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BackgroundIn the past years, there has been a notable increase in interest regarding targeted alpha therapy using Ac-225, driven by the observed promising clinical anti-tumor effects. As the production and technology has advanced, the availability of Ac-225 is expected to increase in the near future, making the treatment available to patients worldwide.Main bodyAc-225 can be labelled to different biological vectors, whereby the success of developing a radiopharmaceutical depends heavily on the labelling conditions, purity of the radionuclide source, chelator, and type of quenchers used to avoid radiolysis. Multiple (methodological) challenges need to be overcome when working with Ac-225; as alpha-emission detection is time consuming and highly geometry dependent, a gamma co-emission is used, but has to be in equilibrium with the mother-nuclide. Because of the high impact of alpha emitters in vivo it is highly recommended to cross-calibrate the Ac-225 measurements for used quality control (QC) techniques (radio-TLC, HPLC, HP-Ge detector, and gamma counter). More strict health physics regulations apply, as Ac-225 has a high toxicity, thereby limiting practical handling and quantities used for QC analysis.ConclusionThis overview focuses specifically on the practical and methodological challenges when working with Ac-225 labelled radiopharmaceuticals, and underlines the required infrastructure and (detection) methods for the (pre-)clinical application.

BACKGROUND: Cabazitaxel frequently causes severe neutropenia. A higher cabazitaxel systemic exposure is related to a lower nadir absolute neutrophil count (ANC).OBJECTIVE: To describe the effect of cabazitaxel systemic exposure on ANC by a population pharmacokinetic/pharmacodynamic (POP-PK/PD) model, and to identify patients at risk of severe neutropenia early in their treatment course using a PK threshold.DESIGN, SETTING, AND PARTICIPANTS: Data from five clinical studies were pooled to develop a POP-PK/PD model using NONMEM, linking both patient characteristics and cabazitaxel systemic exposure directly to ANC.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A PK threshold, predictive of severe neutropenia (grade ≥3), was determined using a receiver operating characteristic curve.RESULTS AND LIMITATIONS: Ninety-six patients were included with a total of 1726 PK samples and 1081 ANCs. The POP-PK/PD model described both cabazitaxel PK and ANC accurately. A cabazitaxel plasma concentration of >4.96 ng/ml at 6 h after the start of infusion was found to be predictive of severe neutropenia, with a sensitivity of 76% and a specificity of 65%.CONCLUSIONS: Early cabazitaxel plasma levels are predictive of severe neutropenia. Implementation of the proposed PK threshold results in early identification of almost 76% of all severe neutropenias. If prospectively validated, patients at risk could benefit from prophylactic administration of granulocyte colony stimulating factors, preventing severe neutropenia in an early phase of treatment. Implementation of this threshold permits a less restricted use of the 25 mg/m2 dose, potentially increasing the therapeutic benefit.PATIENT SUMMARY: Treatment with cabazitaxel chemotherapy often causes neutropenia, leading to susceptibility to infections, which might be life threatening. We found that a systemic cabazitaxel concentration above 4.96 ng/ml 6 h after the start of infusion is predictive

Introduction: A genetic variant explaining a part of the exposure of many kinase inhibitors (KIs) is the single nucleotide polymorphism (SNP) CYP3A4*22, resulting in less CYP3A4 enzyme activity. The primary aim of this study was to investigate if the systemic exposure is non-inferior after a dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to patients without this SNP (i.e., wildtype patients) receiving the standard dose. Methods: In this multicenter, prospective, non-inferiority study, patients were screened for the presence of CYP3A4*22. Patients with the CYP3A4*22 SNP received a 20–33% dose reduction. At steady state, a pharmacokinetic (PK) analysis was performed and compared to the PK results from wildtype patients treated with the registered dose using a two-stage individual patient data meta-analysis approach. Results: In total, 207 patients were included in the final analysis. The CYP3A4*22 SNP was found in 16% of the patients in the final analysis (n = 34). Most of the included patients received imatinib (37%) or pazopanib (22%) treatment. The overall geometric mean ratio (GMR) comparing the exposure of the CYP3A4*22 carriers to the exposure of the wildtype CYP3A4 patients was 0.89 (90% confidence interval: 0.77–1.03). Conclusion: Non-inferiority could not be proven for dose reduction of KIs metabolized by CYP3A4 in CYP3A4*22 carriers compared to the registered dose in wildtype patients. Therefore, an up-front dose reduction based upon the CYP3A4*22 SNP for all KIs does not seem an eligible new way of personalized therapy. Trial Registration: International Clinical Trials Registry Platform Search Portal; number NL7514; registered 11/02/2019.

