Oral anticancer drugs show a high interpatient variability in pharmacokinetics (PK), leading to large differences in drug exposure. For many of these drugs, exposure has been linked to efficacy and ...toxicity. Despite this knowledge, these drugs are still administered in a one-size-fits-all approach. Consequently, individual patients have a high probability to be either underdosed, which can lead to decreased antitumor efficacy, or overdosed, which could potentially result in increased toxicity. Therapeutic drug monitoring (TDM), personalized dosing based on measured drug levels, could be used to circumvent underdosing and overdosing and thereby optimize treatment outcomes.
In this prospective clinical study (www.trialregister.nl; NL6695), the feasibility, tolerability, and efficacy of TDM of oral anticancer drugs will be evaluated. In total, at least 600 patients will be included for (at least) 23 different compounds. Patients starting regular treatment with one of these compounds at the approved standard dose can be included. PK sampling will be performed at 4, 8, and 12 weeks after the start of treatment and every 12 weeks thereafter. Drug concentrations will be measured, and trough concentrations (Cmin) will be calculated. In cases where Cmin falls below the predefined target and acceptable toxicity, a PK-guided intervention will be recommended. This could include emphasizing compliance, adapting concomitant medication (due to drug-drug interactions), instructing to take the drug concomitant with food, splitting intake moments, or recommending a dose increase.
Despite a strong rationale for the use of TDM for oral anticancer drugs, this is currently not yet widely adopted in routine patient care. This prospective study will be a valuable contribution to demonstrate the additional value of dose optimization on treatment outcome for these drugs.
Many oral anticancer drugs are metabolized by CYP3A. Clinical drug-drug interaction (DDI) studies often only examine the effect of strong CYP3A inhibitors and inducers. The effect of moderate or weak ...inhibitors or inducers can be examined using physiologically based pharmacokinetic simulations, but data from these simulations are not always available early after approval of a drug. In this review we provide recommendations for clinical practice on how to deal with DDIs of oral anticancer drugs if only data from strong CYP3A inhibitors or inducers is available. These recommendations were based on reviewed data of oral anticancer drugs primarily metabolized by CYP3A and approved for the treatment of solid tumors from January 1st, 2013 to December 31st, 2015. In addition, three drugs that were registered before the new EMA guideline was issued (i.e., everolimus, imatinib, and sunitinib), were reviewed. DDIs are often complex, but if no data is available from moderate CYP3A inhibitors/inducers, a change in exposure of 50% compared with strong inhibitors/inducers can be assumed. No
a priori
dose adaptations are indicated for weak inhibitors/inducers, because their interacting effect is small. In case pharmacologically active metabolites are involved, the metabolic pathway, the ratio of the parent to the metabolites, and the potency of the metabolites should be taken into account.
Polypharmacy is becoming increasingly prevalent in society. Patients with polypharmacy are at greater risk for drug-drug interactions, which can influence the efficacy of treatment. Especially, in ...oncology this is a concern since neoplasms are increasing prevalent with age, as well as polypharmacy is. Besides drug-drug interactions, also herb-drug and food-drug interactions could be present. Knowledge of these interactions is of great importance for safe and effective anti-cancer treatment, because the therapeutic window of most of these oncologic drugs are small. To study pharmacokinetic interaction effects, a cross-over pharmacokinetic study is a widely used, efficient and scientifically robust design. Yet, several aspects need to be considered when carrying out an interaction study. This includes the knowledge of the advantages and disadvantages of a cross-over design. Furthermore, determination of the end point and research question of interest, calculation of the required sample size, analysis of the generated data with a robust statistical plan and consideration of the logtransformation for some pharmacokinetic parameters are important aspects to consider. Even though some guidelines exist regarding these key issues, no clear overview exists. In this article an overview of these aspects is provided and their effect is discussed.
