Remy B. Verheijen

Individualized pazopanib dosing : A prospective feasibility study in cancer patients

Purpose: Pazopanib is a tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Retrospective analyses have shown that an increased median progression-free survival and tumor shrinkage appear in patients with higher plasma trough levels (Cmin). Therefore, patients with low Cmin might benefit from pharmacokinetically guided individualized dosing. Experimental Design: We conducted a prospective multicenter trial in 30 patients with advanced solid tumors. Pazopanib Cmin was measured weekly by LC-MS/MS. At weeks 3, 5, and 7, the pazopanib dose was increased if the measured Cmin was <20 mg/L and toxicity was <grade 3. Results: In total, 17 patients had at least one Cmin <20 mg/L at weeks 3, 5, and 7. Of these, 10 were successfully treated with a pharmacokinetically guided dose escalation, leading to daily dosages ranging from 1,000 to 1,800 mg. Cmin in these patients increased significantly from 13.2 (38.0%) mg/L [mean (CV%)] to 22.9 mg/L (44.9%). Thirteen patients had all Cmin levels ≥20.0 mg/L. Of these, 9 patients with a high Cmin of 51.3 mg/L (45.1%) experienced ≥grade 3 toxicity and subsequently required a dose reduction to 600 or 400 mg daily, yet in these patients, Cmin remained above the threshold at 28.2 mg/L (25.3%). Conclusions: A pharmacokinetically guided individualized dosing algorithm was successfully applied and evaluated. The dosing algorithm led to patients being treated at dosages ranging from 400 to 1,800 mg daily. Further studies are needed to show a benefit of individualized dosing on clinical outcomes, such as progression-free survival. Clin Cancer Res; 22(23); 5738–46. ©2016 AACR. See related commentary by Ornstein and Rini, p. 5626

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.

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 ≥20xa0mg/L and both tumor shrinkage and progression-free survival has been established. At the currently approved daily dose of 800xa0mg, 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.

Imatinib Pharmacokinetics in a Large Observational Cohort of Gastrointestinal Stromal Tumour Patients

BackgroundLow trough imatinib concentration (Cmin) values have been associated with poor clinical outcomes in gastrointestinal stromal tumour (GIST) patients. This study describes the pharmacokinetics of imatinib in a large cohort of GIST patients in routine clinical care.MethodsAn observational study was performed in imatinib-treated GIST patients. Patient and tumour characteristics were derived from the Dutch GIST Registry and medical records. Imatinib concentrations were measured by liquid chromatography with tandem mass spectrometry. The analyses included the occurrence of a low imatinib Cmin (<1000xa0µg/L), the change in the Cmin over time and the correlation between exposure and response.ResultsIn total, 421 plasma samples were available from 108 GIST patients. Most patients (79.6xa0%) received an imatinib dose of 400xa0mg. The inter- and intrapatient variabilities in Cmin were 54 and 23xa0%, respectively. In the first steady-state sample, 44.4xa0% of patients presented with Cmin valuesxa0<1000xa0µg/L; 32.4xa0% of patients had valuesxa0<1000xa0µg/L in >75xa0% of their samples. Only 33.3xa0% of patients had Cmin values ≥1000xa0µg/L in all measured samples. No decrease in Cmin over time was found (Pxa0>xa00.05). Fifty-seven (91.9xa0%) of 62 palliative-treated patients had a tumour response (median Cmin 1271xa0µg/L). Five palliative patients (8.1xa0%) did not respond (median Cmin 920xa0µg/L). Given the limited number of non-responders in this cohort, no statistically significant association with clinical benefit could be demonstrated.ConclusionIn routine clinical care, one third of GIST patients are systematically underexposed with a fixed dose of imatinib. Prospective clinical studies are needed to investigate the value of Cmin-guided imatinib dosing in GIST patients.