BACKGROUND: Floxuridine's high hepatic extraction ratio and short elimination half-life allows maximum liver exposure with minimal systemic side-effects. This study attempts to quantify the systemic exposure of floxuridine.METHODS: Patients undergoing continuous hepatic arterial infusion pump (HAIP) floxuridine after resection of colorectal liver metastases (CRLM) in two centres underwent six cycles of floxuridine at start dose 0.12 mg/kg/day. No concomitant systemic chemotherapy was administered. Peripheral venous blood samples were drawn during the first two cycles: pre-dose (only in the second cycle), 30 min, 1 h, 2 h, 7 h, and 15 days after floxuridine infusion. Foxuridine concentration in the residual pump reservoir was measured on day 15 of both cycles. A floxuridine assay with a lower boundary of detection of 0.250 ng/mL was developed.RESULTS: 265 blood samples were collected in the 25 patient included in this study. Floxuridine was mostly measurable at day 7 and day 15 (86 % and 88 % of patients respectively). The median dose corrected concentrations were 0.607 ng/mL [IQR: 0.472-0.747] for cycle 1 day 7, 0.579 ng/mL [IQR: 0.470-0.693] for cycle 1 day 15, 0.646 ng/mL [IQR: 0.463-0.8546] for cycle 2 day 7, and 0.534 ng/mL [IQR: 0.4257-0.7075] for cycle 2 day 15. One patient had remarkably high floxuridine concentrations reaching up to 44 ng/mL during the second cycle, without a clear explanation. The floxuridine concentration in the pump decreased by 14.7 % (range 0.5 %-37.8 %) over a period of 15 days (n = 18).CONCLUSION: Overall, negligible systemic concentrations of floxuridine were detected. However, remarkably increased levels were detected in one patient. Floxuridine concentration in the pump decreases over time.

BACKGROUND: Tamoxifen is important in the adjuvant treatment of breast cancer. A plasma concentration of the active metabolite endoxifen of > 16 nM is associated with a lower risk of breast cancer-recurrence. Since inter-individual variability is high and > 20 % of patients do not reach endoxifen levels > 16 nM with the standard dose tamoxifen, therapeutic drug monitoring is advised. However, ideally, the correct tamoxifen dose should be known prior to start of therapy. Our aim is to develop a population pharmacokinetic (POP-PK) model incorporating a continuous CYP2D6 activity scale to support model informed precision dosing (MIPD) of tamoxifen to determine the optimal tamoxifen starting dose.METHODS: Data from eight different clinical studies were pooled (539 patients, 3661 samples) and used to develop a POP-PK model. In this model, CYP2D6 activity per allele was estimated on a continuous scale. After inclusion of covariates, the model was subsequently validated using an independent external dataset (378 patients). Thereafter, dosing cut-off values for MIPD were determined.RESULTS: A joint tamoxifen/endoxifen POP-PK model was developed describing the endoxifen formation rate. Using a continuous CYP2D6 activity scale, variability in predicting endoxifen levels was decreased by 37 % compared to using standard CYP2D6 genotype predicted phenotyping. After external validation and determination of dosing cut-off points, MIPD could reduce the proportion of patients with subtherapeutic endoxifen levels at from 22.1 % toward 4.8 %.CONCLUSION: Implementing MIPD from the start of tamoxifen treatment with this POP-PK model can reduce the proportion of patients with subtherapeutic endoxifen levels at steady-state to less than 5 %.

Peptide receptor radionuclide therapy (PRRT), a form of internal targeted radiation treatment using [177Lu]Lu [DOTA0-Tyr3]octreotate, is used to treat patients with metastasized neuroendocrine tumors (NETs). Even though PRRT is now the second line of treatment for patients with metastasized NETs, the majority of patients will not be cured by the treatment. PRRT functions by inducing DNA damage upon radioactive decay and inhibition of DNA damage repair proteins could therefore be used as a strategy to potentiate PRRT. Previous work has shown promising results on the combination of PRRT with the PARP inhibitor olaparib in cell lines and mice and we have been taken the next step for further in vivo validation using two different xenografted mouse models. We observed that this combination therapy resulted in increased therapeutic efficacy only in one model and not the other. Overall, our findings indicate a tumor-type dependent anti-tumor response to the combination of PRRT and olaparib. These data emphasize the unmet need for the molecular stratification of tumors to predetermine the potential clinical value of combining PARP inhibition with PRRT.