Pharmacokinetic (PK)-based dosage individualization of imatinib: evaluation of efficiency and clinical usefulness

Background: Retrospective analyses suggest that personalized PK-based dosage might be useful for imatinib, as treatment response correlates with trough concentrations (Cmin) in cancer patients. Our objectives were to improve the interpretation of randomly measured concentrations and to confirm its efficiency before evaluating the clinical usefulness of systematic PK-based dosage in chronic myeloid leukemia patients. Methods and Results: A Bayesian method was validated for the prediction of individual Cmin on the basis of a single random observation, and was applied in a prospective multicenter randomized controlled clinical trial. 28 out of 56 patients were enrolled in the systematic dosage individualization arm and had 44 follow-up visits (their clinical follow-up is ongoing). PK-dose-adjustments were proposed in 39% having predicted Cmin significantly away from the target (1000 ng/ml). Recommendations were taken up by physicians in 57%, patients were considered non-compliant in 27%. Median Cmin at study inclusion was 754 ng/ml and differed significantly from the target (p=0.02, Wilcoxon test). On follow-up, Cmin was 984 ng/ml (p=0.82) in the compliant group. CV decreased from 46% to 27% (p=0.02, F-test). Conclusion: PK-based (Bayesian) dosage adjustment is able to bring individual drug exposure closer to a given therapeutic target. Its influence on therapeutic response remains to be evaluated.

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

PURPOSE: This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). METHODS: Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). RESULTS: Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). CONCLUSIONS: This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: Results from the randomized controlled I-COME Trial

Introduction: Imatinib trough plasma concentrations (Cmin) have been correlated with treatment response in chronic myeloid leukemia (CML) patients. The use of Cmin monitoring for optimizing imatinib dosage (therapeutic drug monitoring [TDM]) is therefore proposed for patients with unsatisfying response or tolerance ("rescue TDM"). A cycle of "routine TDM" for dosage individualization could also be beneficial to prevent unfavorable events, yet its clinical usefulness has not been evaluated. We aimed to assess prospectively whether a "routine TDM" intervention targeting imatinib Cmin of 1000 ng/mL (tolerance, 750-1500 ng/mL) could improve efficacy, tolerance, and persistence on treatment compared with "rescue TDM" use only. Patients (or Materials) and Methods: The Swiss Imatinib COncentration Monitoring Evaluation (I-COME) study was a multicenter randomized controlled trial (ISRCTN31181395). Adult patients in chronic or accelerated phase CML receiving imatinib ≤5 years were eligible. Patients were randomly (1:1) allocated to receive "routine TDM" intervention or to serve as controls with access only to "rescue TDM". All had 1-year follow-up. The primary endpoint was a combined efficacy-safety outcome (failure- and toxicity-free survival without imatinib discontinuation), analyzed in intention-to-treat. Results: Among 56 CML recruited patients, 55 had their molecular and cytogenetic response measured. 14/27 of patients receiving "routine TDM" (52% [33%-71%]) remained event-free versus 16/28 of control patients with "rescue TDM" only (57% [39%-75%]; P=0.69). In the "routine TDM" group, dosage recommendations were adopted entirely in 50% of patients (median Cmin at study end, 895 ng/mL; CV = 33%). These patients had fewer unfavorable events (28% [5%-52%]) compared with patients not receiving the advised dosage (77% [54%-99%]; P = 0.03; median Cmin at study end, 648 ng/mL; CV = 38%). Conclusion: This first prospective target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" of imatinib, especially due to a small patient number and limited prescriber's adherence to dosage recommendations. Nevertheless, the patients receiving the advised dosage more often met target concentrations and the combined outcome (efficacy, tolerance, and persistence). A cycle of routine TDM could thus be favorable, at least in patients eligible for dosage adjustment. Its usefulness should, however, be further confirmed in larger trials.

Safe and effective variability-a criterion for dose individualization.

BACKGROUND: : A primary goal of clinical pharmacology is to understand the factors that determine the dose-effect relationship and to use this knowledge to individualize drug dose. METHODS: : A principle-based criterion is proposed for deciding among alternative individualization methods. RESULTS: : Safe and effective variability defines the maximum acceptable population variability in drug concentration around the population average. CONCLUSIONS: : A decision on whether patient covariates alone are sufficient, or whether therapeutic drug monitoring in combination with target concentration intervention is needed, can be made by comparing the remaining population variability after a particular dosing method with the safe and effective variability.

