Pharmacokinetics and Pharmacodynamics of Imatinib in a Phase I Trial With Chronic Myeloid Leukemia Patients

2004 ◽  
Vol 22 (5) ◽  
pp. 935-942 ◽  
Author(s):  
Bin Peng ◽  
Michael Hayes ◽  
Debra Resta ◽  
Amy Racine-Poon ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
Steady State ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Drug Exposure ◽  
Dose Range ◽  
Once Daily ◽  
Concentration Time ◽  
The Relationship ◽  
Dose Proportional

Purpose To evaluate the basic pharmacokinetic (PK) characteristics of imatinib mesylate and assess the relationship between the PK and pharmacodynamic (PD) properties of the drug. Patients and Methods The PK and PD properties of imatinib were investigated during a phase I trial that included 64 adult patients with Philadelphia chromosome–positive leukemias. Patients received imatinib orally once or twice daily. PK parameters of imatinib, derived from the plasma concentration–time curves, were determined. PD response, defined as the WBC after 1 month of treatment with imatinib, was used to develop an efficacy model. A maximum inhibition–effect model was used to describe the relationship between reduction in WBC and drug exposure parameters. Results Imatinib exposure was dose proportional after oral administration for the dose range of 25 to 1,000 mg. There was a 1.5- to three-fold drug accumulation after repeated once-daily dosing. Mean plasma trough concentration was 0.57 μg/mL (approximately 1 μmol/L) 24 hours after administration of 350 mg of imatinib at steady-state, which exceeds the 50% inhibitory concentration required to inhibit proliferation of Bcr-Abl–positive leukemic cells. Analysis of PK/PD relationships indicates that the initial hematologic response depends on the administered dose for patients with chronic myeloid leukemia. Conclusion Drug exposure (area under the concentration-time curve) is dose proportional for the dose range of 25 to 1,000 mg, and there is a 1.5- to three-fold drug accumulation at steady-state after once-daily dosing. Analysis of the relationship between PD (WBC reduction) and PK parameters at steady-state indicates that a dose of 400 mg or greater is required for maximal PD effect.

scholarly journals Efficacy and Tolerability after Unusually Low Doses of Dasatinib in Chronic Myeloid Leukemia Patients Intolerant to Standard-Dose Dasatinib Therapy

2010 ◽  
Vol 4 ◽  
pp. CMO.S6413 ◽  
Author(s):  
Mariana Serpa ◽  
Sabri S. Sanabani ◽  
Israel Bendit ◽  
Fernanda Seguro ◽  
Flávia Xavier ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Chronic Phase ◽  
Patient Treatment ◽  
Hematological Toxicity ◽  
Drug Discontinuation ◽  
Once Daily ◽  
Starting Dose

We report our experience in 4 patients with chronic myeloid leukemia (CML) who had discontinued imatinib as a result of adverse events and had switched to dasatinib. The chronic phase ( n 2) and accelerated phase ( n 2) CML patients received dasatinib at starting dose of 100 and 140 mg once daily, respectively. Reappearance of hematological toxicity was observed in 3 patients and pancreatitis in one patient. Treatment was given at a lower dose and patients were followed. The median follow-up was 13 months and the median dose of dasatinib until achievement of complete cytogenetic remission (CCyR) was 60 mg daily (range = 20 to 120 mg). All four patients had achieved CCyR at a median of 4 months (range = 3 to 5 months) and among them, three had also achieved major molecular remission. We conclude that low-dose dasatinib therapy in intolerant patients appears safe and efficacious and may be tried before drug discontinuation.

scholarly journals Steady-State Plasma and Intrapulmonary Pharmacokinetics and Pharmacodynamics of Cethromycin

2004 ◽  
Vol 48 (9) ◽  
pp. 3508-3515 ◽  
Author(s):  
John E. Conte ◽  
Jeffrey A. Golden ◽  
Juliana Kipps ◽  
Elisabeth Zurlinden
Keyword(s):  
Steady State ◽  
Half Life ◽  
Dose Group ◽  
Drug Exposure ◽  
Pharmacokinetic Parameters ◽  
Multiple Time ◽  
Respiratory Pathogens ◽  
Once Daily ◽  
Standard Deviations ◽  
State Plasma

