Part 2 of the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) offers drug-specific consensus recommendations based on both evidence and practical experience. These recommendations build upon the kidney function assessment and classification guidelines established in Part 1 of ADDIKD. Here we illustrate how dosing recommendations differ between ADDIKD and existing guidance for four commonly used drugs: methotrexate, cisplatin, carboplatin and nivolumab. We then describe how the recommendations can be distilled into practice points for methotrexate and cisplatin. While ADDIKD is a significant improvement from previous guidelines, adoption of this new guideline requires further endorsement from key external stakeholders, 'change championing' by clinicians locally and encouraging its integration into existing reference sources, clinical trial protocols and electronic prescribing systems. Funding:Development of the ADDIKD guideline is funded by the NSW Government as part of the Cancer Institute NSW and received no funding from external commercial sources.

The prognosis for patients with acute promyelocytic leukemia (APL) has improved dramatically since the introduction of all-trans retinoic acid (ATRA) and intravenous arsenic trioxide (ATO). However, ATO administration requires daily infusions over several months, representing an onerous burden for hospitals and patients. We evaluated the bioavailability of a novel encapsulated oral ATO formulation in APL patients in first complete remission during standard-of-care consolidation. After a pilot study exploring the likely oral dose requirement, total arsenic pharmacokinetics were evaluated in 20 patients after both intravenous and oral ATO 0.15 mg/kg/d, with exposure to oral ATO restricted to the first week in 2 of the 4 ATO cycles. The primary endpoint was bioequivalence of area under the curve from 0-24 hours (AUC0-24), with bioequivalence of maximum concentration achieved (Cmax) as the key secondary endpoint. The 90% confidence intervals (CI) around point estimates of the geometric means of the oral/intravenous ratios for AUC0-24 and Cmax were compared with bioequivalence limits specified by the European Medicines Agency (0.80-1.25). The estimated oral/intravenous ratios and 90% CI for AUC0-24 in whole blood and plasma were 0.993 (0.954-1.034) and 1.030 (0.977-1.087) respectively; data for Cmax also satisfied bioequivalence requirements. Exploratory studies of arsenic species in plasma showed bioequivalence for AUC0-24 with As(III) (oral/intravenous ratio 0.966 (0.879-1.063)). The adverse event profiles of oral and intravenous ATO were comparable for cycles commencing with the IV and oral formulations. In conclusion, this novel oral ATO formulation is bioequivalent with intravenous ATO and offers a convenient alternative for patients with APL. Accession Number: ACTRN12616001022459.

PDF file - 43K, Relationship between 13-cisRA AUC0-6h and 13-cisRA Cmax determined from pharmacokinetic profiles obtained following protocol-based 13-cisRA dosing (n=103)

Natural products, also referred to as dietary supplements, complementary and alternative medicines, and health or food supplements are widely used by people living with cancer. These products are predominantly self-selected and taken concurrently with cancer treatments with the intention of improving quality of life, immune function and reducing cancer symptoms and treatment side effects. Concerns have been raised that concurrent use may lead to interactions resulting in adverse effects and unintended treatment outcomes. This review provides an overview of the mechanisms by which these interactions can occur and the current evidence about specific clinically important natural product–drug interactions. Clinical studies investigating pharmacokinetic interactions provide evidence that negative treatment outcomes may occur when Hypericum perforatum, Grapefruit, Schisandra sphenanthera, Curcuma longa or Hydrastis canadensis are taken concurrently with common cancer treatments. Conversely, pharmacodynamic interactions between Hangeshashinto (TJ-14) and some cancer treatments have been shown to reduce the side effects of diarrhoea and oral mucositis. In summary, research in this area is limited and requires further investigation.

Supplemental Figure 1. MALDI FTICR mass spectra selected from a pixel with maximum intensity in the MS images of liver (A) and flank tumor (B) sections showing the two first isotopes of rucaparib (peaks labelled 1 and 2, respectively). (C) MALDI FTICR mass spectrum selected from a pixel located in the orthotopic tumor area in the MS images of the brain section. No peak was detected for rucaparib. Black dotted lines in each H/E stained sister section delineate the MS images displayed in the figure. Supplemental Figure 2: Efficacy of rucaparib and temozolomide in orthotopic xenograft studies. Mice with established orthotopic xenografts from GBM14, GBM43 and GBM59 were randomized and treated with placebo, rucaparib 1 mg/kg/day, Days 1-5 every 28 days × 3 cycles, TMZ 50 mg/kg/day, Days 1-5 every 28 days × 3 cycles, or the combination.

