Protocol versus Nonprotocol Dosing of Vancomycin in Neonates: A Single Center Evaluation of Steady State Trough Levels

2016 ◽  
Vol 33 (07) ◽  
pp. 678-682 ◽  
Author(s):  
Megan Schwartz ◽  
Joanna Wrobel ◽  
Carla Zeilmann ◽  
Jamalee Huntley
Keyword(s):  
Steady State ◽  
Single Center ◽  
Trough Levels

scholarly journals Steady-State Serum IgG Trough Levels Are Adequate for Pharmacokinetic Assessment in Patients with Immunodeficiencies Receiving Subcutaneous Immune Globulin

2021 ◽  
Author(s):  
Zhaoyang Li ◽  
Barbara McCoy ◽  
Werner Engl ◽  
Leman Yel
Keyword(s):  
Steady State ◽  
Trough Level ◽  
Geometric Mean ◽  
Time Profiles ◽  
Level Measurement ◽  
Serum Igg ◽  
Pharmacokinetic Assessment ◽  
Steady State Serum ◽  
Serum Igg Levels ◽  
Trough Levels

AbstractPatients with primary immunodeficiency diseases often require lifelong immunoglobulin (IG) therapy. Most clinical trials investigating IG therapies characterize serum immunoglobulin G (IgG) pharmacokinetic (PK) profiles by serially assessing serum IgG levels. This retrospective analysis evaluated whether steady-state serum IgG trough level measurement alone is adequate for PK assessment. Based on individual patient serum IgG trough levels from two pivotal trials (phase 2/3 European [NCT01412385] and North American [NCT01218438]) of weekly 20% subcutaneous IG (SCIG; Cuvitru, Ig20Gly), trough level-predicted IgG AUC (AUCτ,tp) were calculated and compared with the reported AUC calculated from serum IgG concentration-time profiles (AUCτ). In both studies, mean AUCτ,tp values for Ig20Gly were essentially equivalent to AUCτ with point estimates of geometric mean ratio (GMR) of AUCτ,tp/AUCτ near 1.0 and 90% CIs within 0.80–1.25. In contrast, for IVIG, 10%, mean AUCτ,tp values were lower than AUCτ by >20%, (GMR [90% CI]: 0.74 [0.70–0.78] and 0.77 [0.73–0.81] for the two studies, respectively). Mean AUCτ,tp values calculated for 4 other SCIG products (based on mean IgG trough levels reported in the literature/labels) were also essentially equivalent to the reported AUCτ (differences <10% for all except HyQvia, a facilitated SCIG product), while differences for IVIG products were >20%. In conclusion, steady-state serum IgG levels following weekly SCIG remain stable, allowing for reliable prediction of AUC over the dosing interval using trough IgG levels. These findings indicate that measuring steady-state serum IgG trough levels alone may be adequate for PK assessment of weekly SCIG.

Steady-State Imatinib Trough Levels as Well as Dose Interruptions Are Associated with Clinical Response (CCyR and MMR) and Adverse Events (AEs) in Patients with Chronic Myeloid Leukemia (CML) Receiving IM as Frontline Therapy.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2213-2213
Author(s):  
Richard A. Larson ◽  
Yen Lin Chia ◽  
Camille Granvil ◽  
François Guilhot ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
Steady State ◽  
Clinical Response ◽  
Cumulative Dose ◽  
Research Funding ◽  
Risk Scores ◽  
Employment Equity ◽  
Risk Patients ◽  
Equity Ownership ◽  
Grade 3 ◽  
Trough Levels

