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Aims: Pharmacokinetics of tacrolimus after sublingual administration is not characterized in paediatric liver transplant patients. Therefore, we aimed to develop a population pharmacokinetic model of sublingually administered tacrolimus in patients who cannot swallow the capsules due to their age, sedation status and/or mechanical ventilation during the first weeks post‐transplantation. Methods: Demographic, clinical and pharmacological variables, including tacrolimus whole blood concentrations obtained from therapeutic drug monitoring and data from dense‐sampling pharmacokinetic profiles, were recorded in 26 paediatric patients with biliary atresia who underwent liver transplantation between 2016 and 2021. Population pharmacokinetic analysis was performed with NONMEM v7.4. Results: Disposition of tacrolimus was best characterized by a 2‐compartment model with clearance achieving half of the maximum elimination capacity (CLMAX = 4.1 L/h) at 4.6 days post‐transplantation (T50). Compared to sedated patients, nonsedated status showed an increased first‐order absorption rate constant (1.1 vs. 0.1 h−1) and a 24% reduction in bioavailability (FNS) at 14 days post‐transplant. The model was able to explain the oral absorption pattern in nonsedated patients as the result of gut bioavailability (0.9) and hepatic extraction ratio, with the latter being responsible for first‐pass effects. Estimates of interindividual variability remained moderate (25.9% for the gut bioavailability) to high (79.8% for the apparent volume of distribution of the central compartment, and 101% for T50). Conclusion: A population pharmacokinetic model of sublingually administered tacrolimus in paediatric patients was developed to characterize different absorption mechanisms. Once the model is externally validated, the effect of post‐transplant time on clearance and the sedation status may be considered in routine dosing management. [ABSTRACT FROM AUTHOR]

Aims: We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure. Methods: A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75–100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose‐intensified docetaxel (300–350 mg/m2). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence. Results: Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel‐associated adverse events were significantly higher than in patients free of toxicity (P <.05). Fatigue and decrease in haemoglobin and haematocrit levels were related to docetaxel AUC and Cmax and pain to AUC. AUC and Cmax >4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour recurrence. Conclusion: We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients. [ABSTRACT FROM AUTHOR]

Aims: High‐dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity. Methods: Anonymized, de‐identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non‐profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite. Results: A total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three‐compartment model adequately fitted the data. Time‐dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose‐normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence. Conclusion: We developed a population pharmacometric model that considers weight, albumin and time‐dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination. [ABSTRACT FROM AUTHOR]

Fundoscopy is the standard method for diagnosis and follow‐up of intraocular retinoblastoma, but it is sometimes insufficient to discern whether tumors are inactivated following treatments. In this work, we hypothesized that the amount of conserved nuclear DNA sequences in the cell‐free DNA (cfDNA) fraction of the aqueous humor (AH) might complement fundoscopy for retinoblastoma follow‐up. To address our hypothesis, we developed highly sensitive droplet digital polymerase chain reaction (ddPCR) methods to quantify highly conserved DNA sequences of nucleus‐encoded genes (GAPDH and B4GALNT1) and of a mitochondrial gene, MT‐ATP6. We obtained AH samples during intravitreal treatments. We analyzed 42 AH samples from 25 patients with intraocular retinoblastoma and 11 AH from controls (non‐cancer patients). According to clinical criteria, we grouped patients as having progression‐free or progressive retinoblastoma. cfDNA concentration in the AH was similar in both retinoblastoma groups. Copy counts for nucleus‐derived sequences of GAPDH and B4GALNT1 were significantly higher in the AH from patients with progressive disease, compared to the AH from progression‐free patients and control non‐cancer patients. The presence of mitochondrial DNA in the AH explained that both retinoblastoma groups had similar cfDNA concentration in AH. The optimal cut‐off point for discriminating between progressive and progression‐free retinoblastomas was 108 GAPDH copies per reaction. Among patients having serial AH samples analyzed during their intravitreal chemotherapy, GAPDH copies were high and decreased below the cut‐off point in those patients responding to chemotherapy. In contrast, one non‐responder patient remained with values above the cut‐off during follow‐up, until enucleation. We conclude that the measurement of conserved nuclear gene sequences in AH allows follow‐up of intraocular retinoblastoma during intravitreal treatment. The method is applicable to all patients and could be relevant for those in which fundoscopy evaluation is inconclusive. [ABSTRACT FROM AUTHOR]

