Intra-tumoral pharmacokinetics of pazopanib in combination with radiotherapy in patients with non-metastatic soft-tissue sarcoma

There is a lack of understanding whether plasma levels of anticancer drugs (such as pazopanib) correlate with intra-tumoral levels and whether the plasma compartment is the best surrogate for pharmacokinetic and pharmacodynamic evaluation. Therefore, we aimed to quantify pazopanib concentrations in tumor tissue, to assess the correlation between tumor concentrations and plasma concentrations and between tumor concentrations and efficacy. In this clinical trial, non-metastatic STS patients were treated with neo-adjuvant concurrent radiotherapy and pazopanib. Plasma samples and tumor biopsies were collected, and pazopanib concentrations were measured using liquid chromatography-tandem mass spectrometry. Twenty-four evaluable patients were included. The median pazopanib tumor concentration was 19.2 µg/g (range 0.149–200 µg/g). A modest correlation was found between tumor concentrations and plasma levels of pazopanib (ρ = 0.41, p = 0.049). No correlation was found between tumor concentrations and percentage of viable tumor cells (p > 0.05); however, a trend towards less viable tumor cells in patients with high pazopanib concentrations in tumor tissue was observed in a categorical analysis. Possible explanations for the lack of correlation might be heterogeneity of the tumors and timing of the biopsy procedure

Clinical Pharmacology of Kinase Inhibitors in Oncology : Personalized and Optimzed Dosing

Kinase inhibitors are an important category of molecularly targeted therapies used for cancer. Verheijen’s doctoral thesis describes several clinical pharmacological studies to optimize and personalize the treatment of cancer with kinase inhibitors, using pharmacokinetics, molecular imaging and biomarkers such as circulating tumor DNA. Most novel kinase inhibitors used at a fixed dose (i.e. a “one size fits all” approach).This thesis shows that clinical application of these agents can be optimized and personalized. For example, dosing of the kinase inhibitor pazopanib could be individualized based on measured plasma concentrations, also known as therapeutic drug monitoring. First bioanalytical methods were developed and validated that enable measurement of pazopanib in patient samples. Then exposure-response analyses were performed to investigate the relation between plasma concentrations and clinical outcomes. Finally, a prospective trial in cancer patients was conducted to demonstrate the safety and feasibility of individualized pazopanib dosing. The case of pazopanib illustrates that individualized dosing, through therapeutic drug monitoring, could be used to optimized and personalized the treatment of cancer with kinase inhibitors

Clinical Pharmacokinetics and Pharmacodynamics of Pazopanib : Towards Optimized Dosing

Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors. Studies have demonstrated relationships between systemic exposure to pazopanib and toxicity, such as hypertension. Furthermore, a strong relationship between pazopanib trough level ≥20 mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800 mg, approximately 20% of patients do not reach this threshold and may be at risk of suboptimal treatment. As a result of this, clinical trials have explored individualized pazopanib dosing, which demonstrate the safety and feasibility of individualized pazopanib dosing based on trough levels. In summary, we provide an overview of the complex pharmacokinetic and pharmacodynamic profiles of pazopanib and, based on the available data, we propose optimized dosing strategies

Clinical Pharmacokinetics and Pharmacodynamics of Pazopanib : Towards Optimized Dosing

Pazopanib is an inhibitor of the vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor and stem cell receptor c-Kit, and has been approved for the treatment of renal cell carcinoma and soft tissue sarcoma. The pharmacokinetics of pazopanib are complex and are characterized by pH-dependent solubility, large interpatient variability and low, non-linear and time-dependent bioavailability. Exposure to pazopanib is increased by both food and coadministration of ketoconazole, but drastically reduced by proton pump inhibitors. Studies have demonstrated relationships between systemic exposure to pazopanib and toxicity, such as hypertension. Furthermore, a strong relationship between pazopanib trough level ≥20 mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800 mg, approximately 20% of patients do not reach this threshold and may be at risk of suboptimal treatment. As a result of this, clinical trials have explored individualized pazopanib dosing, which demonstrate the safety and feasibility of individualized pazopanib dosing based on trough levels. In summary, we provide an overview of the complex pharmacokinetic and pharmacodynamic profiles of pazopanib and, based on the available data, we propose optimized dosing strategies

Practical Recommendations for Therapeutic Drug Monitoring of Kinase Inhibitors in Oncology

Despite the fact that pharmacokinetic exposure of kinase inhibitors (KIs) is highly variable and clear relationships exist between exposure and treatment outcomes, fixed dosing is still standard practice. This review aims to summarize the available clinical pharmacokinetic and pharmacodynamic data into practical guidelines for individualized dosing of KIs through therapeutic drug monitoring (TDM). Additionally, we provide an overview of prospective TDM trials and discuss the future steps needed for further implementation of TDM of KIs

Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients : opportunities for dose optimization