Cytoplasmic bridges, intercellular junctions, and individualization of germ cells during spermatogenesis in Dermatobia hominis (Diptera: Cuterebridae)

During mitotic and meiotic divisions in Dermatobia hominis spermatogenesis, the germ cells stay interlinked by cytoplasm, bridges as a result of incomplete cytokinesis. By the end of each division, cytoplasmic bridges flow to the center of the cyst, forming a complex, called the fusoma. During meiotic prophase I, spermatocytes I present desmosome-like junctions and meiotic cytoplasmic bridges. At the beginning of spermiogenesis, the fusoma moves to the future caudal end of the cyst, and at this time the early spermatids are linked by desmosome-like junctions. Throughout spermiogensis, new and sometimes broad cytoplasmic bridges are formed among spermatids at times making them share cytoplasm. In this case the individualization of cells is assured by the presence of smooth cisternae that outline then structures The more differentiated spermatids have in addition to narrow cytoplasmic bridges, plasmic membranes junctions. By the end of spermiogenesis the excess cytoplasmic mass is eliminated leading to spermatid individualization. Desmosome-like junctions of spermatocytes I and early spermatids appear during the fusoma readjustment and segregations; on the other hand, plasmic membrane junctions appear in differentiating spermatids and are eliminated along with the cytoplasmic excess. These circumstances suggest that belt desmosome-like and plasmic membrane junctions are involved in the maintenance of the relative positions of male germ cells in D. hominis while they are inside the cysts. © 1996 Wiley-Liss, Inc.

Individualization of 5-fluorocytosine therapy

Using a convenient and fast HPLC procedure we determined serum concentrations of the fungistatic agent 5-fluorocytosine (5-FC) in 375 samples from 60 patients treated with this drug. The mean trough concentration (n = 127) was 64.3 mg/l (range: 11.8-208.0 mg/l), the mean peak concentration (n = 122) was 99.9 mg/l (range: 25.6-263.8 mg/l), the mean nonpeak/nontrough concentration (n = 126) was 80.1 mg/l (range: 10.5-268.0 mg/l). Totally 134 (35.7%) samples were outside the therapeutic range (25-100 mg/l), 108 (28.8%) being too high, 26 (6.9%) being too low. Forty-four (73%) patients showed 5-FC serum concentrations outside the therapeutic range at least once during the treatment course. In a prospective study we performed 65 dosage predictions on 30 patients by use of a 3-point method previously developed for aminoglycoside dosage adaptation. The mean absolute prediction error of the dosage adaptation was +0.7 mg/l (range: -26.0 to +28.0 mg/l). The root mean square prediction error was 10.7 mg/l. The mean predicted concentration (65.3 mg/l) agreed very well with the mean measured concentration (64.6 mg/l). The frequency distribution of 5-FC serum concentrations indicates that 5-FC monitoring is important. The applied pharmacokinetic method allows individual adaptations of 5-FC dosage with a clinically acceptable prediction error.

Clinical usefulness of therapeutic concentration monitoring for imatinib dosage individualization: results from a randomized controlled trial.

PURPOSE This study assessed whether a cycle of "routine" therapeutic drug monitoring (TDM) for imatinib dosage individualization, targeting an imatinib trough plasma concentration (C min) of 1,000 ng/ml (tolerance: 750-1,500 ng/ml), could improve clinical outcomes in chronic myelogenous leukemia (CML) patients, compared with TDM use only in case of problems ("rescue" TDM). METHODS Imatinib concentration monitoring evaluation was a multicenter randomized controlled trial including adult patients in chronic or accelerated phase CML receiving imatinib since less than 5 years. Patients were allocated 1:1 to "routine TDM" or "rescue TDM." The primary endpoint was a combined outcome (failure- and toxicity-free survival with continuation on imatinib) over 1-year follow-up, analyzed in intention-to-treat (ISRCTN31181395). RESULTS Among 56 patients (55 evaluable), 14/27 (52 %) receiving "routine TDM" remained event-free versus 16/28 (57 %) "rescue TDM" controls (P = 0.69). In the "routine TDM" arm, dosage recommendations were correctly adopted in 14 patients (median C min: 895 ng/ml), who had fewer unfavorable events (28 %) than the 13 not receiving the advised dosage (77 %; P = 0.03; median C min: 648 ng/ml). CONCLUSIONS This first target concentration intervention trial could not formally demonstrate a benefit of "routine TDM" because of small patient number and surprisingly limited prescriber's adherence to dosage recommendations. Favorable outcomes were, however, found in patients actually elected for target dosing. This study thus shows first prospective indication for TDM being a useful tool to guide drug dosage and shift decisions. The study design and analysis provide an interesting paradigm for future randomized TDM trials on targeted anticancer agents.

Individualization and Electrical Characterization of SiGe Nanowires

SiGe nanowires of different Ge atomic fractions up to 15% were grown and ex-situ n-type doped by diffusion from a solid source in contact with the sample. The phenomenon of dielectrophoresis was used to locate single nanowires between pairs of electrodes in order to carry out electrical measurements. The measured resistance of the as-grown nanowires is very high, but it decreases more than three orders of magnitude upon doping, indicating that the doping procedure used has been effective