The microenvironment of retinoblastoma, the solid malignancy of the developing retina, is immunosuppressive. To study the interactions between tumor‐associated microglia/macrophages (TAMs) and tumor cells in retinoblastomas, we analyzed immunohistochemistry markers in 23 patient samples and characterized 105 secreted cytokines of 11 retinoblastoma cell models in culture. We detected profuse infiltration of CD163+ protumoral M2‐like polarized TAMs in eyes enucleated due to cancer progression. Previous treatment of patients increased the number of TAMs but did not affect M2‐like polarization. M2‐like microglia/macrophages were almost absent in five eyes obtained from children enucleated due to nontumoral causes. CD8+ tumor‐infiltrating lymphocytes (TILs) were moderately abundant in tumor eyes and very scarce in nontumoral ones. The expression of the immune checkpoint molecule PD‐L1 was absent in 95% of the tumor samples, which is concordant with the finding of FOXP3+ Tregs infiltrating tumors. We confirmed the pathology results using single‐cell transcriptome analysis of one tumor. We identified the cytokines extracellular matrix metalloproteinase inducer (EMMPRIN) and macrophage migration inhibitory factor (MIF), both with reported immunosuppressive activity, secreted at high levels in retinoblastoma primary cell cultures. Gene expression analysis of a large retinoblastoma cohort and single‐cell transcriptome analysis confirmed that MIF and EMMPRIN were significantly upregulated in retinoblastomas, which led us to quantify both proteins by immunoassays in liquid biopsies (aqueous humor obtained from more than 20 retinoblastoma patients). We found a significant increase in the concentration of MIF and EMMPRIN in cancer patients, compared to 12 noncancer ones. Finally, we showed that macrophages derived from peripheral blood mononuclear cells increased the expression of markers of M2‐like polarization upon exposure to retinoblastoma‐conditioned medium or recombinant MIF. Overall, our findings suggest that retinoblastoma cell secretions induce the protumoral phenotype of this tumor. Our results might have clinical impact in the fields of biomarkers and treatment. © 2022 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Growing interest in the clinical use of cannabidiol (CBD) as adjuvant therapy for pediatric refractory epileptic encephalopathy emphasizes the need for drug treatment optimization. The aim of this study was to characterize the pharmacokinetics of CBD in pediatric patients with refractory epileptic encephalopathy receiving an oil‐based oral solution. To evaluate CBD concentrations, six serial blood samples per patient were collected after the morning dose of CBD, at least 21 days after the beginning of treatment. Twelve patients who received a median (range) dose of 12.2 (5.3‐19.4) mg/kg/d (twice daily) were included in the analysis. Median (range) CBD time to maximum plasma concentration, maximum plasma concentration, and area under the concentration versus time curve up to 6 hours after dosing were 3.2 hours (1.9‐6.2), 49.6 ng/mL (14.4‐302.0), and 226.3 ng ⋅ h/mL (70.5‐861.3), respectively. CBD systemic exposure parameters were in the lower range of previous reports in pediatric patients receiving doses in a similar range. Most of our patients (83%) showed little CBD plasma level fluctuation during a dosing interval, comparable to that encountered after oral administration of an extended release drug delivery system. CDB administration was generally safe and well tolerated, and a novel levothyroxine‐CBD interaction was recorded. Similar to other studies, large interindividual variability in CBD exposure was observed, encouraging the use of CBD therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