PDF file - 72K, Observed and fitted 13-cisRA data from four patients

Supplementary Data from Inhibition of Poly(ADP-Ribose) Polymerase-1 Enhances Temozolomide and Topotecan Activity against Childhood Neuroblastoma

Objective: This study aimed to compare the postoperative and pathological outcomes between carboplatin, paclitaxel, radiotherapy (CROSS) and 5-FU, leucovorine, oxaliplatin and docetaxel (FLOT) in esophageal adenocarcinoma (EAC) patients from an international, multicenter cohort. Summary of Background Data: Ongoing debate exists around optimum approach to locally advanced EAC, with proponents for perioperative chemotherapy, such as FLOT, or multimodal therapy, in particular the CROSS regimen. Methods: Patients undergoing CROSS (n = 350) and FLOT (n = 368), followed by curative esophagectomy for EAC were identified from the Oesophagogastric Anastomosis Audit. Results: The 90-day mortality was higher after CROSS than FLOT (5% vs 1%, P = 0.005), even on adjusted analyses [odds ratio (OR): 3.97, confidence interval (CI)(95%): 1.34-13.67]. Postoperative mortality in CROSS were related to higher pulmonary (74% vs 60%) and cardiac complications (42% vs 20%) compared to FLOT. CROSS was associated with higher pathologic complete response (pCR) rates (18% vs 10%, P = 0.004) and margin-negative resections (93% vs 76%, P < 0.001) compared with FLOT. On adjusted analyses, CROSS was associated with higher pCR rates (OR: 2.05, CI95%: 1.26-3.34) and margin-negative resections (OR: 4.55, CI95%: 2.70-7.69) compared to FLOT. Conclusions: This study provides real-world data CROSS was associated with higher 90-day mortality than FLOT, related to cardio-pulmonary complications with CROSS. These warrant a further review into causes and mechanisms in selected patients, and at minimum suggest the need for strict radiation therapy quality assurance. Research into impact of higher pCR rates and R0 resections with CROSS compared to FLOT on long-term survival is needed.

This study implements a physiologically based pharmacokinetic (PBPK) modelling approach to predict the effect of hydrastine and berberine, two major alkaloids present in goldenseal extract, on pharmacokinetics of imatinib and bosutinib. PBPK models of hydrastine and berberine were developed in the Simcyp Simulator (version 17), integrating prior in vitro knowledge and published clinical pharmacokinetic data. The models account for reversible and irreversible (mechanism-based) inhibition of CYP3A enzymes as well as inhibition of the P-glycoprotein transporter. Inhibitory potencies of hydrastine and berberine on imatinib and bosutinib were estimated based on in vitro inhibition of metabolite formation. The PBPK models provided reliable estimates on the magnitude of interactions due to co-administration of goldenseal extract or high-dose berberine on substrates of CYP3A enzymes (midazolam, indinavir and cyclosporine) and P-glycoprotein (digoxin). PBPK simulations predicted a moderate twofold increase (5th to 95th percentiles of prediction of 1.4–3.1) in systemic exposure (AUC) of bosutinib when co-administered with clinically relevant doses of goldenseal extract. A high dose of berberine (300 mg thrice daily) was also expected to affect bosutinib exposure, albeit to a lesser extent than that predicted with goldenseal (AUC ratio of 1.3, 5th to 95th percentile: 1.1–1.6). Conversely, the corresponding effects on imatinib exposure are unlikely to be of clinical importance (predicted AUC ratios of 1.0–1.2). PBPK model-based predictions highlighted potential clinically significant interactions between goldenseal extract and bosutinib, but not imatinib. Dose adjustment may need to be considered if co-administration is desirable. These findings should be confirmed with optimally designed controlled drug interaction studies.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which causes coronavirus disease 2019 (COVID-19), manifests as mild respiratory symptoms to severe respiratory failure and is associated with inflammation and other physiological changes. Of note, substantial increases in plasma concentrations of α1 -acid-glycoprotein and interleukin-6 have been observed among patients admitted to the hospital with advanced SARS-CoV-2 infection. A physiologically based pharmacokinetic (PBPK) approach is a useful tool to evaluate and predict disease-related changes on drug pharmacokinetics. A PBPK model of imatinib has previously been developed and verified in healthy people and patients with cancer. In this study, the PBPK model of imatinib was successfully extrapolated to patients with SARS-CoV-2 infection by accounting for disease-related changes in plasma α1 -acid-glycoprotein concentrations and the potential drug interaction between imatinib and dexamethasone. The model demonstrated a good predictive performance in describing total and unbound imatinib concentrations in patients with SARS-CoV-2 infection. PBPK simulations highlight that an equivalent dose of imatinib may lead to substantially higher total drug concentrations in patients with SARS-CoV-2 infection compared to that in patients with cancer, while the unbound concentrations remain comparable between the 2 patient populations. This supports the notion that unbound trough concentration is a better exposure metric for dose adjustment of imatinib in patients with SARS-CoV-2 infection, compared to the corresponding total drug concentration. Potential strategies for refinement and generalization of the PBPK modeling approach in the patient population with SARS-CoV-2 are also provided in this article, which could be used to guide study design and inform dose adjustment in the future.

