Monte Carlo simulations of the clinical benefits from therapeutic drug monitoring of sunitinib in patients with gastrointestinal stromal tumours

Goulooze, Sebastiaan C.; Galettis, Peter; Boddy, Alan V.; Martin, Jennifer

doi:10.1007/s00280-016-3071-1

Cited by 19 publications

(13 citation statements)

References 23 publications

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“…The use of a C0 level may provide a convenient method for monitoring systemic exposure to SU in a clinical setting, thereby allowing optimization of the dosing regimen to gain maximum efficacy and minimum toxicity [ 15 ]. Algorithms for therapeutic drug monitoring of tyrosine kinase inhibitors have not been proposed until now [ 1 , 6 , 16 ], and the result of this study can contribute to the current literature.…”

Section: Discussionmentioning

confidence: 99%

Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients

et al. 2018

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In this study, we examined the association between the pharmacokinetics (PK) level of sunitinib malate (SU) and its metabolite N-desethyl-sunitinib (DSU) in terms of adverse events (AEs) and clinical outcomes in patients with metastatic renal cell carcinoma (mRCC). The PK of sunitinib (SU and DSU) was examined in 26 patients (20 men and 6 women) with mRCC. The associations between SU/DSU C0 and AE occurrence, best response rate, time to treatment failure, progression-free survival (PFS), and overall survival (OS) were investigated. Occurrence of grade 1 or higher hand-foot syndrome and thrombocytopenia (p = 0.002 and 0.024, respectively) was associated with a high concentration before morning intake (C0) level of SU. Low C0 levels of DSU were significantly associated with drug discontinuation due to disease progression (p = 0.035). Patients with DSU C0 level higher than 15.0 ng/mL showed a tendency toward increased PFS (61 weeks vs 12 weeks, p = 0.004) and OS (36 months vs 8 months, p = 0.040). The C0 level of SU and SU + DSU were not associated with prognosis. The higher level of C0 of SU may predict developing AEs and DSU C0 >15.0 ng/mL may lead to better prognosis of patients treated with sunitinib. PK of sunitinib may be useful for determining adequate dosages and prevention of severe AEs. Further studies are required to establish the utility of the PK of sunitinib in patients with mRCC.

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Section: Discussionmentioning

confidence: 99%

Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients

et al. 2018

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“…Similarly, optimal sampling times to enable appropriate dose recommendations across patients and diseases are not known, for example, the sunitinib target area under the curve (AUC) in gastrointestinal stromal tumors (GISTs) may not be the same as in chronic myeloid leukemia (CML). 32 Clinical contexts in which pharmacokinetic-guided dosing of oral therapies is useful are where, as with other drugs for which TDM is used, there is severe or unanticipated toxicity, suboptimal therapeutic response, expected drug-drug interactions, or suspected patient nonadherence to therapy. 5 However, optimal sampling times (OSTs) and appropriate pharmacokinetic targets need to be pragmatic in a clinical setting, that is, during clinical hours (summarized in Ward et al).…”

Section: What Do We Need To Do To Utilize Routine Tdm For Oral Tkis?mentioning

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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“…Furthermore, there are several AEs variables that need to be taken into consideration as they may hamper dose increments. This in turn give rise to marginal treatment benefits that would require large patient populations to reach adequate power in prospective clinical trials (Goulooze et al, 2016;Centanni et al, 2018). Given the fact that there are over 25 TKIs available, and most are approved for several treatment indications, the number of combinations to be explored would be extensive and require a large amount of monetary and patient resources.…”

Section: Introductionmentioning

confidence: 99%

Model-Based Biomarker Selection for Dose Individualization of Tyrosine-Kinase Inhibitors

Centanni

Friberg

2020

Front. Pharmacol.

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Tyrosine-kinase inhibitors (TKIs) demonstrate high inter-individual variability with respect to safety and efficacy and would therefore benefit from dose or schedule adjustments. This study investigated the efficacy, safety, and economical aspects of alternative dosing options for sunitinib in gastro-intestinal stromal tumors (GIST) and axitinib in metastatic renal cell carcinoma (mRCC). Dose individualization based on drug concentration, adverse effects, and sVEGFR-3 was explored using a modeling framework connecting pharmacokinetic and pharmacodynamic models, as well as overall survival. Model-based simulations were performed to investigate four different scenarios: (I) the predicted value of high-dose pulsatile schedules to improve clinical outcomes as compared to regular daily dosing, (II) the potential of biomarkers for dose individualizations, such as drug concentrations, toxicity measurements, and the biomarker sVEGFR-3, (III) the costeffectiveness of biomarker-guided dose-individualizations, and (IV) model-based dosing approaches versus standard sample-based methods to guide dose adjustments in clinical practice. Simulations from the axitinib and sunitinib frameworks suggest that weekly or once every two weeks high-dosing result in lower overall survival in patients with mRCC and GIST, compared to continuous daily dosing. Moreover, sVEGFR-3 appears a safe and cost-effective biomarker to guide dose adjustments and improve overall survival (€36 784.-per QALY). Model-based estimations were for biomarkers in general found to correctly predict dose adjustments similar to or more accurately than single clinical measurements and might therefore guide dose adjustments. A simulation framework represents a rapid and resource saving method to explore various propositions for dose and schedule adjustments of TKIs, while accounting for complicating factors such as circulating biomarker dynamics and inter-or intra-individual variability.

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Monte Carlo simulations of the clinical benefits from therapeutic drug monitoring of sunitinib in patients with gastrointestinal stromal tumours

Cited by 19 publications

References 23 publications

Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients

Clinical implications of pharmacokinetics of sunitinib malate and N-desethyl-sunitinib plasma concentrations for treatment outcome in metastatic renal cell carcinoma patients

Pharmacokinetic‐Guided Dosing of New Oral Cancer Agents

Model-Based Biomarker Selection for Dose Individualization of Tyrosine-Kinase Inhibitors

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