AEs during immunosuppressive treatment with tacrolimus are very common. We retrospectively evaluated FK safety and efficacy in a large pediatric liver transplant cohort in Latin America. During 2-year follow-up, we analyzed data from patients who underwent liver transplantation over the period 2010-2012 and recorded FK exposure, AEs, and AR episodes. AEs were classified according causality and severity. Tacrolimus exposure before and during AE was compared using Wilcoxon matched-pairs test. Kaplan-Meier curves were used for survival analysis. In total, 46 patients (out of 72 patients) experienced 69 AEs, such as hypomagnesemia (49%), PTLD (6%), hypertension (6%), and/or nephrotoxicity (22%). 43% of AEs were classified as moderate or serious, and 89% were assigned as probable or definitive. Patients who had one or more AR episodes accounted for 65%. The 12-month acute rejection-free survival was 41% (95% CI, 30.1%-53.1%). A significant difference was observed in FK trough concentrations before and during hypomagnesemia and nephrotoxicity ( P<.05). This study is the first report of FK safety in a large group of pediatric liver transplant patients in Latin America. Children experience AEs, even in protocols with low FK doses. Therapeutic monitoring is an important tool to manage immunosuppressive schemes containing tacrolimus in vulnerable populations. [ABSTRACT FROM AUTHOR]

BACKGROUND: The authors demonstrated previously that the combination of topotecan (TPT) and carboplatin (CBP) was more effective than current chemotherapeutic combinations used to treat retinoblastoma in an orthotopic xenograft model. However, systemic coadministration of these agents is not ideal, because both agents cause dose-limiting myelosuppression in children. METHODS: To overcome the toxicity associated with systemic TPT and CBP, the authors explored subconjunctival delivery of TPT or CBP in an orthotopic xenograft model and in a genetic mouse model of retinoblastoma (Chx10-Cre;Rblox/lox;p107-/-;p53lox/lox). The effects of combined subconjunctival CBP (CBPsubcon) and systemic TPT (TPTsyst) were compared with the effects of combined TPTsubcon and CBPsyst. at clinically relevant dosages. RESULTS: Pharmacokinetic and tumor-response studies, including analyses of ocular and he-matopoietic toxicity, revealed that CBPsubcon/TPTsyst was more effective and had fewer side effects than TPTsubcon/ CBPsyst. CONCLUSIONS: For the first time, retinoblastoma was ablated and long-term vision was preserved in a mouse model by using a clinically relevant chemotherapy regimen. These results eventually may be translated into a clinical trial for children with this debilitating cancer. [ABSTRACT FROM AUTHOR]

Individualization of topotecan dosing reduces inter-patient variability in topotecan exposure, presumably reducing toxicity and increasing efficacy. However, logistical limitations (e.g. requirement for plasma, intensive bedside plasma processing) have prevented widespread application of this approach to dosing topotecan. Thus, the objectives of the present study were to develop and validate an HPLC with fluorescence detection method to measure topotecan lactone in whole blood samples and to evaluate its application to individualizing topotecan dosing. Plasma samples (200 µL) were prepared using methanolic precipitation, a filtration step and then injection of 100 µL of the methanolic extract onto a Novapak® C18, 4 µm, 3.9 × 150 mm column with an isocratic mobile phase. Analytes were detected with a Shimadzu Fluorescence RF-10AXL detector with an excitation and emission wavelength of 370 and 520 nm, respectively. This method had a lower limit of quantification of 1 ng/mL (S/N ≥ 5; RSD 4.9%) and was validated over a linear range of 1-100 ng/mL. Results from a 5-day validation study demonstrated good within-day and between-day precision and accuracy. Data are presented to demonstrate that the present method can be used with whole blood samples to individualize topotecan dosing in children with cancer. Copyright © 2009 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article presents a study assessing the oxaliplatin and irinotecan toxicities in children with solid tumors. The study was performed through an oral cephalosporin and administration of oxaliplatin with irinotecan. Results of the study show different variations in the response of patients and an indication of antitumor activity.