The Experts below are selected from a list of 4701 Experts worldwide ranked by ideXlab platform

Yoonkoo Kang - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetic pk and exposure response er analysis of pertuzumab p in patients pts with her2 positive metastatic gastroesophageal junction and gastric cancer mgejc gc
    2018
    Co-Authors: Whitney P Kirschbrown, Yoonkoo Kang, Bei Wang, Ihsan Nijem, Atsushi Ohtsu, Paulo M Hoff, Manish A Shah, Lin Shen, Josep Tabernero, Sandhya Girish
    Abstract:

    2564Background: The phase 2a, dose-finding JOSHUA study reported increased P clearance (CL; 37% lower P steady-state Cmin [Cmin,ss]) in pts with HER2+ mGEJC/GC vs metastatic breast cancer (MBC). Ba...

  • changes in imatinib plasma trough level during long term treatment of patients with advanced gastrointestinal stromal tumors correlation between changes in covariates and imatinib exposure
    2012
    Co-Authors: Changhoon Yoo, Minhee Ryu, Baekyeol Ryoo, Mo Youl Beck, Heungmoon Chang, Jaelyun Lee, Tae Won Kim, Yoonkoo Kang
    Abstract:

    A pharmacokinetic study in patients with gastrointestinal stromal tumors (GIST) suggested that imatinib plasma concentration may decrease following long-term exposure. We assessed changes in imatinib plasma trough levels (Cmin) during long-term treatment. Follow-up (FU) imatinib Cmin was measured in 65 patients who received the same dose of imatinib for at least 9 months after previous (initial) tests. After exclusion of 7 patients who had been treated with imatinib for over 2 years at the time of initial testing, 58 patients were included in this analysis. The median intervals from initiation of imatinib to initial testing and from initial to FU testing were 5.5 months (range, 0.5–24.0 months) and 13.0 months (range, 9.6–17.9 months), respectively. Mean inter- and intra-subject variability values were 47.7% and 20.9%, respectively, at initial measurements, and 45.2% and 19.4%, respectively, at FU. Mean FU imatinib Cmin (1,370 ± 661 ng/mL) was significantly higher than mean initial Cmin (1,171 ± 573 ng/mL; p = 0.003). Compared with initial Cmin, FU Cmin was decreased in 22 patients and increased in 36, with median changes of 13% and 32%, respectively. Multivariate analysis showed a significant correlation between the ratio of FU to initial imatinib Cmin and that of albumin (r = −0.39, p = 0.003). During long-term treatment, imatinib Cmin did not decrease significantly but remained stable or increased in most patients. Changes in imatinib Cmin were associated with changes in albumin concentration. Monitoring of imatinib Cmin only for concerns about time-dependent increases in imatinib clearance is not necessary.

Changhoon Yoo - One of the best experts on this subject based on the ideXlab platform.

  • serial monitoring of imatinib pharmacokinetics pk in perioperative imatinib treatment in patients pts with gastrointestinal stromal tumors gists results from the multinational phase ii trial
    2017
    Co-Authors: Changhoon Yoo, Minhee Ryu, Yukinori Kurokawa, Hankwang Yang, Toshirou Nishida, Seongho Kong, Toshimasa Tsujinaka, Kyung Hee Lee, Hiroshi Yabusaki, Hongsuk Song
    Abstract:

    118Background: Imatinib plasma levels may be affected by the duration of exposure to imatinib and resection of the stomach. Therefore, we performed PK study to monitor imatinib plasma levels serially in the multinational phase II trial of perioperative imatinib for pts with large ( ≥ 10 cm) gastric GISTs without distant metastasis. Methods: In this trial conducted in Japan and Korea, 53 pts received neoadjuvant imatinib 400 mg daily and 40 pts received adjuvant imatinib after surgery. Blood samples for imatinib trough levels (Cmin) were collected after 1, 3, 6 months of each neoadjuvant and adjuvant imatinib and measured by using liquid chromatography-tandem mass spectrometry. For the comparison of imatinib Cmin between different time points, values were dose-adjusted and log-transformed. Results: During the neoadjuvant treatment, imatinib Cmin (mean ± standard deviation) was 2253.0 ± 1148.0 ng/mL (n = 49), 1623.3 ± 832.4 ng/mL (n = 47), and 1852.0 ± 1572.4 ng/mL (n = 45) after 1, 3, and 6 months of imati...

