Analysis of the Bile Acid Composition in a Fibroblast Growth Factor 19-Expressing Liver-Humanized Mouse Model and Its Use for CYP3A4-Mediated Drug-Drug Interaction Studies.

Numerous biomedical applications have been described for liver-humanized mouse models, such as in drug metabolism or drug-drug interaction (DDI) studies. However, the strong enlargement of the bile acid (BA) pool due to lack of recognition of murine intestine-derived fibroblast growth factor-15 by human hepatocytes and a resulting upregulation in the rate-controlling enzyme for BA synthesis, cytochrome P450 (CYP) 7A1, may pose a challenge in interpreting the results obtained from such mice. To address this challenge, the human fibroblast growth factor-19 (FGF19) gene was inserted into the Fah-/- , Rag2-/- , Il2rg-/- NOD (FRGN) mouse model, allowing repopulation with human hepatocytes capable of responding to FGF19. While a decrease in CYP7A1 expression in human hepatocytes from humanized FRGN19 mice (huFRGN19) and a concomitant reduction in BA production was previously shown, a detailed analysis of the BA pool in these animals has not been elucidated. Furthermore, there are sparse data on the use of this model to assess potential clinical DDI. In the present work, the change in BA composition in huFRGN19 compared with huFRGN control animals was systematically evaluated, and the ability of the model to recapitulate a clinically described CYP3A4-mediated DDI was assessed. In addition to a massive reduction in the total amount of BA, FGF19 expression in huFRGN19 mice resulted in significant changes in the profile of various primary, secondary, and sulfated BAs in serum and feces. Moreover, as observed clinically, administration of the pregnane X receptor agonist rifampicin reduced the oral exposure of the CYP3A4 substrate triazolam. SIGNIFICANCE STATEMENT: Transgenic expression of FGF19 normalizes the unphysiologically high level of bile acids in a chimeric liver-humanized mouse model and leads to massive changes in bile acid composition. These adaptations could overcome one of the potential impediments in the use of these mouse models for drug-drug interaction studies.

Clinical evaluation of deep learning and atlas-based auto-segmentation for critical organs at risk in radiation therapy.

INTRODUCTION: Contouring organs at risk (OARs) is a time-intensive task that is a critical part of radiation therapy. Atlas-based automatic segmentation has shown some success at reducing this time burden on practitioners; however, this method often requires significant manual editing to reach a clinically accurate standard. Deep learning (DL) auto-segmentation has recently emerged as a promising solution. This study compares the accuracy of DL and atlas-based auto-segmentation in relation to clinical 'gold standard' reference contours. METHODS: Ninety CT datasets (30 head and neck, 30 thoracic, 30 pelvic) were automatically contoured using both atlas and DL segmentation techniques. Sixteen critical OARs were then quantitatively measured for accuracy using the Dice similarity coefficient (DSC) and Hausdorff distance (HD). Qualitative analysis was performed to visually classify the accuracy of each structure into one of four explicitly defined categories. Additionally, the time to edit atlas and DL contours to a clinically acceptable level was recorded for a subset of 9 OARs. RESULTS: Of the 16 OARs analysed, DL delivered statistically significant improvements over atlas segmentation in 13 OARs measured with DSC, 12 OARs measured with HD, and 12 OARs measured qualitatively. The mean editing time for the subset of DL contours was 50%, 23% and 61% faster (all P < 0.05) than that of atlas segmentation for the head and neck, thorax, and pelvis respectively. CONCLUSIONS: Deep learning segmentation comprehensively outperformed atlas-based contouring for the majority of evaluated OARs. Improvements were observed in geometric accuracy and visual acceptability, while editing time was reduced leading to increased workflow efficiency.

Credibility dilemmas under the Paris agreement: explaining fossil fuel subsidy reform references in INDCs.

Fossil fuel subsidies are a market distortion commonly identified as an obstacle to decarbonization. Yet  due to trenchant political economic risks, reform attempts can be fraught for governments. Despite these concerns, an institutionally and economically diverse group of states included references to fossil fuel subsidy reform (FFSR) in their Intended Nationally Determined Contributions (INDCs) under the Paris Agreement. What conditions might explain why some states reference politically risky reforms within treaty commitments, while most others would not? We argue that the Article 4 process under the Paris Agreement creates a "credibility dilemma" for states-articulating ambitious emissions reduction targets while also defining national climate plans engenders a need to seek out appropriate policy ideas that can justify overarching goals to international audiences. Insomuch as particular norms are institutionalized and made salient in international politics, a window of opportunity is opened: issue advocates can "activate" norms by demonstrating how related policies can make commitments credible. Using mixed methods, we find support for this argument. We identify contextual factors advancing FFSR in the lead-up to the Paris Agreement, including norm institutionalization in regimes and international organization programs as well as salience-boosting climate diplomacy. Further, we find correspondences between countries targeted by transnational policy advocates and FFSR references in INDCs, building on the momentum in international politics more generally. Though drafting INDCs and NDCs is a government-owned process, the results suggest that understanding their content requires examining international norms alongside domestic circumstances.