BACKGROUND: Pazopanib is an angiogenesis inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Post hoc analysis of a clinical trial demonstrated a relationship between pazopanib trough concentrations (Cmin) and treatment efficacy. The aim of this study was to explore the pharmacokinetics and exposure-survival relationships of pazopanib in a real-world patient cohort. PATIENTS AND METHODS: Renal cell cancer and soft tissue sarcoma patients who had at least one pazopanib plasma concentration available were included. Using calculated Cminvalues and a threshold of > 20 mg/L, univariate and multivariate exposure-survival analyses were performed. RESULTS: Sixty-one patients were included, of which 16.4% were underexposed (mean Cmin  20 mg/L was related to longer progression free survival in renal cell cancer patients (34.1 vs. 12.5 weeks, n = 35, p = 0.027) and the overall population (25.0 vs. 8.8 weeks, n = 61, p = 0.012), but not in the sarcoma subgroup (18.7 vs. 8.8 weeks, n = 26, p = 0.142). In multivariate analysis Cmin > 20 mg/L was associated with hazard ratios of 0.25 (p = 0.021) in renal cancer, 0.12 (p = 0.011) in sarcoma and 0.38 (p = 0.017) in a pooled analysis. CONCLUSION: This study confirms that pazopanib Cmin > 20 mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. Cminmonitoring of pazopanib can help identify patients with low Cminfor whom individualized treatment at a higher dose may be appropriate

Pharmacokinetic Optimization of Everolimus Dosing in Oncology : A Randomized Crossover Trial

BACKGROUND: The mammalian target of rapamycin (mTOR) inhibitor everolimus is used in the treatment of breast cancer, neuroendocrine tumors, and renal cancer. The approved 10 mg once-daily dose is associated with considerable adverse effects and it has been suggested that these are associated with the maximum concentration (Cmax) of everolimus. Twice-daily dosing might be an alternative strategy with improved tolerability; however, a direct pharmacokinetic comparison of 10 mg once-daily with 5 mg twice-daily dosing is lacking. METHODS: We performed a prospective, randomized, pharmacokinetic, crossover trial comparing everolimus 10 mg once daily with 5 mg twice daily. Patients received the first dose schedule for 2 weeks and then switched to the alternative regimen for 2 weeks. Pharmacokinetic sampling was performed on days 14 and 28. RESULTS: Eleven patients were included in the study, of whom 10 were evaluable for pharmacokinetic analysis. On the 10 mg once-daily schedule, Cmax, minimum concentration (Cmin), and area under the concentration-time curve from time zero to 24 h (AUC24) were 61.5 ng/mL [mean percentage coefficient of variation (CV%) 29.6], 9.6 ng/mL (CV% 35.0), and 435 ng h/mL (CV% 28.1), respectively. Switching to the 5 mg twice-daily schedule resulted in a reduction of Cmaxto 40.3 ng/mL (CV% 46.6) (p = 0.013), while maintaining AUC24at 436 ng h/mL (CV% 34.8) (p = 0.952). Cminincreased to 13.7 ng/mL (CV% 53.9) (p = 0.018). The overall reduction in Cmaxwas 21.2 ng/mL, or 32.7%. The Cmax/Cminratio was reduced from 6.44 (CV% 36.2) to 3.18 (CV% 35.5) (p < 0.001). CONCLUSIONS: We demonstrated that switching from a once-daily to a twice-daily everolimus dose schedule reduces Cmaxwithout negatively impacting Cminor AUC24. These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy. REGISTRATION: This trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908)

Therapeutic Drug Monitoring of Oral Anti-Hormonal Drugs in Oncology

Oral anti-hormonal drugs are essential in the treatment of breast and prostate cancer. It is well known that the interpatient variability in pharmacokinetic exposure is high for these agents and exposure-response relationships exist for many oral anti-hormonal drugs. Yet, they are still administered at fixed doses. This could lead to underdosing and thus suboptimal efficacy in some patients, while other patients could be overdosed resulting in unnecessary side effects. Therapeutic drug monitoring (TDM), individualized dosing based on measured blood concentrations of the drug, could therefore be a valid option to further optimize treatment. In this review, we provide an overview of relevant clinical pharmacokinetic and pharmacodynamic characteristics of oral anti-hormonal drugs in oncology and translate these into practical guidelines for TDM. For some agents, TDM targets are not well established yet and as a reference the median pharmacokinetic exposure could be targeted (exemestane: minimum plasma concentration (Cmin) 4.1 ng/mL and enzalutamide: Cmin 11.4 mg/L). However, for most drugs, exposure-efficacy analyses could be translated into specific targets (abiraterone: Cmin 8.4 ng/mL, anastrozole: Cmin 34.2 ng/mL, and letrozole: Cmin 85.6 ng/mL). Moreover, prospective clinical trials have shown TDM to be feasible for tamoxifen, for which the exposure-efficacy threshold of its active metabolite endoxifen is 5.97 ng/mL. Based on the available data, we therefore conclude that individualized dosing based on drug concentrations is feasible and promising for oral anti-hormonal drugs and should be developed further and implemented into clinical practice