  • changes in imatinib plasma trough level during long term treatment of patients with advanced gastrointestinal stromal tumors correlation between changes in covariates and imatinib exposure
    2012
    Co-Authors: Changhoon Yoo, Minhee Ryu, Baekyeol Ryoo, Mo Youl Beck, Heungmoon Chang, Jaelyun Lee, Tae Won Kim, Yoonkoo Kang
    Abstract:

    A pharmacokinetic study in patients with gastrointestinal stromal tumors (GIST) suggested that imatinib plasma concentration may decrease following long-term exposure. We assessed changes in imatinib plasma trough levels (Cmin) during long-term treatment. Follow-up (FU) imatinib Cmin was measured in 65 patients who received the same dose of imatinib for at least 9 months after previous (initial) tests. After exclusion of 7 patients who had been treated with imatinib for over 2 years at the time of initial testing, 58 patients were included in this analysis. The median intervals from initiation of imatinib to initial testing and from initial to FU testing were 5.5 months (range, 0.5–24.0 months) and 13.0 months (range, 9.6–17.9 months), respectively. Mean inter- and intra-subject variability values were 47.7% and 20.9%, respectively, at initial measurements, and 45.2% and 19.4%, respectively, at FU. Mean FU imatinib Cmin (1,370 ± 661 ng/mL) was significantly higher than mean initial Cmin (1,171 ± 573 ng/mL; p = 0.003). Compared with initial Cmin, FU Cmin was decreased in 22 patients and increased in 36, with median changes of 13% and 32%, respectively. Multivariate analysis showed a significant correlation between the ratio of FU to initial imatinib Cmin and that of albumin (r = −0.39, p = 0.003). During long-term treatment, imatinib Cmin did not decrease significantly but remained stable or increased in most patients. Changes in imatinib Cmin were associated with changes in albumin concentration. Monitoring of imatinib Cmin only for concerns about time-dependent increases in imatinib clearance is not necessary.

Egbert F. Smit - One of the best experts on this subject based on the ideXlab platform.

  • exposure response analyses of anaplastic lymphoma kinase inhibitors crizotinib and alectinib in non small cell lung cancer patients
    2021
    Co-Authors: Dieuwertje R Geel, Hilde Rosing, Julie M Janssen, Niels De Vries, Jacobus A. Burgers, Egbert F. Smit
    Abstract:

    Crizotinib and alectinib are anaplastic lymphoma kinase (ALK)-inhibitors indicated for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). At the currently used fixed doses, interindividual variability in exposure is high. The aim of this study was to investigate whether minimum plasma concentrations (Cmin ) of crizotinib and alectinib are related to efficacy and toxicity. An observational study was performed, in which ALK-positive NSCLC patients who were treated with crizotinib and alectinib and from whom pharmacokinetic samples were collected in routine care, were included in the study. Exposure-response analyses were explored using previously proposed Cmin thresholds of 235 ng/mL for crizotinib and 435 ng/mL for alectinib. Forty-eight crizotinib and 52 alectinib patients were included. For crizotinib, median progression-free survival (mPFS) was 5.7 vs. 17.4 months for patients with Cmin  < 235 ng/mL (48%) and ≥ 235 ng/mL, respectively (P = 0.08). In multivariable analysis, Cmin  < 235 ng/mL resulted in a hazard ratio (HR) of 1.79 (95% confidence interval (CI), 0.90-3.59, P = 0.100). In a pooled analysis of all crizotinib patients (not only ALK-positive, n = 79), the HR was 2.15 (95% CI, 1.21-3.84, P = 0.009). For alectinib, mPFS was 12.6 months vs. not estimable (95% CI, 19.8-not estimable) for patients with Cmin  < 435 ng/mL (37%) and ≥ 435 ng/mL, respectively (P = 0.04). Multivariable analysis resulted in an HR of 4.29 (95% CI, 1.33-13.90, P = 0.015). In conclusion, PFS of crizotinib and alectinib treated NSCLC patients is prolonged in patients with Cmin  ≥ 235 ng/mL and 435 ng/mL, respectively. Therefore, therapeutic drug monitoring should be part of routine clinical management for these agents.