•Polypharmacy is highly prevalent and the risk of drug interactions increases.•Drug interactions are preferably studied with a pharmacokinetic cross-over design.•This type of design differs significantly in various aspects from a parallel design.•An overview regarding design and statistics of this type of study is lacking.•In this paper, recommendations regarding these aspects are discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Small molecule tyrosine kinase inhibitors (TKIs) are developed to block intracellular signaling pathways in tumor cells, leading to deregulation of key cell functions such as proliferation and ...differentiation. Over 25 years ago, tyrosine kinases were found to function as oncogenes in animal carcinogenesis; however, only recently TKIs were introduced as anti cancer drugs in human cancer treatment. Tyrosine kinase inhibitors have numerous good qualities. First, in many tumor types they tend to stabilize tumor progression and may create a chronic disease state which is no longer immediately life threatening. Second, side effects are minimal when compared to conventional chemotherapeutic agents. Third, synergistic effects are seen in vitro when TKIs are combined with radiotherapy and/or conventional chemotherapeutic agents. In this article, we will give an update of the tyrosine kinase inhibitors that are currently registered for use or in an advanced stage of development, and we will discuss the future role of TKIs in the treatment of solid tumors. The following TKIs are reviewed: Imatinib (Gleevec/Glivec), Gefitinib (Iressa), Erlotinib (OSI-774, Tarceva), Lapatinib (GW-572016, Tykerb), Canertinib (CI-1033), Sunitinib (SU 11248, Sutent), Zactima (ZD6474), Vatalanib (PTK787/ZK 222584), Sorafenib (Bay 43-9006, Nexavar), and Leflunomide (SU101, Arava).
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Most patients with cancer treated with everolimus experience stomatitis, which seriously affects the quality of life. The salivary concentrations of everolimus may predict the incidence and severity ...of stomatitis. The authors aimed to examine whether it was feasible to quantify the everolimus concentration in saliva and subsequently use it to predict stomatitis.
Saliva and whole blood samples were taken from patients with cancer, who were treated with everolimus in the dosage of either 10 mg once a day or 5 mg twice a day. Everolimus concentrations in saliva samples were measured by liquid chromatography-tandem mass spectrometry. A published population pharmacokinetic model was extended with the everolimus concentration in saliva to assess any association between everolimus in the blood and saliva. Subsequently, the association between the occurrence of stomatitis and the everolimus concentration in saliva was studied.
Eleven patients were included in this study; saliva samples were available from 10 patients, including 3 patients with low-grade stomatitis. Everolimus concentrations were more than 100-fold lower in saliva than in whole blood (accumulation ratio 0.00801 and relative standard error 32.5%). Interindividual variability (67.7%) and residual unexplained variability (84.0%) were high. The salivary concentration of everolimus tended to be higher in patients with stomatitis, 1 hour postdose ( P = 0.14).
Quantification of the everolimus concentration in saliva was feasible and revealed a nonsignificant correlation between everolimus concentration in the saliva and the occurrence of stomatitis. If future research proves this relationship to be significant, the everolimus concentration in the saliva may be used as an early predictor of stomatitis without invasive sampling. Thereby, in patients with high salivary everolimus concentrations, precautions can be taken to decrease the incidence and severity of stomatitis.
Sarcoma is a heterogeneous group of rare malignancies arising from mesenchymal tissues. Recurrence rates are high and methods for early detection by blood-based biomarkers do not exist. Hence, ...development of blood-based liquid biopsies as disease recurrence monitoring biomarkers would be an important step forward. Recently, it has been shown that tumor-educated platelets (TEPs) harbor specific spliced ribonucleic acid(RNA)-profiles. These RNA-repertoires are potentially applicable for cancer diagnostics. We aim to evaluate the potential of TEPs for blood-based diagnostics of sarcoma patients. Fifty-seven sarcoma patients (active disease), 38 former sarcoma patients (cancer free for ≥3 years) and 65 healthy donors were included. RNA was isolated from platelets and sequenced. Quantified read counts were processed with self-learning particle-swarm optimization-enhanced thromboSeq analysis and subjected to analysis of variance (ANOVA) statistics. Highly correlating spliced platelet messenger RNAs (mRNAs) of sarcoma patients were compared to controls (former sarcoma + healthy donors) to identify a quantitative sarcoma-specific signature measure, the TEP-score. ANOVA analysis identified distinctive platelet RNA expression patterns of 2647 genes (false discovery rate <0.05) in sarcoma patients as compared to controls. The self-learning algorithm reached a diagnostic accuracy of 87% (validation set only; n = 53 samples, area under the curve (AUC): 0.93, 95% confidence interval (CI): 0.86-1). Our data indicates that TEP RNA-based liquid biopsies may enable for sarcoma diagnostics.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose
Treatment with the tyrosine kinase inhibitor (TKI) imatinib in patients with gastrointestinal stromal tumours (GIST) causes symptoms that could negatively impact health-related quality of ...life (HRQoL). Treatment-related symptoms are usually clinician-reported and little is known about patient reports. We used survey and online patient forum data to investigate (1) prevalence of patient-reported symptoms; (2) coverage of symptoms mentioned on the forum by existing HRQoL questionnaires; and (3) priorities of prevalent symptoms in HRQoL assessment.