Development and clinical validation of an LC–MS/MS method for the quantification of pazopanib in DBS

BACKGROUNDnPazopanib is approved for the treatment of renal cell carcinoma and soft tissue sarcoma. Analyses show increased benefit in patients with plasma trough concentrations ≥20.5 μg/ml compared with patients with lower concentrations.nnnMETHODS & RESULTSnWe developed a DBS assay as a patient friendly approach to guide treatment. The method was validated according to US FDA and EMA guidelines and European Bioanalysis Forum recommendations. Influence of spot homogeneity, spot volume and hematocrit were shown to be within acceptable limits. Analysis of paired clinical samples showed a good correlation between the measured plasma and DBS concentrations (R(2) of 0.872).nnnCONCLUSIONnThe method was successfully validated, applied to paired clinical samples and is suitable for application to therapeutic drug monitoring of pazopanib.

Molecular Imaging of ABCB1 and ABCG2 Inhibition at the Human Blood–Brain Barrier Using Elacridar and 11C-Erlotinib PET

Transporters such as ABCB1 and ABCG2 limit the exposure of several anticancer drugs to the brain, leading to suboptimal treatment in the central nervous system. The purpose of this study was to investigate the effects of the ABCB1 and ABCG2 inhibitor elacridar on brain uptake using 11C-erlotinib PET. Methods: Elacridar and cold erlotinib were administered orally to wild-type (WT) and Abcb1a/b;Abcg2 knockout mice. In addition, brain uptake was measured using 11C-erlotinib imaging and ex vivo scintillation counting in knockout and WT mice. Six patients with advanced solid tumors underwent 11C-erlotinib PET scans before and after a 1,000-mg dose of elacridar. 11C-erlotinib brain uptake was quantified by pharmacokinetic modeling using volume of distribution (VT) as the outcome parameter. In addition, 15O-H2O scans to measure cerebral blood flow were acquired before each 11C-erlotinib scan. Results: Brain uptake of 11C-erlotinib was 2.6-fold higher in Abcb1a/b;Abcg2 knockout mice than in WT mice, measured as percentage injected dose per gram of tissue (P = 0.01). In WT mice, the addition of elacridar (at systemic plasma concentrations of ≥200 ng/mL) resulted in an increased brain concentration of erlotinib, without affecting erlotinib plasma concentration. In patients, the VT of 11C-erlotinib did not increase after intake of elacridar (0.213 ± 0.12 vs. 0.205 ± 0.07, P = 0.91). 15O-H2O PET showed no significant changes in cerebral blood flow. Elacridar exposure in patients was 401 ± 154 ng/mL. No increase in VT with increased elacridar plasma exposure was found over the 271–619 ng/mL range. Conclusion: When Abcb1 and Abcg2 were disrupted in mice, brain uptake of 11C-erlotinib increased both at a tracer dose and at a pharmacologic dose. In patients, brain uptake of 11C-erlotinib was not higher after administration of elacridar. The more pronounced role that ABCG2 appears to play at the human blood–brain barrier and the lower potency of elacridar to inhibit ABCG2 may be an explanation of these interspecies differences.

Clinical pharmacokinetics of an amorphous solid dispersion tablet of elacridar

Elacridar is an inhibitor of the permeability glycoprotein (P-gp) and the breast cancer resistance protein (BCRP) and is a promising absorption enhancer of drugs that are substrates of these drug-efflux transporters. However, elacridar is practically insoluble in water, resulting in low bioavailability which currently limits its clinical application. We evaluated the in vitro dissolution and clinical pharmacokinetics of a novel amorphous solid dispersion (ASD) tablet containing elacridar. The dissolution from ASD tablets was compared to that from a crystalline powder mixture in a USP type II dissolution apparatus. The pharmacokinetics of the ASD tablet were evaluated in an exploratory clinical study at oral doses of 25, 250, or 1000xa0mg in 12 healthy volunteers. A target Cmax was set at ≥xa0200xa0ng/mL based on previous clinical data. The in vitro dissolution from the ASD tablet was 16.9xa0±xa03.7 times higher compared to that from a crystalline powder mixture. Cmax and AUC0-∞ increased linearly with dose over the explored range. The target Cmax of ≥xa0200xa0ng/mL was achieved at the 1000-mg dose level. At this dose, the Cmax and AUC0-∞ were 326xa0±xa067xa0ng/mL and 13.4xa0±xa08.6xa0·xa0103xa0ngxa0·xa0h/mL, respectively. In summary, the ASD tablet was well tolerated, resulted in relevant pharmacokinetic exposure, and can be used for proof-of-concept clinical studies.