  • exposure response relationship for ramucirumab ram from the randomized double blind phase iii revel trial docetaxel doc vs doc plus ram in second line treatment of metastatic non small cell lung cancer nsclc
    2015
    Co-Authors: Egbert F. Smit, Maurice Perol, Martin Reck, Federico Cappuzzo, Paolo Bidoli, Roger B Cohen, Steven C Ernest, Annamaria Zimmermann, David Ferry, Joseph Treat
    Abstract:

    8053 Background: An exploratory exposure-response analysis for RAM was performed using data from the REVEL trial (NCT01168973). Methods: Patients received RAM (10 mg/kg) or placebo (PL) + DOC (75 mg/m2) every 3 weeks (q3w). Sparse pharmacokinetic (PK) samples were collected; a population PK (PopPK) analysis was conducted. PopPK model-predicted RAM exposure parameters (Cmin,1, Cmin,ss, Cmax,ss, and Cave,ss) were used to evaluate the relationship between RAM exposure and measures of efficacy and safety. Cmin,1 and Cave,ss are presented. Kaplan-Meier, Cox regression, and ordered categorical analyses evaluated these relationships. Results: Analyses included 376 RAM+DOC pts and 366 PL+DOC pts. Similar trends were seen for all four exposure parameters. As RAM exposure increased, greater improvements (smaller HRs) were seen in OS and PFS (table below). A statistically significant correlation was also seen for RAM exposure and grade ≥ 3 febrile neutropenia and hypertension. Conclusions: Results from exposure-resp...

Jos H Beijnen - One of the best experts on this subject based on the ideXlab platform.

  • concomitant intake of abiraterone acetate and food to increase pharmacokinetic exposure real life data from a therapeutic drug monitoring programme
    2020
    Co-Authors: Stefanie L Groenland, Merel Van Nuland, Andries M Bergman, Jeantine M De Feijter, Vincent O Dezentje, Hilde Rosing, Jos H Beijnen, Alwin D R Huitema, Neeltje Steeghs
    Abstract:

    Abstract Aim Abiraterone acetate is approved for the treatment of metastatic prostate cancer. At the currently used fixed dose of 1000 mg once daily in modified fasting state, 40% of patients do not reach the efficacy threshold of a minimum plasma concentration (Cmin) ≥ 8.4 ng/mL and are thereby at risk of decreased treatment efficacy. This study aims to evaluate whether pharmacokinetically (PK) guided abiraterone acetate dosing with a food intervention is feasible and results in an increased percentage of patients with concentrations above the target. Methods Patients starting regular treatment with abiraterone acetate in modified fasting state were included. Pharmacokinetic analysis was performed 4, 8 and 12 weeks after start of treatment and every 12 weeks thereafter. In case of Cmin Results In total, 32 evaluable patients were included, of which 20 patients (63%) had a Cmin Conclusion Therapeutic drug monitoring of abiraterone was applied in clinical practice and proved to be feasible. Concomitant intake with food resulted in a significant increase in Cmin and offers a cost-neutral opportunity to optimise exposure in patients with low Cmin.