ImportanceEmerging policies drafted by the pharmaceutical industry indicate that they will transparently share clinical trial data. These data offer an unparalleled opportunity to advance evidence-based medicine and support decision-making.ObjectiveTo evaluate the eligibility of independent, qualified researchers to access individual participant data (IPD) from oncology trials that supported US Food and Drug Administration (FDA) approval of new anticancer medicines within the past 10 years.Design, Setting, and ParticipantsIn this quality improvement study, a cross-sectional analysis was performed of pivotal clinical trials whose results supported FDA-approved anticancer medicines between January 1, 2011, and June 30, 2021. These trials’ results were identified from product labels.ExposuresEligibility for IPD sharing was confirmed by identification of a public listing of the trial as eligible for sharing or by receipt of a positive response from the sponsor to a standardized inquiry.Main Outcomes and MeasuresThe main outcome was frequency of IPD sharing eligibility. Reasons for data sharing ineligibility were requested and collated, and company-, drug-, and trial-level subgroups were evaluated and presented using χ2 tests and forest plots.ResultsDuring the 10-year period examined, 115 anticancer medicines were approved by the FDA on the basis of evidence from 304 pharmaceutical industry–sponsored trials. Of these trials, 136 (45%) were eligible for IPD sharing and 168 (55%) were not. Data sharing rates differed substantially among industry sponsors, with the most common reason for not sharing trial IPD being that the collection of long-term follow-up data was still ongoing (89 of 168 trials [53%]). Of the top 10 anticancer medicines by global sales, nivolumab, pembrolizumab, and pomalidomide had the lowest eligibility rates for data sharing (<10% of trials).Conclusions and RelevanceThere has been a substantial increase in IPD sharing for industry-sponsored oncology trials over the past 5 years. However, this quality improvement study found that more than 50% of queried trials for FDA-approved anticancer medicines were ineligible for IPD sharing. Data accessibility would be substantially improved if, at the time of FDA registration of a medicine, all data that support the registration were made available.

Aims This study implements a physiologically-based pharmacokinetic (PBPK) modelling approach to investigate inter-ethnic differences in imatinib pharmacokinetics and dosing regimens. Methods A PBPK model of imatinib was built in the Simcyp Simulator (version 17) integrating in vitro drug metabolism and clinical pharmacokinetic data. The model accounts for ethnic differences in body size and abundance of drug-metabolising enzymes and proteins involved in imatinib disposition. Utility of this model for prediction of imatinib pharmacokinetics was evaluated across different dosing regimens and ethnic groups. The impact of ethnicity on imatinib dosing was then assessed based on the established range of trough concentrations (C-ss,C-min). Results The PBPK model of imatinib demonstrated excellent predictive performance in describing pharmacokinetics and the attained C-ss,C-min in patients from different ethnic groups, shown by prediction differences that were within 1.25-fold of the clinically-reported values in published studies. PBPK simulation suggested a similar dose of imatinib (400-600 mg/d) to achieve the desirable range of C-ss,C-min (1000-3200 ng/mL) in populations of European, Japanese and Chinese ancestry. The simulation indicated that patients of African ancestry may benefit from a higher initial dose (600-800 mg/d) to achieve imatinib target concentrations, due to a higher apparent clearance (CL/F) of imatinib compared to other ethnic groups; however, the clinical data to support this are currently limited. Conclusion PBPK simulations highlighted a potential ethnic difference in the recommended initial dose of imatinib between populations of European and African ancestry, but not populations of Chinese and Japanese ancestry.