Abstract Abstract 2213 Poster Board II-190 Background: Correlations between IM trough plasma levels (Cmin) and clinical response have been previously reported [Picard et al. Blood 2007; Larson et al. (IRIS) Blood 2008; Guilhot et al. (TOPS) ASH 2008]. This analysis correlates IM Cmin on Day 29 of initial treatment with complete cytogenetic response (CCyR) and major molecular responses (MMR) at 12 months and with cumulative Grade 3&4 toxicity over 12 months based on data pooled from 2 studies, IRIS (400 mg qd) and TOPS (400 mg bid (800 mg/daily) vs 400 mg qd), in newly diagnosed, previously untreated, Ph+ CML-CP. Methods: Steady-state Cmin was defined as predose blood level collected within ±3 hours of the scheduled dosing time on Day 29 without any dose interruptions within 5 days prior to PK sampling. The correlation between IM Cmin and CCyR and MMR at 12 months was studied by two approaches: 1) analysis of outcomes by quartile groups based on patients' IM Cmin levels; 2) logistic regression analysis with Cmin as a continuous variable plus Sokal risk scores and cumulative days with any dose interruptions during the initial 12 months. Safety parameters included Grade 3&4 AEs, as well as all frequently-occurring (>10%) AEs of any grade that occurred during the 12 months. Patients with missing covariates were excluded. Results: Steady-state IM Cmin trough levels were available in 526 patients: 319 in IRIS and 207 from TOPS. At the time of assessment most patients received either 400 mg or 800 mg; 8 patients received reduced doses (6 at 300 mg; 2 at 600 mg). The median IM Cmin [25-75% quartiles] for 400 mg in the pooled dataset was 943 ng/mL [688-1280 ng/mL], and that for 800 mg was 2910 ng/mL [2333-3900 ng/mL]. IM Cmin showed large inter-patient variability for both 400 mg and 800 mg dose groups (52.7% and 39.9%, respectively). Both CCyR and MMR rates at 12 months were significantly correlated with IM Cmin on Day 29. Besides Cmin on Day 29, Sokal risk scores and cumulative dose interruptions (due either to treatment-related toxicities or non-adherence) were significant covariates for 12 month CCyR and MMR. Patients with high Sokal scores (H) had lower CCyR and MMR rates than those with low Sokal scores (L), 64% (H), 69% (intermediate (I)), and 83% (L), respectively, for CCyR, and 37%, 48%, and 59%, respectively, for MMR. Response rates at 12 months were significantly lower for patients with cumulative dose interruptions > 28 days (in the first 12 months): 45% vs 76% for CCyR, and 27% vs 48% for MMR. Modeling predicts that at a Cmin level of 1000 ng/mL and assuming no or minimal dose interruptions, the CCyR at 12 months would be 85%, 78%, and 68% for L, I, and H Sokal risk patients, respectively, and for MMR 55%, 45% and 36%, respectively. If the Cmin were 2000 ng/mL, the CCyR at 12 months would be 93%, 89%, and 83% for L, I, and H Sokal risk patients, respectively, and for MMR 65%, 55% and 44%, respectively. The predicted CCyR and MMR would be lower if there were dose interruptions. Patients who had Grade 3&4 AEs over first 12 months period (n=136) had a higher IM Cmin on Day 29 (median [25-75% quartiles], 1985 [982-2943] ng/mL vs 1010 [728-1468] ng/mL, P<0.001), than those without (n=390) as well as longer cumulative dose interruptions (20 [8-41] days vs 0 [0-2] days, P<0.001), lower CCyR rate (66%; 77/117 vs 75%; 277/369, P=0.05), and lower MMR rate (37%; 49/131 vs 48%; 155/323, P=0.006). Most Grade 3&4 AEs were treatment-related hematologic AEs with median times to onset between 50-63 days. Regression analysis showed the correlation between hematologic Grade 3&4 AEs and IM Cmin level for the population (Figure). Among all-grade non-hematologic AEs, rash and vomiting were associated with higher IM Cmin levels. Conclusion: IRIS+TOPS pooled data confirmed earlier findings that higher steady-state IM levels correlate with better CCyR and MMR responses but also with more Grade 3&4 treatment-related toxicities. Dose interruptions compromise CCyR and MMR rates at 12 months. IM Cmin levels provide additional information together with clinical response and tolerability to inform dose changes for individual patients. Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding. Chia:Novartis: Employment. Granvil:Novartis: Employment. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. O'Brien:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Wyeth: Research Funding. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Nedelman:Novartis: Employment, Equity Ownership. Wang:Novartis: Employment, Equity Ownership.

Comparison of Steady-State Imatinib (IM) Trough Levels, Clinical Response, and Safety Between Caucasian and Asian Patients with Chronic Lyeloid Leukemia in Chronic Phase (CML-CP) Treated with 400mg and 800mg Daily Doses of IM in the Tyrosine Kinase Inhibitor Optimization and Selectivity (TOPS) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1127-1127
Author(s):  
Dong-Wook Kim ◽  
Camille Granvil ◽  
Eren Demirhan ◽  
John Reynolds ◽  
Yu Jin ◽  
...  
Keyword(s):  
Adverse Event ◽  
Steady State ◽  
Clinical Response ◽  
Board Of Directors ◽  
Research Funding ◽  
Average Dose ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Grade 3 ◽  
Trough Levels