Methods
In the cross-sectional population-based survey study, Dutch GIST patients completed items from the EORTC QLQ-C30 and Symptom-Based Questionnaire (SBQ). In the forum study, machine learning algorithms were used to extract TKI side-effects from English messages on an international online forum for GIST patients. Prevalence of symptoms related to imatinib treatment in both sources was calculated and exploratively compared.
Results
Fatigue and muscle pain or cramps were reported most frequently. Seven out of 10 most reported symptoms (i.e. fatigue, muscle pain or cramps, facial swelling, joint pain, skin problems, diarrhoea, and oedema) overlapped between the two sources. Alopecia was frequently mentioned on the forum, but not in the survey. Four out of 10 most reported symptoms on the online forum are covered by the EORTC QLQ-C30. The EORTC-SBQ and EORTC Item Library cover 9 and 10 symptoms, respectively.
Conclusion
This first overview of patient-reported imatinib-related symptoms from two data sources helps to determine coverage of items in existing questionnaires, and prioritize HRQoL issues. Combining cancer-generic instruments with treatment-specific item lists will improve future HRQoL assessment in care and research in GIST patients using TKI.
Pazopanib is a tyrosine kinase inhibitor indicated for the treatment of renal cell carcinoma and soft tissue sarcoma. Despite the high inter-patient variability in pharmacokinetic exposure, pazopanib ...is administered at a fixed dose of 800 mg once daily (QD). Pharmacokinetic exposure is linked to both efficacy and toxicity. In this case report, we illustrate the value of therapeutic drug monitoring by describing two patients with adequate pazopanib trough concentrations (C
) at an eight times lower than standard dose.
Patient A is a 69-year-old woman with metastatic leiomyosarcoma who had significant toxicities and a high C
on the standard dose. While dose reductions to 200 mg QD and later 200 mg every other day were made, pazopanib C
remained above the efficacy threshold. Patient B is a 50-year-old male with metastatic angiosarcoma and a history of Gilbert syndrome. Pazopanib treatment was initiated at the standard dose of 800 mg QD, but was reduced to 200 mg QD 1-week-on - 1-week-off due to total bilirubin elevation. Pazopanib C
was adequate in this patient as well.
It could be valuable to measure pazopanib levels in case of dose reductions due to toxicity, as exposure could still be adequate at considerably lower than standard doses.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of gastrointestinal stromal tumors (GISTs), resulting in a substantial gain in median overall survival. ...Subsequently, health-related quality of life (HRQoL) has become more relevant. Here, we systematically review the available literature on HRQoL issues and side effects of different TKIs registered for the treatment of GIST.
A search through five databases was performed. Full reports in English describing HRQoL outcomes and/or side effects in GIST patients on TKI therapy were included.
A total of 104 papers were included; 13 studies addressed HRQoL, and 96 studies investigated adverse events. HRQoL in patients treated with imatinib, regorafenib, and ripretinib remained stable, whereas most sunitinib-treated patients reported a decrease in HRQoL. Severe fatigue and fear of recurrence or progression were specifically assessed as HRQoL issues and had a negative impact on overall HRQoL as well as psychological and physical well-being. The majority of studies focused on physician-reported side effects. Nearly all GIST patients treated with a TKI experienced at least one adverse event, mostly mild to moderate.
Despite the fact that almost all patients treated with a TKI experienced side effects, this did not seem to affect overall HRQoL during TKI therapy. In daily practice, it are the side effects that hamper a patient's HRQoL resulting in treatment adjustments, suggesting that the reported side effects were underestimated by physicians, or the measures used to assess HRQoL do not capture all relevant issues that determine a GIST patient's HRQoL.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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