Background: No evidence currently exists characterising global outcomes following major cancer surgery, including esophageal cancer. Therefore, this study aimed to characterise impact of high income countries (HIC) versus low and middle income countries (LMIC) on the outcomes following esophagectomy for esophageal cancer. Method: This international multi-center prospective study across 137 hospitals in 41 countries included patients who underwent an esophagectomy for esophageal cancer, with 90-day follow-up. The main explanatory variable was country income, defined according to the World Bank Data classification. The primary outcome was 90-day postoperative mortality, and secondary outcomes were composite leaks (anastomotic leak or conduit necrosis) and major complications (Clavien-Dindo Grade III-V). Multivariable generalized estimating equation models were used to produce adjusted odds ratios (ORs) and 95% confidence intervals (CI95%). Results: Between April 2018 to December 2018, 2247 patients were included. Patients from HIC were more significantly older, with higher ASA grade, and more advanced tumors. Patients from LMIC had almost three-fold increase in 90-day mortality, compared to HIC (9.4% vs 3.7%, p < 0.001). On adjusted analysis, LMIC were independently associated with higher 90-day mortality (OR: 2.31, CI95%: 1.17-4.55, p = 0.015). However, LMIC were not independently associated with higher rates of anastomotic leaks (OR: 1.06, CI95%: 0.57-1.99, p = 0.9) or major complications (OR: 0.85, CI95%: 0.54-1.32, p = 0.5), compared to HIC. Conclusion: Resections in LMIC were independently associated with higher 90-day postoperative mortality, likely reflecting a failure to rescue of these patients following esophagectomy, despite similar composite anastomotic leaks and major complication rates to HIC. These findings warrant further research, to identify potential issues and solutions to improve global outcomes following esophagectomy for cancer. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

AbstractBackgroundThe complexity of oesophageal surgery and the significant risk of morbidity necessitates that oesophagectomy is predominantly performed by a consultant surgeon, or a senior trainee under their supervision. The aim of this study was to determine the impact of trainee involvement in oesophagectomy on postoperative outcomes in an international multicentre setting.MethodsData from the multicentre Oesophago-Gastric Anastomosis Study Group (OGAA) cohort study were analysed, which comprised prospectively collected data from patients undergoing oesophagectomy for oesophageal cancer between April 2018 and December 2018. Procedures were grouped by the level of trainee involvement, and univariable and multivariable analyses were performed to compare patient outcomes across groups.ResultsOf 2232 oesophagectomies from 137 centres in 41 countries, trainees were involved in 29.1 per cent of them (n = 650), performing only the abdominal phase in 230, only the chest and/or neck phases in 130, and all phases in 315 procedures. For procedures with a chest anastomosis, those with trainee involvement had similar 90-day mortality, complication and reoperation rates to consultant-performed oesophagectomies (P = 0.451, P = 0.318, and P = 0.382, respectively), while anastomotic leak rates were significantly lower in the trainee groups (P = 0.030). Procedures with a neck anastomosis had equivalent complication, anastomotic leak, and reoperation rates (P = 0.150, P = 0.430, and P = 0.632, respectively) in trainee-involved versus consultant-performed oesophagectomies, with significantly lower 90-day mortality in the trainee groups (P = 0.005).ConclusionTrainee involvement was not found to be associated with significantly inferior postoperative outcomes for selected patients undergoing oesophagectomy. The results support continued supervised trainee involvement in oesophageal cancer surgery.

Anthracyclines are used to treat solid and haematological cancers, particularly breast cancers, lymphomas and childhood cancers. Myelosuppression and cardiotoxicity are the primary toxicities that limit treatment duration and/or intensity. Cardiotoxicity, particularly heart failure, is a leading cause of morbidity and mortality in cancer survivors. Cumulative anthracycline dose is a significant predictor of cardiotoxicity risk, suggesting a role for anthracycline pharmacokinetic variability. Population pharmacokinetic modelling in children has shown that doxorubicin clearance in the very young is significantly lower than in older children, potentially contributing to their higher risk of cardiotoxicity. A model of doxorubicin clearance based on body surface area and age offers a patient-centred dose-adjustment strategy that may replace the current disparate initial-dose selection tools, providing a rational way to compensate for pharmacokinetic variability in children aged <7 years. Population pharmacokinetic models in adults have not adequately addressed older ages, obesity, hepatic and renal dysfunction, and potential drug-drug interactions to enable clinical application. Although candidate gene and genome-wide association studies have investigated relationships between genetic variability and anthracycline pharmacokinetics or clinical outcomes, there have been few clinically significant reproducible associations. Precision-dosing of anthracyclines is currently hindered by lack of clinically useful pharmacokinetic targets and models that predict cumulative anthracycline exposures. Combined with known risk factors for cardiotoxicity, the use of advanced echocardiography and biomarkers, future validated pharmacokinetic targets and predictive models could facilitate anthracycline precision dosing that truly maximises efficacy and provides individualised early intervention with cardioprotective therapies in patients at risk of cardiotoxicity.