Abstract Abstract 1127 Poster Board I-149 Background In the TOPS study, IM trough levels (Cmin) were collected from different race groups, mainly Caucasian and Asian, but also Black and others. Inter-ethnic differences in the PK of a drug are known to be important factors accounting for inter-individual variation in drug responsiveness. This analysis reports the comparison between Caucasian and Asian CML patients (pts) treated at doses of 400 mg QD and 400 mg bid (800 mg daily) of IM Cmin on Day 29 of initial treatment, clinical response, safety and tolerability. Methods Steady state IM Cmin on Day 29 and clinical response and safety data obtained during the first 12 months (mos) of treatment were obtained from pts randomized 2:1 to 800 mg or 400 mg daily IM. The steady-state Cmin was defined as predose concentration collected approximately within ±3 hours of the scheduled dosing time on Day 29. The associations of race with the rates of major molecular response (MMR) and complete cytogenetic response (CCyR) were evaluated. Correlation of IM exposure with clinical response (MMR and CCyR) was assessed by grouping pts into quartiles based on their measured IM Cmin levels at Day 29. The safety endpoint for each pt was the presence or absence of an adverse event (AE) of grade 3 or higher in the first 12 mos from the first dose. Results IM Cmin levels were available from 229 pts in TOPS including 54 Caucasians, 18 Asians, and 14 Black and others at 400 mg (total 86) and 103 Caucasians, 29 Asians, and 11 Black and others at 800 mg (total 143). For the first 12 mos, the means of the average dose intensities for Asian (mean [range], 362 [267-400] in 400 mg and 666 [226-800] in 800 mg) were not significantly different from Caucasian (386 [204-597] in 400 mg and 666 [289-800] in 800 mg) (P=0.070 and P=0.995 for the 400 mg and 800 mg arms, respectively). Mean (± SD) of IM Cmin levels (ng/mL) with respect to race are shown in Table 1. IM Cmin was slightly over-proportional to dose and showed large interpatient variability (CV=42-60%) for both dose groups regardless of the race group. In the lower quartile Cmin group (Cmin<1290 ng/mL), the differences in CCyR and MMR rates between Asian and Caucasian pts were significant (P=0.031 and P=0.022 respectively), which was probably due to a higher rate of dose interruptions in the 1st 12 mos in Asian pts. A definitive conclusion cannot be drawn due to the small number of Asian pts. Occurrences of at least one grade 3 or 4 adverse event were found to be significantly higher in Asian pts (69% and 75% in the 1st 6 and 12 mos respectively) compared to Caucasian pts (53% and 57% in the 1st 6 and 12 mos respectively) (P=0.028 and P=0.008 respectively). Conclusion The results of this analysis from TOPS show that IM Cmin levels were similar between Caucasian and Asian CML pts in each treatment arm. There were no major differences in efficacy, as measured by MMR and CCyR rates by 12 mos, between Asian and Caucasian pts. There were no unexpected differences in patterns of AEs between Caucasian and Asian pts; however, occurrences of one or more grade 3 AEs were higher in Asian. Further analysis on a larger group of CML pts will be needed to evaluate the impact of AE rate differences between Caucasian and Asian pts. Disclosures Kim: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Granvil:Novartis: Employment. Demirhan:Novartis: Employment. Reynolds:Novartis: Employment. Jin:Novartis: Employment. Wang:Novartis: Employment, Equity Ownership. Baccarani:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Mayer Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cortes-Franco:Novartis: Honoraria, Research Funding, Speakers Bureau; Wyeth: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau. Druker:OHSU patent #843 - Mutate ABL Kinase Domains: Patents & Royalties; MolecularMD: Equity Ownership; Roche: Consultancy; Cylene Pharmaceuticals: Consultancy; Calistoga Pharmaceuticals: Consultancy; Avalon Pharmaceuticals: Consultancy; Ambit Biosciences: Consultancy; Millipore via Dana-Farber Cancer Institute: Patents & Royalties; Novartis, ARIAD, Bristol-Myers Squibb: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Guilhot:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria.

