administration decreased oral bioavailability by ~64%. Mezigdomide demonstrated a linear dose‐exposure relationship in HSs. The PK model suggests a modest effect of high‐fat meal, and a substantial effect of PPIs on mezigdomide oral bioavailability. This population PK model enables data integration across studies to identify important covariate effects and is being used to guide dose selection in clinical study designs for mezigdomide in patients with MM.
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7دورية أكاديمية
المؤلفون: Cheng, Yiming, Ye, Ying, Gaudy, Allison, Ghosh, Atalanta, Xue, Yongjun, Wang, Alice, Zhou, Simon, Li, Yan
المصدر: Clinical Pharmacology: Advances and Applications ; volume Volume 15, page 9-19 ; ISSN 1179-1438
الإتاحة: https://doi.org/10.2147/cpaa.s397826Test
https://www.dovepress.com/getfile.php?fileID=87805Test -
8دورية أكاديمية
المؤلفون: Kiesel, Brian, Osawa, Mayu, Masilamani, Madhan, Bar, Merav, Hsu, Kevin, Godwin, Colin, Burgess, Michael, Lamba, Manisha, Gaudy, Allison
المصدر: Clin Pharmacol Ther ; ISSN:1532-6535
الوصف: Alnuctamab, a B-cell maturation antigen (BCMA)-targeting T-cell engager, has demonstrated encouraging antitumor activity in the phase I study CC-93269-MM-001 treating patients with relapsed or refractory multiple myeloma. Identification of a recommended Phase III dose (RP3D) was a key objective, as such population pharmacokinetic (PopPK) and exposure-response analysis was critical. Intravenous (IV) alnuctamab was administered in fixed doses (0.15-10 mg) or in step-up doses to a maximum 10-mg target dose. Subcutaneous (SC) step-up doses of 3 and 6 mg were followed by a target dose range of 10-60 mg. Concentration data from IV and SC alnuctamab administration was pooled and was well described by a two-compartment PopPK model with first-order absorption and elimination. Covariate analysis determined that the inclusion of baseline soluble BCMA (sBCMA) on clearance significantly improved model fitting. Individual exposure parameters were estimated from the final model to characterize exposure-response relationships. Switching from IV to SC administration improved the safety profile of alnuctamab by limiting the frequency of grade ≥2 CRS events. A significant exposure-CRS relationship was observed after the first SC dose, but not subsequent dose administrations. Exposure-safety analysis did not find a statistically significant relationship between increasing exposure and the probability of key safety events of interest. Logistic regression analysis for patients administered SC alnuctamab identified that increased exposure significantly increased the probability of response, although the additional benefit was minimal at exposures above 30 mg target dose. Considering the totality of exposure-response data, the clinical pharmacology assessment supported a SC RP3D of 3/6/30 mg.
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9دورية أكاديمية
المؤلفون: Ye, Ying, Gaudy, Allison, Thomas, Michael, Reyes, Josephine, Burkhardt, Barbara, Horan, Gerald, Liu, Liangang, Chen, Jian, Ghosh, Atalanta, Carayannopoulos, Leonidas N., Tatosian, Daniel A., Palmisano, Maria
المصدر: Clinical Pharmacology in Drug Development ; volume 11, issue 12, page 1394-1404 ; ISSN 2160-763X 2160-7648
الوصف: CC‐90001 selectively inhibits c‐Jun N‐terminal kinase (JNK), a stress‐activated protein implicated in fibrosis. In 3 phase 1 trials evaluating CC‐90001 pharmacokinetics, pharmacodynamics, and safety, healthy adults ( N = 184) received oral CC‐90001 in a single dose (10–720 mg) or multiple doses (30–480 mg once daily for 7–18 days) or placebo. CC‐90001 was rapidly absorbed (median time to maximum concentration, 1–4 hours) and eliminated with a mean terminal elimination half‐life of 12–28 hours. Steady state was reached on day 5, with a mean accumulation ratio of 1.5‐ to 2‐fold following daily dosing. Exposure was similar in fed versus fasted participants and in Japanese versus non‐Japanese participants. CC‐90001 demonstrated dose‐ and exposure‐dependent inhibition of JNK as determined by histopathological analysis of c‐Jun phosphorylation in ultraviolet‐irradiated skin. The most common treatment‐emergent adverse events were nausea and headache; all were mild or moderate in intensity. Based on exposure‐response analysis using high‐quality electrocardiogram data, no clinically relevant QT prolongation liability for CC‐90001 was observed. Overall, single‐ and multiple‐dose CC‐90001 were generally safe and well tolerated at the tested doses and demonstrated JNK pathway engagement. These results support further clinical evaluation of CC‐90001.
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10دورية أكاديمية
المؤلفون: Furie, Richard A, Hough, Douglas R, Gaudy, Allison, Ye, Ying, Korish, Shimon, Delev, Nikolay, Weiswasser, Michael, Zhan, Xiaojiang, Schafer, Peter H, Werth, Victoria P
المساهمون: Bristol Myers Squibb
المصدر: Lupus Science & Medicine ; volume 9, issue 1, page e000581 ; ISSN 2053-8790
الوصف: Objective To evaluate safety, pharmacokinetics, pharmacodynamics and efficacy of iberdomide in patients with SLE. Iberdomide is a high-affinity cereblon ligand that targets the hematopoietic transcription factors Ikaros and Aiolos for proteasomal degradation. Methods A 12-week, multicentre, double-blind, placebo-controlled, dose-escalation study in active SLE was followed by a 2-year, open-label active treatment extension phase (ATEP) ( NCT02185040 ). In the dose-escalation phase, adults with active SLE were randomised to oral placebo or iberdomide (0.3 mg every other day, 0.3 mg once daily, 0.6 mg and 0.3 mg alternating once daily, or 0.6 mg once daily). Primary endpoints were safety and tolerability. Results The dose-escalation phase enrolled 42 patients, with 33 completing this phase and 17 patients enrolling into the ATEP. In the dose-escalation phase, the most common treatment-emergent adverse events (TEAEs; iberdomide/placebo groups) were nausea (20.6%/12.5%), diarrhoea (17.6%/12.5%) and upper respiratory tract infection (11.8%/12.5%). Most TEAEs were mild or moderate in severity and more common in the highest dose groups in both study phases. In the dose-escalation phase, Physician’s Global Assessment and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) activity scores improved relative to baseline and placebo in all iberdomide groups, with a trend toward continued score improvements in the ATEP. In the dose-escalation phase, iberdomide treatment resulted in dose-dependent reductions in total B cells and plasmacytoid dendritic cells in blood. Improvements in CLASI activity scores correlated with plasmacytoid dendritic cell depletion. Conclusions These proof-of-concept findings suggest a favourable benefit/risk ratio in SLE for iberdomide, a drug with a novel immunomodulatory mechanism of action, supporting further clinical investigation.