Time to Break the "Lock-In" Impediments to Chemicals Management.

Despite enormous national, regional, and global efforts on chemical management, the widespread use of hazardous chemicals continues in many parts of the world even after decades of there being well-known risks to public and/or ecosystem health. This continued supply and use, despite strong evidence of negative impacts, is not unique to chemicals management. In the field of climate change, the concept of "lock-in" has been used to explain the complex interactions among economic, social, technological, and political dynamics that reinforce global reliance on the extraction and use of fossil fuels. Learning from carbon "lock-in" phenomena, this Perspective explores the challenges of chemicals management from the perspective of lock-in through three case studies: paraquat, perfluorooctanesulfonic acid (PFOS), and asbestos. These case studies illustrate that most current chemicals management frameworks fail to address the concerns arising from this complex interplay by not involving all relevant stakeholder groups that are part of lock-in, from producers to consumers. This results in a relatively narrow consideration (e.g., only demand but not supply) of the effectiveness and consequences of regulations. We submit that to break lock-in and address the global threat of chemical pollution, current approaches to managing hazardous chemicals should be broadened to take a comprehensive approach to understanding and managing factors contributing to lock-in, notably both supply and demand on national and international scales.

Metaplastic carcinoma of the breast: Clinicopathological features and treatment outcomes with long-term follow up.

Metaplastic breast carcinoma is an uncommon subtype of invasive ductal carcinoma with a tendency towards poorer clinical outcomes. Following ethical approval, the current study reviewed the institutional records of ~2,500 women with breast cancer. A total of 14 cases of metaplastic breast cancer were reviewed for management and treatment outcomes. The results demonstrated that patients had median follow up of 30 months, a 5-year disease-free survival of 57.1% and 5-year overall survival of 57.1%. The majority of patients had at least T2 disease and all tumours were high grade. Additionally, most patients were triple negative and nodal metastases were uncommon. Metaplastic breast cancer is an aggressive variant of invasive breast cancer. Most patients can be treated with breast conservation and survival parameters tend to be worse than more common breast cancer subtypes.

Assessing ISUP prostate cancer grade groups in patients treated with definitive dose escalated external beam radiation.

PURPOSE: The five grade group system has been validated for men treated with radical prostatectomy. However, the prognostic value for men treated with radiation therapy is uncertain, with prior studies utilising old techniques and doses. We aimed to validate the International Society of Urological Pathology (ISUP) groupings for men treated with contemporary radiation therapy. METHODS: Men with localised prostate cancer treated with image-guided, dose-escalated (≥78 Gy) external beam radiation were identified across four institutions. Primary outcome was time to biochemical failure. Harrell's C index assessed performance of the ISUP system against other grading stratifications. RESULTS: 2205 men were included, withmedian follow-up of 5.6 years. Seven-year actuarial rates of biochemical failure for grade groups 1-5 were 9.3%, 10.4%, 13.2%, 12.4% and 23.4%. On multivariate analysis, hazard ratios for biochemical failure were1.19, 1.00, 1.10, 1.05 and 2.10 for grade groups 1-5, relative to 2. P values were only significant for grade group 5. Harrell's C index favoured an alternative three group model (comprising Gleason scores [6 and 3 + 4 = 7] vs [4 + 3 = 7 and 8] vs [9 and 10]) over ISUP grade groups. CONCLUSIONS: The ISUP grade groups were not validated in a contemporary cohort treated with dose-escalated, image-guided radiation therapy. Grade groups 1-4 were not statistically different from each other; however, grade group 5 had a significantly worse prognosis. We identified a new three group model that better predicted biochemical outcomes. Further work is requiredto validate optimal groupings for modern radiation therapy and investigate the contrasting prognostic capability of grade groups in surgical and radiation therapy patients.