  • exposure survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients opportunities for dose optimization
    2017
    Co-Authors: Remy B Verheijen, Jos H Beijnen, Alwin D R Huitema, Jan H M Schellens, Laurens E Swart, Neeltje Steeghs
    Abstract:

    Pazopanib is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Post hoc analysis of a clinical trial demonstrated a relationship between pazopanib trough concentrations (Cmin) and treatment efficacy. The aim of this study was to explore the pharmacokinetics and exposure-survival relationships of pazopanib in a real-world patient cohort. Renal cell cancer and soft tissue sarcoma patients who had at least one pazopanib plasma concentration available were included. Using calculated Cmin values and a threshold of > 20 mg/L, univariate and multivariate exposure-survival analyses were performed. Sixty-one patients were included, of which 16.4% were underexposed (mean Cmin   20 mg/L was related to longer progression free survival in renal cell cancer patients (34.1 vs. 12.5 weeks, n = 35, p = 0.027) and the overall population (25.0 vs. 8.8 weeks, n = 61, p = 0.012), but not in the sarcoma subgroup (18.7 vs. 8.8 weeks, n = 26, p = 0.142). In multivariate analysis Cmin > 20 mg/L was associated with hazard ratios of 0.25 (p = 0.021) in renal cancer, 0.12 (p = 0.011) in sarcoma and 0.38 (p = 0.017) in a pooled analysis. This study confirms that pazopanib Cmin > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. Cmin monitoring of pazopanib can help identify patients with low Cmin for whom individualized treatment at a higher dose may be appropriate.

  • individualized pazopanib dosing a prospective feasibility study in cancer patients
    2016
    Co-Authors: Remy B Verheijen, Jos H Beijnen, Sander Bins, Ron H J Mathijssen, Martijn P Lolkema, Leni Van Doorn, Jan H M Schellens
    Abstract:

    Purpose: Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median progression-free survival and tumor shrinkage appear in patients with higher plasma trough levels (Cmin). Therefore, patients with low Cmin might benefit from pharmacokinetically guided individualized dosing. Experimental Design: We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cmin was measured weekly by LC-MS/MS. At weeks 3, 5, and 7, the pazopanib dose was increased if the measured Cmin was <20 mg/L and toxicity was Cmin <20 mg/L at weeks 3, 5, and 7. Of these, 10 were successfully treated with a pharmacokinetically guided dose escalation, leading to daily dosages ranging from 1,000 to 1,800 mg. Cmin in these patients increased significantly from 13.2 (38.0%) mg/L [mean (CV%)] to 22.9 mg/L (44.9%). Thirteen patients had all Cmin levels ≥ 20.0 mg/L. Of these, 9 patients with a high Cmin of 51.3 mg/L (45.1%) experienced ≥ grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients, Cmin remained above the threshold at 28.2 mg/L (25.3%). Conclusions: A pharmacokinetically guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1,800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes, such as progression-free survival

Yalin Dong - One of the best experts on this subject based on the ideXlab platform.

  • desired vancomycin trough concentration to achieve an auc 0 24 mic 400 in chinese children with complicated infectious diseases
    2020
    Co-Authors: Tao Zhang, Yuzhu Dong, Ying Zhang, Hua Cheng, Zhenyu Pan, Dan Sun, Xiaoliang Cheng, Yalin Dong
    Abstract:

    A vancomycin steady-state trough concentration (Cmin ) of 15-20 mg/L is recommended for achieving a ratio of the 24-hour area under the curve to the minimum inhibitory concentration (AUC0-24 /MIC) of ≥400 in adults. Since few paediatric data are available, our objectives were to (a) measure the pharmacokinetic indices of vancomycin and (b) determine the correlation between Cmin and AUC0-24 /MIC in paediatric patients. Population-based pharmacokinetic modelling was performed for paediatric patients to estimate the individual parameters. The relationship between Cmin and the calculated AUC0-24 /MIC was explored using linear regression and a probabilistic framework. A sensitivity analysis was also conducted using Monte Carlo simulations. Body-weight significantly influenced the pharmacokinetics of vancomycin. Based on real data and simulations, Cmin ranges of 5.0-5.9 and 9.0-12.9 mg/L were associated with AUC0-24 /MIC ≥400 for MIC values of ≤0.5 and ≤1 mg/L, respectively. Vancomycin regimens of 10 and 15 mg/kg every 6 hours achieved a Cmin of 5.0-5.9 mg/L and AUC0-24 /MIC ≥400 in >90% of the children when MIC was ≤0.5 mg/L. At a MIC of ≤1 mg/L, vancomycin at 15 mg/kg every 6 hours achieved Cmin of 9.0-12.9 mg/L and AUC0-24 /MIC ≥400 in 2.0- and 1.6-fold as many children compared to a dose of 10 mg/kg every 6 hours, respectively. Vancomycin Cmin values of 5.0-12.9 mg/L were strongly predictive of achieving AUC0-24 /MIC ≥400, and rational dosing regimens of 10-15 mg/kg q6h were required in paediatric patients, depending on the pathogen.

