A Long-term Prospective Population Pharmacokinetic Study on Imatinib Plasma Concentrations in GIST Patients

Eechoute, Karel; Fransson, Moa; Reyners, An; Jong, Floris A. de; Sparreboom, Alex; Graaf, Winette T.A. van der; Friberg, Lena E.; Schiavon, Gaia; Wiemer, Erik A.C.; Verweij, Jaap; Loos, Walter J.; Mathijssen, Ron H.J.; Giorgi, Ugo De

doi:10.1158/1078-0432.ccr-12-0490

Cited by 99 publications

(84 citation statements)

References 21 publications

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“…We thank Chatelut and colleagues for their interest in our prospective population pharmacokinetic analysis of imatinib exposure in patients treated for gastrointestinal stromal tumor (1). In their letter to the editor, these authors suggested an alternative explanation for the approximately 30% decrease in imatinib exposure after a treatment duration of 3 months or longer.…”

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confidence: 99%

Long-term Prospective Population PK Study in GIST Patients—Response

Mathijssen

Bruijn

Eechoute

et al. 2013

Clinical Cancer Research

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We thank Chatelut and colleagues for their interest in our prospective population pharmacokinetic analysis of imatinib exposure in patients treated for gastrointestinal stromal tumor (1). In their letter to the editor, these authors suggested an alternative explanation for the approximately 30% decrease in imatinib exposure after a treatment duration of 3 months or longer. They hypothesized that this decrease in imatinib plasma concentrations resulted from a decrease in a1-acid-glycoprotein (AGP) levels with time. Because this theory could be plausible, at least as a factor contributing to the clearance of imatinib, we studied their hypothesis in the patients included in our study.For a subset of patients (n ¼ 22), we prospectively determined plasma AGP concentrations during the first year of imatinib treatment. On the first day of imatinib treatment, and also at months 1, 6, and 12, AGP concentrations were correlated to a WinNonlin-derived area under the curve (AUC) of imatinib, and the sum of imatinib and active metabolite CGP74588, respectively. This metabolite results from a CYP3A-mediated conversion of imatinib (2). Next, we plotted AGP levels against the AUC ratio of active metabolite and parent drug.Interestingly, good correlations were found between AGP and imatinib, and the sum of imatinib and CGP74588, respectively. No correlation was seen for AGP and the AUC ratio. As we show in Fig. 1, a change in AGP resulted in a proportional change in drug AUC in many individual cases, although the magnitude of this change may differ substantially. Moreover, not only decreases in AGP over time were found but also substantial increases. This finding contrasts with the expectations mentioned in the letter. Although the correlation these authors found (Fig. 1) is quite good at first glance (r 2 ¼ 0.76; P < 0.001), we may wonder whether this correlation is useful (yet) in daily clinical practice, as a single AGP measurement may not be implemented directly into a dosing algorithm for imatinib. In our opinion, Judson's proposal (3), a scheme to integrate therapeutic drug monitoring in clinical practice, is probably more clinically applicable. Still, the correlation between AGP and imatinib exposure is very interesting, as the mechanisms behind the changes in drug exposure with time are not elucidated yet. As AGP levels did not correlate with the AUC ratio of CGP74588/imatinib, a relationship between AGP and CYP3A metabolism is less likely. Therefore, more research is warranted to discover the mechanisms behind the time dependency of imatinib. Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

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confidence: 99%

Long-term Prospective Population PK Study in GIST Patients—Response

Mathijssen

Bruijn

Eechoute

et al. 2013

Clinical Cancer Research

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“…The typical total carrying capacity (both lesions accounted for) was estimated to 1,730 and 1,818 mL for V actual and V ellipsoid , respectively; these values are similar to literature values of liver volume in living donors ( c.a . 1,500 mL)36 and to the baseline liver volume in a similar GIST patient population14 (median = 1,755; range = 1,112–3,354 mL), of which some of the patients reported in this study were part, and, therefore, clinically plausible. When tumor size is very small compared to the carrying capacity, logistic growth can be approximated by an exponential growth with rate constant K G .…”