Assessment of drug-drug interactions of CC-90001, a potent and selective inhibitor of c-Jun N-terminal kinase.

CC-90001 is predominantly metabolised via glucuronidation, while oxidative metabolism is a minor pathway in human hepatocytes and liver microsomes. In vitro, CC-90001 glucuronidation was catalysed by UGT1A9, UGT1A4, and UGT1A1, while oxidative metabolism was primarily mediated by CYP3A4/5 with minor contributions from CYP1A2, CYP2C9, CYP2B6, and CYP2D6.CC-90001 in vitro inhibits CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4 ≤ 55% at 100 µM, and the inhibition was negligible at ≤30 µM. CC-90001 is not a time-dependent CYP inhibitor.In human hepatocytes CC-90001 is an inducer of CYP2B6 and CYP3A, with mRNA levels increased 34.4% to 52.8% relative to positive controls.In vitro CC-90001 is a substrate of P-gp, and an inhibitor of P-gp, BCRP, OAT3, OATP1B1, OATP1B3, OCT2, MATE1, and MATE2k with IC50 values of 30.3, 25.8, 17.7, 0.417, 19.9, 0.605, 4.17, and 20 µM, respectively.A clinical study demonstrated that CC-90001 has no or little impact on the exposure of warfarin (CYP2C9), omeprazole (CYP2C19), midazolam (CYP3A) or metformin (OCT2, MATE1/2k). CC-90001 co-administration increases the AUCt and Cmax 176% and 339% for rosuvastatin (BCRP/OATP1B1/3), 116% and 171% for digoxin (P-gp), and 266% and 321% for nintedanib (CYP3A & P-gp), respectively.In conclusion, CC-90001 in unlikely to be a victim or perpetrator of clinically relevant interactions involving CYPs or UGTs. Weak to moderate interactions are expected in clinic with substrates of P-gp and OATP1B1 due to CC-90001 inhibition of these transporters.

Patterns of relapse following hippocampal avoidance prophylactic cranial irradiation for small cell lung carcinoma.

BACKGROUND: Hippocampal avoidance techniques are an evolving standard of care for patients undergoing cranial irradiation. Our aim was to assess the oncological outcomes and patterns of failure following hippocampal avoidance prophylactic cranial irradiation (HA-PCI) as a standard of care in unselected patients with both limited and extensive stage small cell lung carcinoma. MATERIALS AND METHODS: Consecutive patients with small cell lung carcinoma with a complete (limited stage) or good partial (extensive stage) response following chemotherapy were eligible to receive HA-PCI, with a total dose of 25 Gray in 10 fractions. All patients had a negative baseline MRI brain scan with gadolinium prior to HA-PCI. Patients had baseline and follow up Common Toxicity Criteria Adverse Event assessments. Following completion of HA-PCI, all patients had three-monthly MRI brain scans with gadolinium until confirmation of intracranial relapse, as well as three-monthly CT of the chest, abdomen and pelvis. Overall and progression-free survival were calculated using the Kaplan-Meier method. RESULTS: A total of 17 consecutive patients, 9 men and 8 women, with a mean age of 70 years received HA-PCI between May 2016 and June 2020 after completion of their initial chemotherapy. There were no Grade 4 or greater adverse events. No patient had an isolated hippocampal avoidance zone relapse alone; three of 17 patients had multifocal relapses that included the hippocampal avoidance zone. CONCLUSION: In our series, there were no hippocampal only relapses and we conclude that HA-PCI is a safe alternative to standard PCI in the setting of small cell lung cancer.

A critical literature review on the use of bellyboard devices to control small bowel dose for pelvic radiotherapy.

Delivering curative radiotherapy doses for rectal and gynaecological tumours has historically been complicated by the dose tolerance of the small bowel. Acute radiation-induced small bowel toxicity includes side effects such as abdominal pain, nausea and diarrhoea. With the advent of new treatment delivery modalities, such as IMRT (Intensity modulated radiotherapy) and VMAT (Volumetric modulated Arc radiotherapy), there has been an expectation that small bowel doses can be better controlled with the use of these technologies. These capabilities enable the creation of treatment plans that can better avoid critical radiosensitive organs. The purpose of this review is to look beyond advances in linear accelerator technology in seeking improvements to small bowel dose and toxicity. This review examines whether an alternative prone patient positioning approach using a bellyboard device in conjunction with IMRT and VMAT treatment delivery can reduce small bowel doses further than using these technologies with the patient in a traditional supine position.