ABSTRACT The objective of this study was to determine the steady-state plasma and intrapulmonary pharmacokinetic parameters of orally administered cethromycin in healthy volunteers. The study design included administering 150 or 300 mg of cethromycin once daily to 25 or 35 healthy adult subjects, respectively, for a total of five doses. Standardized and timed bronchoalveolar lavage (BAL) was performed after the last dose. Blood was obtained for drug assay prior to the first and last dose, at multiple time points following the last dose, and at the time of BAL. Cethromycin was measured in plasma, BAL, and alveolar cell (AC) by using a combined high-performance liquid chromatography-mass spectrometric technique. Plasma, epithelial lining fluid (ELF), and AC pharmacokinetics were derived by noncompartmental methods. C max/90% minimum inhibitory concentration (MIC90) ratios, area under the concentration-time curve (AUC)/MIC90 ratios, intrapulmonary drug exposure ratios, and percent time above MIC90 during the dosing interval (%T > MIC90) were calculated for recently reported respiratory pathogens. The kinetics were nonlinear, i.e., not proportional to dose. In the 150-mg-dose group, the C max (mean ± standard deviations), AUC0-24, and half-life for plasma were 0.181 ± 0.084 μg/ml, 0.902 ± 0.469 μg · h/ml, and 4.85 ± 1.10 h, respectively; for ELF the values were 0.9 ± 0.2 μg/ml, 11.4 μg · h/ml, and 6.43 h, respectively; for AC the values were 12.7 ± 6.4 μg/ml, 160.8 μg · h/ml, and 10.0 h, respectively. In the 300-mg-dose group, the C max (mean ± standard deviations), AUC0-24, and half-life for plasma were 0.500 ± 0.168 μg/ml, 3.067 ± 1.205 μg · h/ml, and 4.94 ± 0.66 h, respectively; for ELF the values were 2.7 ± 2.0 μg/ml, 24.15 μg · h/ml, and 5.26 h, respectively; for AC the values were 55.4 ± 38.7 μg/ml, 636.2 μg · h/ml, and 11.6 h, respectively. We concluded that the C max/MIC90 ratios, AUC/MIC90 ratios, %T > MIC90 values, and extended plasma and intrapulmonary half-lives provide a pharmacokinetic rationale for once-daily administration and are favorable for the treatment of cethromycin-susceptible pulmonary infections.

scholarly journals Fosamprenavir plus Ritonavir Increases Plasma Ketoconazole and Ritonavir Exposure, while Amprenavir Exposure Remains Unchanged

2007 ◽  
Vol 51 (8) ◽  
pp. 2982-2984 ◽  
Author(s):  
Mary B. Wire ◽  
Charles H. Ballow ◽  
Julie Borland ◽  
Mark J. Shelton ◽  
Yu Lou ◽  
...  
Keyword(s):  
Steady State ◽  
Healthy Subjects ◽  
Open Label ◽  
Time Curve ◽  
Once Daily ◽  
Open Label Study ◽  
Label Study ◽  
Concentration Time

ABSTRACT Plasma ketoconazole (KETO), amprenavir (APV), and ritonavir (RTV) pharmacokinetics were evaluated in 15 healthy subjects after being treated with KETO at 200 mg once daily (QD), fosamprenavir (FPV)/RTV at 700/100 mg twice daily (BID), and then KETO at 200 mg QD plus FPV/RTV at 700/100 mg BID in this open-label study. The KETO area under the concentration-time curve at steady state was increased 2.69-fold with FPV/RTV. APV exposure was unchanged, and RTV exposure was slightly increased.

scholarly journals Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial

2016 ◽  
Vol 34 (20) ◽  
pp. 2333-2340 ◽  
Author(s):  
Jorge E. Cortes ◽  
Giuseppe Saglio ◽  
Hagop M. Kantarjian ◽  
Michele Baccarani ◽  
Jiří Mayer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Pleural Effusion ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Phase Iii ◽  
Blast Phase ◽  
Once Daily ◽  
Study Results ◽  
Treatment Naïve

Purpose We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib. Patients and Methods Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). Results At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms. Conclusion These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.

scholarly journals Evaluating the Relationship between Vancomycin Trough Concentration and 24-Hour Area under the Concentration-Time Curve in Neonates

2018 ◽  
Vol 62 (4) ◽  
pp. e01647-17 ◽  
Author(s):  
Sheng-Hsuan Tseng ◽  
Chuan Poh Lim ◽  
Qi Chen ◽  
Cheng Cai Tang ◽  
Sing Teang Kong ◽  
...  
Keyword(s):  
Steady State ◽  
Trough Concentration ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time ◽  
Vancomycin Trough ◽  
Trough Concentrations ◽  
The Relationship