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 monitoringxa0(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 axa0reference the median pharmacokineticxa0exposure could be targeted (exemestane: minimum plasma concentrationxa0(Cmin) 4.1xa0ng/mL and enzalutamide: Cmin 11.4xa0mg/L). However, for most drugs, exposure–efficacy analyses could be translated into specific targets (abiraterone: Cmin 8.4xa0ng/mL, anastrozole: Cmin 34.2xa0ng/mL, and letrozole: Cmin 85.6xa0ng/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 5.97xa0ng/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.

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

BackgroundThe mammalian target of rapamycin (mTOR) inhibitor everolimus is used in the treatment of breast cancer, neuroendocrine tumors, and renal cancer. The approved 10xa0mg 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 10xa0mg once-daily with 5 mg twice-daily dosing is lacking.MethodsWe 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 2xa0weeks and then switched to the alternative regimen for 2xa0weeks. Pharmacokinetic sampling was performed on days 14 and 28.ResultsEleven 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 24xa0h (AUC24) were 61.5xa0ng/mL [mean percentage coefficient of variation (CV%) 29.6], 9.6 ng/mL (CV%xa035.0), and 435 ngxa0h/mL (CV% 28.1), respectively. Switching to the 5xa0mg twice-daily schedule resulted in a reduction of Cmax to 40.3xa0ng/mL (CV% 46.6) (pxa0=xa00.013), while maintaining AUC24 at 436 ngxa0h/mL (CV%xa034.8) (pxa0=xa00.952). Cmin increased to 13.7 ng/mL (CV%xa053.9) (pxa0=xa00.018). The overall reduction in Cmax was 21.2xa0ng/mL, or 32.7%. The Cmax/Cmin ratio was reduced from 6.44 (CV%xa036.2) to 3.18 (CV%xa035.5) (pxa0<xa00.001).ConclusionsWe demonstrated that switching from a once-daily to a twice-daily everolimus dose schedule reduces Cmax without negatively impacting Cmin or AUC24. These results merit further investigation of the twice-daily schedule in an effort to reduce everolimus toxicity while maintaining treatment efficacy.RegistrationThis trial was registered in the EurdaCT database (2014-004833-25) and the Netherlands Trial Registry (NTR4908).

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

BackgroundPazopanib 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 methodsRenal cell cancer and soft tissue sarcoma patients who had at least one pazopanib plasma concentration available were included. Using calculated Cmin values and a threshold of >u200920xa0mg/L, univariate and multivariate exposure-survival analyses were performed.ResultsSixty-one patients were included, of which 16.4% were underexposed (mean Cminu2009<u200920xa0mg/L) using the 800xa0mg fixed-dosed schedule. In univariate analysis Cminu2009>u200920xa0mg/L was related to longer progression free survival in renal cell cancer patients (34.1 vs. 12.5xa0weeks, nu2009=u200935, pu2009=u20090.027) and the overall population (25.0 vs. 8.8xa0weeks, nu2009=u200961, pu2009=u20090.012), but not in the sarcoma subgroup (18.7 vs. 8.8xa0weeks, nu2009=u200926, pu2009=u20090.142). In multivariate analysis Cminu2009>u200920xa0mg/L was associated with hazard ratios of 0.25 (pu2009=u20090.021) in renal cancer, 0.12 (pu2009=u20090.011) in sarcoma and 0.38 (pu2009=u20090.017) in a pooled analysis.ConclusionThis study confirms that pazopanib Cminu2009>u200920xa0mg/L relates to better progression free survival in renal cancer and points towards a similar trend in sarcoma patients. Cmin monitoring of pazopanib can help identify patients with low Cmin for whom individualized treatment at a higher dose may be appropriate.