Single-Dose Pharmacokinetics, Safety, and Tolerability of Avadomide (CC-122) in Subjects With Mild, Moderate, or Severe Renal Impairment.

CC-122 (Avadomide) is a nonphthalimide analogue of thalidomide that has multiple pharmacological activities including immune modulation of several immune cell subsets, antigrowth activity, antiproliferative activity, and antiangiogenic activity. CC-122 as monotherapy and in combination with other agents is being evaluated for multiple indications including hematologic malignancies and advanced solid tumors. Given that renal clearance is one of the major routes of elimination for CC-122 and its clearance/exposure could be affected by renal impairment, a total of 50 subjects with various degrees of renal function were enrolled in an open-label, single-dose study to evaluate the impact of renal impairment on CC-122 pharmacokinetic disposition. The study showed that following administration of a single oral dose of 3 mg CC-122, renal impairment reduced both the apparent total plasma clearance and renal clearance of CC-122, but it had less impact on CC-122 absorption, as demonstrated by similar Tmax and Cmax among groups with various degrees of renal function. Compared with exposure in subjects with normal renal function, total plasma exposure to CC-122 increased by ∼20%, ∼50%, and ∼120% in subjects with mild, moderate, and severe renal insufficiency, respectively. Results from this study combined with modeling/simulation suggest that dose adjustments are necessary in patients with moderate or severe but not with mild renal impairment. Finally, a single dose of 3 mg CC-122 was safe and well tolerated by healthy subjects and subjects with mild, moderate, and severe renal impairment.

Absorption, distribution, metabolism and excretion of an isocitrate dehydrogenase-2 inhibitor enasidenib in rats and humans.

1. The absorption, distribution, metabolism and excretion of enasidenib were studied following a single oral dose of [14C]enasidenib to rats (10 mg/kg; 100 µCi/kg) and healthy volunteers (100 mg; 318 nCi). 2. Enasidenib was readily absorbed, extensively metabolized and primarily eliminated via the hepatobiliary pathway. Enasidenib-derived radioactivity was widely distributed in rats. Excretion of radioactivity was approximately 95-99% of the dose from rats in 168 h post-dose and 82.4% from human volunteers in 504 h post-dose. In rat bile, approximately 35-42% of the administered dose was recovered, with less than 5% of the dose excreted as the parent drug. Renal elimination was a minor pathway, with <12% of the dose excreted in rat urine and <10% of the dose excreted in human urine. 3. Enasidenib was the prominent radioactive component in rat and human systemic circulation. Enasidenib was extensively metabolized in rats and human volunteers through N-dealkylation, oxidation, direct glucuronidation and combinations of these pathways. Glucuronidation was the major metabolic pathway in rats while N-dealkylation was the prominent metabolic pathway in human volunteers. All human metabolites were detected in rats.

In vitro inhibition of human nucleoside transporters and uptake of azacitidine by an isocitrate dehydrogenase-2 inhibitor enasidenib and its metabolite AGI-16903.

1. The present study investigated inhibitory effects of enasidenib and its metabolite AGI-16903 on (a) recombinant human nucleoside transporters (hNTs) in hNT-producing Xenopus laevis oocytes, and (b) azacitidine uptake in a normal B-lymphoblast peripheral blood cell line (PBC) and acute myeloid leukemia (AML) cell lines. 2. Enasidenib inhibited hENT1, hENT2, hENT3, and hENT4 in oocytes with IC50 values of 7, 63, 27, and 76 µM, respectively, but exhibited little inhibition of hCNT1-3. AGI-16903 exhibited little inhibition of any hNT produced in oocytes. 3. Azacitidine uptake was more than 2-fold higher in AML cells than in PBC. Enasidenib inhibited azacitidine uptake into OCI-AML2, TF-1 and PBC cells in a concentration-dependent manner with IC50 values of 0.27, 1.7, and 1.0 µM in sodium-containing transport medium, respectively. 4. IC50 values shifted approximately 100-fold higher when human plasma was used as the incubation medium (27 µM in OCI-AML2, 162 µM in TF-1, and 129 µM in PBC), likely due to high human plasma protein binding of enasidenib (98.5% bound). 5. Although enasidenib inhibits hENTs and azacitidine uptake in vitro, plasma proteins attenuate this inhibitory effect, likely resulting in no meaningful in vivo effects in humans.

Analysis of a volumetric-modulated arc therapy (VMAT) single phase prostate template as a class solution.