  • therapeutic drug monitoring and receiver operating characteristic curve prediction may reduce the development of linezolid associated thrombocytopenia in critically ill patients
    2014
    Co-Authors: Haiyan Dong, Taotao Wang, Lihong Chen, Y R Zhao, Yalin Dong
    Abstract:

    To investigate the risk factors associated with the development of thrombocytopenia, and define the thresholds of efficacy and safety in critically ill patients who received linezolid therapy. A retrospective study was performed in critically ill patients treated with linezolid. Risk factors associated with thrombocytopenia were identified via medical records and trough levels (Cmin) measured during linezolid treatment. By establishing a logistic model, the risks were predicted by the receiver operating characteristic (ROC) curve and the thresholds of efficacy and safety were identified in the patients. Logistic analysis showed that, weight (OR = 0.906; 95 % CI, 0.839–0.978; P = 0.011), baseline platelet count (OR = 0.989; 95 % CI, 0.977–1.000; P = 0.049), Cmin (OR = 1.545; 95 % CI, 1.203–1.983; P = 0.001), and APACHE II score (OR = 1.130; 95 % CI, 1.003–1.273; P = 0.044) were significant factors for linezolid-associated thrombocytopenia. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was the maximum, the best optimal cut-off point was 205.6 on the ROC curve; when Cmin ≥ 2 mg/L, the probability of bacterial eradication was more than 80 %; when Cmin ≥ 6.3 mg/L, the probability of thrombocytopenia was more than 50 %. In clinical practice, when the calculating results of the combined predictor ≤205.6, the risk of the development of thrombocytopenia may be higher. Furthermore, maintenance of Cmin between 2 and 6.3 mg/L over time may be helpful in retaining appropriate efficacy and reducing the associated thrombocytopenia.

  • therapeutic drug monitoring and receiver operating characteristic curve prediction may reduce the development of linezolid associated thrombocytopenia in critically ill patients
    2014
    Co-Authors: Haiyan Dong, Taotao Wang, Y R Zhao, Jiao Xie, Lu Chen, Yalin Dong
    Abstract:

    To investigate the risk factors associated with the development of thrombocytopenia, and define the thresholds of efficacy and safety in critically ill patients who received linezolid therapy. A retrospective study was performed in critically ill patients treated with linezolid. Risk factors associated with thrombocytopenia were identified via medical records and trough levels (Cmin) measured during linezolid treatment. By establishing a logistic model, the risks were predicted by the receiver operating characteristic (ROC) curve and the thresholds of efficacy and safety were identified in the patients. Logistic analysis showed that, weight (OR = 0.906; 95 % CI, 0.839–0.978; P = 0.011), baseline platelet count (OR = 0.989; 95 % CI, 0.977–1.000; P = 0.049), Cmin (OR = 1.545; 95 % CI, 1.203–1.983; P = 0.001), and APACHE II score (OR = 1.130; 95 % CI, 1.003–1.273; P = 0.044) were significant factors for linezolid-associated thrombocytopenia. The area under the ROC curve of the combined predictor was larger based on the above factors. When the Youden index was the maximum, the best optimal cut-off point was 205.6 on the ROC curve; when Cmin ≥ 2 mg/L, the probability of bacterial eradication was more than 80 %; when Cmin ≥ 6.3 mg/L, the probability of thrombocytopenia was more than 50 %. In clinical practice, when the calculating results of the combined predictor ≤205.6, the risk of the development of thrombocytopenia may be higher. Furthermore, maintenance of Cmin between 2 and 6.3 mg/L over time may be helpful in retaining appropriate efficacy and reducing the associated thrombocytopenia.