ABSTRACT Bacterial sepsis is a major cause of morbidity and mortality in neonates, especially those involving methicillin-resistant Staphylococcus aureus (MRSA). Guidelines by the Infectious Diseases Society of America recommend the vancomycin 24-h area under the concentration-time curve to MIC ratio (AUC24/MIC) of >400 as the best predictor of successful treatment against MRSA infections when the MIC is ≤1 mg/liter. The relationship between steady-state vancomycin trough concentrations and AUC24 values (mg·h/liter) has not been studied in an Asian neonatal population. We conducted a retrospective chart review in Singapore hospitals and collected patient characteristics and therapeutic drug monitoring data from neonates on vancomycin therapy over a 5-year period. A one-compartment population pharmacokinetic model was built from the collected data, internally validated, and then used to assess the relationship between steady-state trough concentrations and AUC24. A Monte Carlo simulation sensitivity analysis was also conducted. A total of 76 neonates with 429 vancomycin concentrations were included for analysis. Median (interquartile range) was 30 weeks (28 to 36 weeks) for postmenstrual age (PMA) and 1,043 g (811 to 1,919 g) for weight at the initiation of treatment. Vancomycin clearance was predicted by weight, PMA, and serum creatinine. For MRSA isolates with a vancomycin MIC of ≤1, our major finding was that the minimum steady-state trough concentration range predictive of achieving an AUC24/MIC of >400 was 8 to 8.9 mg/liter. Steady-state troughs within 15 to 20 mg/liter are unlikely to be necessary to achieve an AUC24/MIC of >400, whereas troughs within 10 to 14.9 mg/liter may be more appropriate.

scholarly journals Pharmacokinetics of Daptomycin in Critically Ill Pediatric Patients

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Charalampos Antachopoulos ◽  
Stavroula Ilia ◽  
Paschalis Kadiltzoglou ◽  
Eirini Baira ◽  
Aristides Dokoumetzidis ◽  
...  
Keyword(s):  
Critically Ill ◽  
Drug Exposure ◽  
Pediatric Patients ◽  
Plasma Concentrations ◽  
Therapeutic Drug ◽  
Burn Patients ◽  
Time Curve ◽  
Once Daily ◽  
Concentration Time ◽  
Optimal Drug

ABSTRACT The pharmacokinetics of daptomycin (10 mg/kg once daily) was studied in 4 critically ill pediatric patients aged 8 to 14 yrs. The area under the concentration-time curve from time zero to infinity (AUC 0–∞ ) of plasma concentrations on day 1 ranged between 123.8 to 663.9 μg · h/ml, with lower values observed in septic and burn patients; clearance ranged from 15.1 to 80.7 ml/h/kg. Higher-than-recommended doses of daptomycin may be needed in septic children to ensure optimal drug exposure. Interpatient variability may suggest a role for therapeutic drug monitoring.

scholarly journals Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNα via accelerating the degradation of its receptor

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4179-4187 ◽  
Author(s):  
Sabyasachi Bhattacharya ◽  
Hui Zheng ◽  
Christos Tzimas ◽  
Martin Carroll ◽  
Darren P. Baker ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Protein Kinase ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Primary Treatment ◽  
Interferon Α ◽  
Type I ◽  
Constitutive Activity ◽  
Β Receptor ◽  
The Relationship

Abstract Constitutive activity of Bcr-abl fusion protein kinase causes chronic myeloid leukemia (CML). Inhibitors of Bcr-abl such as imatinib mesylate have replaced the cytokine IFNα as the primary treatment for the management of patients with this malignancy. We found that pretreatment of CML cells with imatinib mesylate augments the antigrowth effects of IFNα. Furthermore, introduction of Bcr-abl into non-CML cells inhibits the cellular responses to IFNα. This inhibition is mediated via a mechanism that involves activation of protein kinase D2. The latter promotes an accelerated phosphorylation-dependent degradation of the interferon-α/β receptor 1 chain of the type I interferon receptor, leading to attenuation of IFNα signaling. We discuss the relationship between Bcr-abl activity and IFNα signaling as a molecular basis of the combination of inhibitors of Bcr-abl and IFNα for CML treatment.

Concentration-QTc (C-QTc) Analysis of the MDM2 Inhibitor KRT-232 (formerly AMG 232) in Subjects with Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5768-5768
Author(s):  
Adekemi Taylor ◽  
Martine Allard ◽  
Cecile Kresja ◽  
Dana Lee ◽  
Greg Slatter
Keyword(s):  
Multiple Myeloma ◽  
Steady State ◽  
Solid Tumors ◽  
Upper Bound ◽  
Myeloid Leukemia ◽  
Employment Equity ◽  
Equity Ownership ◽  
The Mean ◽  
The Relationship ◽  
Mdm2 Inhibitor