AIM: To assess a class solution template for volumetric-modulated arc therapy (VMAT) for prostate cancer using plan analysis software. BACKGROUND: VMAT is a development of intensity-modulated radiotherapy (IMRT) with potential advantages for the delivery of radiotherapy (RT) in prostate cancer. Class solutions are increasingly used for facilitating RT planning. Plan analysis software provides an objective tool for evaluating class solutions. MATERIALS AND METHODS: The class solution for VMAT was based on the current static field IMRT template. The plans of 77 prostate cancer patients were evaluated using a set of in-house plan quality metrics (scores) (PlanIQ™, Sun Nuclear Corporation). The metrics compared the class solution for VMAT planning with the IMRT template and the delivered clinical plan (CP). Eight metrics were associated with target coverage and ten with organs-at-risk (OAR). Individual metrics were summed and the combined scores were subjected to non-parametric analysis. The low-dose wash for both static IMRT and VMAT plans were evaluated using 40 Gy and 25 Gy isodose volumes. RESULTS: VMAT plans were of equal or better quality than the IMRT template and CP for target coverage (combined score) and OAR combined score. The 40 Gy isodose volume was marginally higher with VMAT than IMRT (4.9%) but lower than CP (-6.6%)(P = 0.0074). The 25 Gy volume was significantly lower with VMAT than both IMRT (-32.7%) and CP (-34.4%)(P < 0.00001). CONCLUSIONS: Automated VMAT planning for prostate cancer is feasible and the plans are equal to or better than the current IMRT class solution and the delivered clinical plan.

A Phase I, open-label, randomized, crossover study in healthy subjects to evaluate the bioavailability of, and the food effect on, a pomalidomide oral liquid suspension.

OBJECTIVE: The aim of this study was to evaluate the bioavailability of a pomalidomide oral liquid suspension relative to the commercial capsule formulation and to assess the food effect on the pomalidomide oral liquid suspension when administered as a single 4 mg dose. METHODS: This was an open-label, randomized, three-period, two-sequence crossover study in healthy subjects consisting of a screening phase, a baseline assessment phase, a treatment phase with three periods, and a follow-up phone call phase. Blood samples for pharmacokinetics (PK) assessment were collected up to 48 h postdose during each treatment period. Safety was evaluated throughout the study. RESULTS: Pomalidomide exposures were comparable in healthy subjects administered with a single oral 4 mg dose as the reference capsule or as the test liquid suspension formulations, demonstrated as the 90% confidence intervals of the geometric mean ratios for area under the plasma concentration-time curve calculated from time 0 to the last measurable concentration at time t (AUC0-t), area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞), and peak (maximum) plasma drug concentration (Cmax) were completely contained within the bioequivalence range of 80-125%. Administration of the pomalidomide liquid suspension with a high fat meal resulted in a 3.0 h delay in pomalidomide time to Cmax (tmax) and an ~ 34.5% reduction in Cmax. However, the AUCs were comparable after dose administration with and without food. CONCLUSION: A single oral dose of 4 mg of liquid suspension was bioequivalent to a single oral dose of 4 mg of capsule formulation. There was no clinically relevant impact of food on pomalidomide liquid suspension. Single oral doses of 4 mg pomalidomide were safe and well tolerated when administered as a liquid suspension under fed and fasted conditions or as a capsule under fasted conditions.

Application of an incident taxonomy for radiation therapy: Analysis of five years of data from three integrated cancer centres.

AIM: To develop and apply a clinical incident taxonomy for radiation therapy. BACKGROUND: Capturing clinical incident information that focuses on near-miss events is critical for achieving higher levels of safety and reliability. METHODS AND MATERIALS: A clinical incident taxonomy for radiation therapy was established; coding categories were prescription, consent, simulation, voluming, dosimetry, treatment, bolus, shielding, imaging, quality assurance and coordination of care. The taxonomy was applied to all clinical incidents occurring at three integrated cancer centres for the years 2011-2015. Incidents were managed locally, audited and feedback disseminated to all centres. RESULTS: Across the five years the total incident rate (per 100 courses) was 8.54; the radiotherapy-specific coded rate was 6.71. The rate of true adverse events (unintended treatment and potential patient harm) was 1.06. Adverse events, where no harm was identified, occurred at a rate of 2.76 per 100 courses. Despite workload increases, overall and actual rates both exhibited downward trends over the 5-year period. The taxonomy captured previously unidentified quality assurance failures; centre-specific issues that contributed to variations in incident trends were also identified. CONCLUSIONS: The application of a taxonomy developed for radiation therapy enhances incident investigation and facilitates strategic interventions. The practice appears to be effective in our institution and contributes to the safety culture. The ratio of near miss to actual incidents could serve as a possible measure of incident reporting culture and could be incorporated into large scale incident reporting systems.