Safety and Efficacy Of BEZ235, a Dual PI3-Kinase /mTOR Inhibitor, In Adult Patients With Relapsed Or Refractory Acute Leukemia: Results Of a Phase I Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2675-2675 ◽  
Author(s):  
Lydia Wunderle ◽  
Susanne Badura ◽  
Fabian Lang ◽  
Andrea Wolf ◽  
Eberhard Schleyer ◽  
...  
Keyword(s):  
Steady State ◽  
Acute Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Pi3k Pathway ◽  
Molecular Remission ◽  
Starting Dose ◽  
Level 1 ◽  
Trough Levels

Abstract Activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling plays a role in cell proliferation, survival, and drug resistance in solid tumors and hematologic malignancies including chronic myeloid leukemia (CML), B-cell precursor acute lymphoblastic leukemia (BCP-ALL), T-ALL and acute myeloid leukemia (AML). The investigational compound BEZ235 is a potent dual pan-class I PI3K and mTOR complex C1 and C2 inhibitor and an attractive agent for relapsed or refractory leukemias. Primary objectives of this phase I study were determination of the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in pts. with advanced acute leukemia. Secondary objectives included assessment of pharmacokinetics (PK), pharmakodynamic (PD) parameters and preliminary evidence of anti-leukemic activity. Inclusion criteria included age > 18years, relapsed or refractory AML, ALL or CML-BP considered ineligible for intensive or established treatment. Pts. with a fasting blood glucose >160mg/dl or an HbA1c >8% were excluded. The starting dose of BEZ235 was 400 mg twice daily (BID), administered orally during 28d cycles. Dose escalation was based on a “rolling-six”design, followed by an expansion phase at the RP2D. PK analyses were performed on days 1 and 15 by HPLC and fluorescence detection, PD analysis included assessment of phosphorylation of AKT, S6 and 4EBP1 by Western blotting (WB) and flow cytometry. The presence of PI3KCA, AKT or PTEN mutations was evaluated by direct sequencing of exons with known mutation hotspots. All pts. gave informed written consent, the study was approved by the Ethics Committee of the University of Frankfurt. 22 pts. (13m, 9f), median age 62.5 years (range 29-82), were enrolled. Types of leukemia were AML (n=11), BCP-ALL (n=9), T-ALL (n=1) and CML in myeloid blast phase (CML-BP, n=1). 6 pts. were in first and 9 pts. in second or later relapse, 7 refractory or in refractory relapse, 7 pts. had extramedullary leukemia, 14 pts. previously received an allogeneic stem cell transplant (SCT). Six pts. were evaluated at the starting dose of BEZ235 (400 mg BID). No DLTs were observed, but BEZ235-related AEs (stomatitis and GI toxicity grades 1-3) necessitated treatment interruptions in 3 of 6 pts. 400 mg BID was considered not tolerable for prolonged administration and 16 pts. were subsequently treated at dose level -1 (300 mg BID). The most frequent non-hematologic AEs were gastrointestinal primarily of grades 1 and 2 with diarrhea (n=20), nausea/vomiting (n=18/6), stomatitis/mucositis (n=20), decreased appetite (n=14), fatigue (n=10) and hyperglycemia (n=21). Grade 3/4 AEs included sepsis (n=6), pneumonia (n=4), diarrhea (n=3), hyperglycemia (n=2), mucositis and fatigue (2 each). No patient started at dose level -1 was dose-reduced and none discontinued BEZ235 because of toxicity, 300 mg BID was selected as the RP2D. Clinical responses were observed in 4 of 22 pts. (3/10 ALL): one pat. with pro-B ALL achieved a complete hematologic and molecular remission with full donor chimerism, ongoing after 11 cycles of BEZ235. Hematologic improvement was observed in two pts. with BCP-ALL (1 Ph+, 1 Ph neg) and stable disease of 4 mos. duration in an AML patient. Nineteen of 22 pts. discontinued because of disease progression, median time to progression was 28 days (5d-112d). PK analysis revealed substantial interpatient variability of peak and trough levels at steady state, with no clear dose-dependency. All three responders in whom PK data are already available had low steady state trough levels below 100 ng/ml. No activating mutations of PIK3CA, AKT or PTEN were identified in any of the 22 pts. Phospho-flow and WB analysis provided no evidence of PI3K pathway activation, even in responding pts. In conclusion, the RP2D for BEZ235 was determined to be 300 mg BID, without formal definition of DLTs and an MTD. Single-agent anti-leukemic efficacy was most pronounced in ALL, with an overall response rate of 30% and a sustained molecular remission in one patient. Results of PK analysis and assessment of PD markers associated with PI3K signaling did not correlate with response. The PI3K pathway appears to be a “driver pathway” in only a small minority of pts. with ALL or AML, but more comprehensive genomic analysis may identify a subset of patients likely to benefit from treatment with dual PI3K-mTOR inhibitors. Disclosures: Ottmann: Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Prospective Evaluation of a Model-Based Dosing Regimen for Amikacin in Preterm and Term Neonates in Clinical Practice