Introduction: KRT-232 is a potent and selective, targeted small molecule inhibitor of human mouse double minute 2 (MDM2) homolog interactions with tumor protein 53 (p53). MDM2 prevents p53 activation and reduces p53-mediated transcription and cell cycle control. KRT-232 is under development by Kartos Therapeutics for treatment of myelofibrosis, polycythemia vera, acute myeloid leukemia (AML) and Merkel cell carcinoma (see NCT03662126, NCT03669965, NCT03787602). The KRT-232 no effect-level for in vitro inhibition of hERG function (10 μM) was approximately 147- and 73-fold greater than KRT-232 unbound Cmax concentrations for steady state doses of 240 mg and 480 mg, respectively, based on population pharmacokinetic (PK)-derived parameters for subjects with AML (Ma et al. submitted, ASH 2019). The primary objective of this analysis was to evaluate the relationship between KRT-232 plasma concentration and changes in heart rate-corrected QT interval duration (QTc) in oncology patients treated in Amgen studies 20120106 (Gluck et al. Invest New Drugs; in press, NCT01723020) and 20120234 (Erba et al. Blood Adv 2019; NCT02016729). Methods Study 20120106 was a 2-part Phase 1 dose-exploration and dose-expansion monotherapy study in advanced solid tumors or multiple myeloma. KRT-232 doses of 15 mg (n=3), 30 mg (n=3), 60 mg (n=4), 120 mg (n=7), 240 mg (n=76), 300 mg (n=4), 360 mg (n=4) and 480 mg (n=6) were administered daily (QD) for 7 days in 21-day cycles. Subjects received up to 31 cycles of treatment. Study 20120234 was a Phase 1b study evaluating KRT-232 alone and in combination with trametinib in relapsed/refractory AML. Subjects received the following KRT-232 doses: 60 mg (n=14; n=10 co-administered with 2 mg trametinib daily [excluded from C-QTc analysis]); n=4 as single agent), 90 mg (n=4), 180 mg (n=5), 240 mg (n=3), and 360 mg (n=10). Doses were administered QD for 7 days in 14-day cycles. Subjects received up to 46 cycles of treatment. In both studies, time-matched PK and ECG measurements were collected intensively during Cycle 1 and less frequently at other visits. Triplicate 12-lead ECG data (N=3) were read by a central laboratory. A linear mixed effects model using R (v 3.5.2) was used to analyze the relationship between KRT-232 plasma concentrations and the QT interval corrected using Fridericia's method (QTcF). Effects of baseline QTcF, study, sex and tumor type on C-QTc were investigated. The upper bound of 2-sided 90% CIs for the mean QTcF change from baseline (ΔQTcF) predicted at Cmax was compared to the 10 ms threshold of regulatory concern (FDA Guidance: E14(R3) 2017; Garnett et al. Pharmacokinet Pharmacodyn 2018). Results ECG and PK data for this analysis were available from 130 subjects. The final model was a linear mixed-effect model with parameters for intercept, KRT-232 concentration-ΔQTcF slope, and baseline QTcF effect on the intercept. Diagnostic plots indicated an adequate model fit. The final C-QTc model was used to predict mean ΔQTcF and associated 2-sided 90% CI mean steady-state KRT-232 Cmax at doses up to the maximum clinical dose of 480 mg QD, in subjects with AML or solid tumors. The mean and upper bound of the 90% CI of ΔQTcF were predicted not to exceed 10 ms at doses of up to 480 mg QD in subjects with AML, multiple myeloma or solid tumors. Mean (90% CI) predicted ΔQTcF values at 480 mg QD were 2.040 (0.486, 3.595) ms for subjects with solid tumors and 4.521 (2.348, 6.693) ms for subjects with AML (Figure A). The KRT-232 concentrations at which the upper bounds of 90% CI of mean ΔQTcF are predicted to reach 10 ms and 20 ms are 4298 ng/mL and 7821 ng/mL, respectively. These concentrations are 2.2- and 4-fold higher, respectively, than the predicted mean steady-state Cmax for 480-mg KRT-232 in subjects with solid tumors, and 1.4- and 2.5-fold higher, respectively, than the corresponding mean steady-state Cmax in subjects with AML. Conclusion Since the mean and upper bound of the 90% CI of mean ΔQTcF were predicted not to exceed 10 ms at KRT-232 doses of up to 480 mg QD in solid tumor or AML patients, KRT-232 should not result in clinically meaningful QT prolongation at the doses currently under investigation in Kartos clinical trials. Disclosures Taylor: Certara Strategic Consulting: Consultancy, Employment. Allard:Certara Strategic Consulting: Consultancy, Employment. Kresja:Kartos Therapeutics: Employment, Equity Ownership. Lee:Kartos Therapeutics: Employment, Equity Ownership. Slatter:Kartos Therapeutics: Employment, Equity Ownership. OffLabel Disclosure: KRT-232 (formerly AMG 232) is a small molecule MDM2 inhibitor

Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1493-1493
Author(s):  
Kohei Yamaguchi ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with <0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

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