Section: Discussionmentioning

confidence: 59%

Pharmacometric Modeling of Liver Metastases' Diameter, Volume, and Density and Their Relation to Clinical Outcome in Imatinib‐Treated Patients With Gastrointestinal Stromal Tumors

Schindler

Krishnan

Mathijssen

et al. 2017

CPT Pharmacom & Syst Pharma

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Three‐dimensional and density‐based tumor metrics have been suggested to better discriminate tumor response to treatment than unidimensional metrics, particularly for tumors exhibiting nonuniform size changes. In the developed pharmacometric modeling framework based on data from 77 imatinib‐treated gastrointestinal patients, the time‐courses of liver metastases' maximum transaxial diameters, software‐calculated actual volumes (Vactual) and calculated ellipsoidal volumes were characterized by logistic growth models, in which imatinib induced a linear dose‐dependent size reduction. An indirect response model best described the reduction in density. Substantial interindividual variability in the drug effect of all response assessments and additional interlesion variability in the drug effect on density were identified. The predictive ability of longitudinal tumor unidimensional and three‐dimensional size and density on overall survival (OS) and progression‐free survival (PFS) were compared using parametric time‐to‐event models. Death hazard increased with increasing Vactual. This framework may guide early clinical interventions based on three‐dimensional tumor responses to enhance benefits for patients with gastrointestinal stromal tumors (GIST).

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“…Accordingly, the imatinib target trough concentration of 1100 ng/mL that has been proposed for GISTs 59 only applies to samples collected specifically on day 29. 157 No systematic change in imatinib trough concentrations has been observed in CML. 159 As such, TDM sampling for some molecules is indication specific.…”

Section: Temporal Changes In Pharmacokineticsmentioning

confidence: 99%

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

Lucas

Martin

2017

The Journal of Clinical Pharma

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Generally, licensed drug-dosing recommendations for chemotherapy are based on results from clinical trials in which subjects are usually of relatively normal body size, middle-aged, and are relatively racially homogeneous, with minimal comorbidity and specific tumor characteristics. Very few nontrial patients meet these characteristics, resulting in clinical practice having to extrapolate dosing recommendations to the specific patient. There is insufficient research on the impact of obesity-associated physiological changes prevalent in patients with common cancers on standard pharmacokinetic and pharmacodynamic parameters. Yet quantifying the influence of obesity on the pharmacology of chemotherapy is vital, as dosing inappropriate for body composition (ie, flat dosing or mg/kg based on total body weight) may increase the risk of adverse events and reduce clinical effectiveness. Unfortunately, there are few cancer guidelines to aid clinicians in selecting the optimal dose in the obese-even recent guidelines are based predominantly on clinical opinion/current practice in treating obese patients, rather than evidence. Data in many other vulnerable groups, for example, those with significant comorbidity and older patients, are also scarce. Because of the known limitations of body surface area-guided dosing, therapeutic drug monitoring or pharmacokinetic-guided dosing, which predicts an individual's exposure, has increasingly been shown to be a powerful tool in cancer therapy. Used appropriately, it can adjust for differences in pharmacokinetic parameters not considered when body size-based dosing or "one dose fits all" is used. This review will focus predominantly on the rationale for pharmacokinetic-guided dosing of the newer oral molecularly targeted antineoplastics in people whose drug exposure is not predicted by their physiology or body composition.

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A Long-term Prospective Population Pharmacokinetic Study on Imatinib Plasma Concentrations in GIST Patients

Cited by 99 publications

References 21 publications

Long-term Prospective Population PK Study in GIST Patients—Response

Long-term Prospective Population PK Study in GIST Patients—Response

Pharmacometric Modeling of Liver Metastases' Diameter, Volume, and Density and Their Relation to Clinical Outcome in Imatinib‐Treated Patients With Gastrointestinal Stromal Tumors

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

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