2015 ◽  
Vol 59 (10) ◽  
pp. 6344-6351 ◽  
Author(s):  
A. Smits ◽  
R. F. W. De Cock ◽  
K. Allegaert ◽  
S. Vanhaesebrouck ◽  
M. Danhof ◽  
...  
Keyword(s):  
Monte Carlo ◽  
Steady State ◽  
Monte Carlo Simulations ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Prospective Evaluation ◽  
Dosing Regimen ◽  
Model Based ◽  
Almost All ◽  
Trough Levels

ABSTRACTBased on a previously derived population pharmacokinetic model, a novel neonatal amikacin dosing regimen was developed. The aim of the current study was to prospectively evaluate this dosing regimen. First, early (before and after second dose) therapeutic drug monitoring (TDM) observations were evaluated for achieving target trough (<3 mg/liter) and peak (>24 mg/liter) levels. Second, all observed TDM concentrations were compared with model-predicted concentrations, whereby the results of a normalized prediction distribution error (NPDE) were considered. Subsequently, Monte Carlo simulations were performed. Finally, remaining causes limiting amikacin predictability (i.e., prescription errors and disease characteristics of outliers) were explored. In 579 neonates (median birth body weight, 2,285 [range, 420 to 4,850] g; postnatal age 2 days [range, 1 to 30 days]; gestational age, 34 weeks [range, 24 to 41 weeks]), 90.5% of the observed early peak levels reached 24 mg/liter, and 60.2% of the trough levels were <3 mg/liter (93.4% ≤5 mg/liter). Observations were accurately predicted by the model without bias, which was confirmed by the NPDE. Monte Carlo simulations showed that peak concentrations of >24 mg/liter were reached at steady state in almost all patients. Trough values of <3 mg/liter at steady state were documented in 78% to 100% and 45% to 96% of simulated cases with and without ibuprofen coadministration, respectively; suboptimal trough levels were found in patients with postnatal age <14 days and current weight of >2,000 g. Prospective evaluation of a model-based neonatal amikacin dosing regimen resulted in optimized peak and trough concentrations in almost all patients. Slightly adapted dosing for patient subgroups with suboptimal trough levels was proposed. This model-based approach improves neonatal dosing individualization.

Correlation of Pharmacokinetic Data with Cytogenetic and Molecular Response in Newly Diagnosed Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib - An Analysis of IRIS Study Data.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 429-429 ◽  
Author(s):  
Richard A. Larson ◽  
Brian J. Druker ◽  
Francois Guilhot ◽  
Stephen G. O’Brien ◽  
Insa Gathmann ◽  
...  
Keyword(s):  
Steady State ◽  
Active Metabolite ◽  
Trough Level ◽  
Plasma Concentrations ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Inter Quartile Range ◽  
Quartile Range ◽  
Trough Levels ◽  
Trough Plasma