Abstract Aim Increased institutional volume and surgeon experience with antireflux surgery has been shown to improve patient outcomes. We have sought to illustrate the discrepancy between the perceived (self-reported) and observed annual volume of anti-reflux operations completed by each surgeon. Method A retrospective questionnaire was delivered to all upper-gastrointestinal (UGI) surgeons performing antireflux surgeries (ARS) at a University Teaching Hospital. Surgeons were asked to estimate the quantity of NHS antireflux cases completed annually. Objective, anonymised data was retrieved from the Surgical Workload Outcomes Audit Database (SWORD) from 2017 to 2020 for comparison. Results 127 ARS were completed by 6 UGI consultants between January 2018 and December 2020. The average number of ARS completed per surgeon was 5.8 (2-10) in 2018, 8.7 (4-11) in 2019 and 6.7 (1-11) in 2020. Conversely, the average number of self-reported annual procedures per surgeon was 22.4 (12-35). On average, participants overestimated the number of NHS ARS completed by 14.5 (4-27) cases or a factor of 2.08. No surgeon correctly or underestimated the number of ARS performed. Conclusions We conclude that self-reported operation volume should not be relied upon for the purposes of assessment or audit. Estimations of annual ARS procedures could be up to triple that suggested by objective data. We recommend that all surgeons maintain a database of ARS for the purpose of self-assessment and audit.

AimsThis study aimed to investigate the potential interaction between Schisandra sphenanthera, imatinib and bosutinib combining in vitro and in silico methods.MethodsIn vitro metabolism of imatinib and bosutinib using recombinant enzymes and human liver microsomes were investigated in the presence and absence of Schisandra lignans. Physiologically‐based pharmacokinetic (PBPK) models for the lignans accounting for reversible and mechanism‐based inhibitions and induction of CYP3A enzymes were built in the Simcyp Simulator (version 17) and evaluated for their capability to predict interactions with midazolam and tacrolimus. Their potential effect on systemic exposures of imatinib and bosutinib were predicted using PBPK in silico simulations.ResultsSchisantherin A and schisandrol B, but not schisandrin A, potently inhibited CYP3A4‐mediated metabolism of imatinib and bosutinib. All three compounds showed a strong reversible inhibition on CYP2C8 enzyme with ki of less than 0.5 μmol L−1. The verified PBPK models were able to describe the increase in systemic exposure of midazolam and tacrolimus due to co‐administration of S. sphenanthera, consistent with the reported changes in the corresponding clinical interaction study (AUC ratio of 2.0 vs 2.1 and 2.4 vs 2.1, respectively). The PBPK simulation predicted that at recommended dosing regimens of S. sphenanthera, co‐administration would result in an increase in bosutinib exposure (AUC ratio 3.0) but not in imatinib exposure.ConclusionPBPK models for Schisandra lignans were successfully developed. Interaction between imatinib and Schisandra lignans was unlikely to be of clinical importance. Conversely, S. sphenanthera at a clinically‐relevant dose results in a predicted three‐fold increase in bosutinib systemic exposure.

Long-term use of imatinib is effective and well-tolerated in children with chronic myeloid leukaemia (CML) yet defining an optimal dosing regimen for imatinib in younger patients is a challenge. The potential interactions between imatinib and coadministered drugs in this "special" population also remains largely unexplored. This study implements a physiologically based pharmacokinetic (PBPK) modeling approach to investigate optimal dosing regimens and potential drug interactions with imatinib in the paediatric population. A PBPK model for imatinib was developed in the Simcyp Simulator (version 17) utilizing in silico, in vitro drug metabolism, and in vivo pharmacokinetic data and verified using an independent set of published clinical pharmacokinetic data. The model was then extrapolated to children and adolescents (aged 2-18 years) by incorporating developmental changes in organ size and maturation of drug-metabolising enzymes and plasma protein responsible for imatinib disposition. The PBPK model described imatinib pharmacokinetics in adult and paediatric populations and predicted drug interaction with carbamazepine, a cytochrome P450 (CYP)3A4 and 2C8 inducer, with a good accuracy (evaluated by visual inspections of the simulation results and predicted pharmacokinetic parameters that were within 1.25-fold of the clinically observed values). The PBPK simulation suggests that the optimal dosing regimen range for imatinib is 230-340 mg/m2/d in paediatrics, which is supported by the recommended initial dose for treatment of childhood CML. The simulations also highlighted that children and adults being treated with imatinib have similar vulnerability to CYP modulations. A PBPK model for imatinib was successfully developed with an excellent performance in predicting imatinib pharmacokinetics across age groups. This PBPK model is beneficial to guide optimal dosing regimens for imatinib and predict drug interactions with CYP modulators in the paediatric population.