Abstract A total of 551 pts with newly diagnosed CML-CP received imatinib (IM) 400 mg orally once daily as part of the IRIS study (O’Brien et al, NEJM 2003). We now summarize the correlation of clinical responses with the steady-state trough plasma concentrations (Cmin) of IM and its major active metabolite CGP74588. Cmin is a reflection of IM clearance and metabolism in CML pts. Trough PK samples (24 hrs post dose) were obtained in IM pts at Day 1 and steady state (Day 29). The plasma concentrations of IM and CGP74588 were determined by liquid chromatography/mass spectrometry. Estimated rates of complete cytogenetic response (CCyR - 0% Ph+) and major molecular response (MMR - ≥ 3 log reduction in BCR-ABL/BCR ratio from a standardized baseline value for untreated pts) were given for the lower and upper quartiles (below Q1=25th percentile, above Q3=75th percentile) and the inter-quartile range of PK trough levels. After 4 weeks of IM at 400 mg, the overall mean (±SD, CV%) steady-state trough levels (Cmin) for IM and CGP74588 (n=351 pts) were 979 (±530, 54.1%) and 242 (±106, 43.6%) ng/mL, respectively. Median (Q1–Q3, min-max) values (in ng/mL) were 879 (647–1170, 153–3910) for IM and 223 (169–291, 50–841) for CGP74588. Times to CCyR and MMR within CCyR pts were significantly different between the three groups of IM plasma exposure (low/intermediate/high; p&lt;0.025). The same was observed for CGP74588, since the parent drug and metabolite levels were highly correlated (0.77, Spearman correlation coefficient). Overall, Cmin of IM was statistically significantly higher in pts who achieved CCyR (1009±544 ng/mL vs. 812±409 ng/mL, p=0.0116). The estimated MMR rate among all pts was significantly lower in pts with low IM levels: only an estimated 59%x43%=25% of all pts with IM levels &lt;647 ng/mL achieved a MMR at 1 year (yr), compared to 40% of all other pts. By 4 yrs an estimated 53% achieved MMR despite low steady state Cmin levels compared with 80% for pts with high Cmin (and 72% for pts within inter-quartile range). CCyR and MMR rates [95% CI] within 1, 2, and 4 yrs by categories of IM trough plasma concentrations measured on Day 29 IM trough level &lt; 647 ng/mL (Q1) N = 87 647–1170 ng/mL N = 178 &gt; 1170 ng/mL (Q3) N = 86 CCyR (%) − 1 yr 59 [48, 70] 71 [64, 78] 73 [63, 83] − 2 yrs 73 [63, 83] 80 [73, 86] 84 [75, 92] − 4 yrs 81 [71, 91] 87 [81, 93] 89 [82, 96] MMR (%) in pts with CCyR − 1 yr 43 [28, 59] 56 [47, 66] 55 [41, 68] − 2 yrs 63 [49, 78] 78 [69, 86] 86 [76, 96] − 4 yrs 65 [50, 80] 83 [75, 91] 90 [81, 100] The trough plasma level following the 1st dose also showed a correlation with CCyR and MMR responses, but appeared to be less predictive than the trough level at steady state. Although all CML-CP pts had received 400 mg qd IM, CCyR and MMR rates at 1 to 4 yrs were depending on their IM trough level (24 hrs after the last dose) after 4 weeks of IM. Similar results were observed for the major active metabolite of IM. These results suggest that achieving and maintaining an adequate plasma concentration of IM is important for a good clinical response, and that therapeutic drug monitoring could be done by measuring trough levels at steady state conditions.

Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: a subanalysis of the IRIS study

Blood ◽  
2008 ◽  
Vol 111 (8) ◽  
pp. 4022-4028 ◽  
Author(s):  
Richard A. Larson ◽  
Brian J. Druker ◽  
Francois Guilhot ◽  
Stephen G. O'Brien ◽  
Gilles J. Riviere ◽  
...  
Keyword(s):  
Steady State ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Plasma Concentrations ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Free Survival ◽  
Clinical Responses ◽  
Trough Levels

AbstractImatinib at 400 mg daily is standard treatment for chronic myeloid leukemia in chronic phase. We here describe the correlation of imatinib trough plasma concentrations (Cmins) with clinical responses, event-free survival (EFS), and adverse events (AEs). Trough level plasma samples were obtained on day 29 (steady state, n = 351). Plasma concentrations of imatinib and its metabolite CGP74588 were determined by liquid chromatography/mass spectrometry. The overall mean (± SD, CV%) steady-state Cmin for imatinib and CGP74588 were 979 ng/mL (± 530 ng/mL, 54.1%) and 242 ng/mL (± 106 ng/mL, 43.6%), respectively. Cumulative estimated complete cytogenetic response (CCyR) and major molecular response (MMR) rates differed among the quartiles of imatinib trough levels (P = .01 for CCyR, P = .02 for MMR). Cmin of imatinib was significantly higher in patients who achieved CCyR (1009 ± 544 ng/mL vs 812 ± 409 ng/mL, P = .01). Patients with high imatinib exposure had better rates of CCyR and MMR and EFS. An exploratory analysis demonstrated that imatinib trough levels were predictive of higher CCyR independently of Sokal risk group. AE rates were similar among the imatinib quartile categories except fluid retention, rash, myalgia, and anemia, which were more common at higher imatinib concentrations. These results suggest that an adequate plasma concentration of imatinib is important for a good clinical response. This study is registered at http://clinicaltrials.gov as NCT00333840.

Sign in / Sign up

Export Citation Format

Share Document