In Vivo Assessment of the Effect of CYP1A2 Inhibition and Induction on Pomalidomide Pharmacokinetics in Healthy Subjects.

Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies. Following administration of a single oral dose of 4 mg pomalidomide, the plasma exposure when coadministered with fluvoxamine was 225.1% and 123.7% of that when administered alone for the total plasma exposure (AUC0-inf ) and the plasma peak exposure (Cmax ), respectively. In smokers with elevated CYP1A2 activity demonstrated by high caffeine clearance (a marker of CYP1A2 induction), the AUC0-inf was 32.3% lower, whereas the Cmax was 14.4% higher than that in nonsmokers. In addition, pomalidomide was safe and well tolerated as a single oral dose of 4 mg in healthy male smokers and nonsmokers ≥ 40 to ≤ 80 years old, and a single oral dose of 4 mg pomalidomide coadministered with multiple oral 50-mg doses of the CYP1A2 inhibitor fluvoxamine compared with pomalidomide alone was safe and well tolerated by the healthy male subjects.

The politics of decarbonization and the catalytic impact of subnational climate experiments.

The Paris Agreement of 2015 marks a formal shift in global climate change governance from an international legal regime that distributes state commitments to solve a collective action problem to a catalytic mechanism to promote and facilitate transformative pathways to decarbonization. It does so through a system of nationally determined contributions, monitoring and ratcheting up of commitments, and recognition that the practice of climate governance already involved an array of actors and institutions at multiple scales. In this article, we develop a framework that focuses on the politics of decarbonization to explore policy pathways and mechanisms that can disrupt carbon lock-in through these diverse, decentralized responses. It identifies political mechanisms-normalization, capacity building, and coalition building-that contribute to the scaling and entrenchment of discrete decarbonization initiatives within or across jurisdictions, markets, and practices. The role for subnational (municipal, state/provincial) climate governance experiments in this new context is especially profound. Drawing on such cases, we illustrate the framework, demonstrate its utility, and show how its political analysis can provide insight into the relationship between climate governance experiments and the formal global response as well as the broader challenge of decarbonization.

Software-based evaluation of a class solution for prostate IMRT planning.

AIM: To use plan analysis software to evaluate a class solution for prostate intensity modulated radiotherapy (IMRT) planning. BACKGROUND: Class solutions for radiotherapy planning are increasingly being considered for streamlining planning. Plan analysis software provides an objective approach to evaluating radiotherapy plans. MATERIALS AND METHODS: Three iterations of a class solution for prostate IMRT planning (T1, T2 and Tfinal) were compared to the clinical plan of 74 prostate patients using radiotherapy plan analysis software (Plan IQ™, Sun Nuclear Corporation). A set of institution-specific plan quality metrics (scores) were established, based on best practice guidelines. RESULTS: For CTV coverage, Tfinal was not significantly different to the clinical plan. With the exception of 95% PTV coverage, Tfinal metrics were significantly better than the clinical plan for PTV coverage. In the scoring analysis, mean dose, 95% and 107% isodose coverage scores were similar for all the templates and clinical plan. 100% coverage of the CTV clinical plan was similar to Tfinal but scored higher than T1 and T2. There were no significant differences between Tfinal and the clinical plan for the metrics and scores associated with organs at risk. The total plan score was similar for Tfinal and the clinical plan, although the scores for volume receiving total dose outside the PTV were higher for Tfinal than for the clinical plan (P < 0.0001). CONCLUSIONS: The radiotherapy plan analysis software was useful for evaluating a class solution for prostate IMRT planning and provided evidence that the class solution produced clinically acceptable plans for these patients.

Application of a "Fit for Purpose" PBPK Model to Investigate the CYP3A4 Induction Potential of Enzalutamide.

BACKGROUND: Oncology therapy typically involves drug combinations since monotherapy seldom provides the desired outcome. But combination therapy presents the potential for drug-drug interactions (DDIs). Due to the narrow window between therapeutic concentrations and onset of toxicity often observed with oncology therapeutics, managing DDIs with combination therapy in cancer is critical. Physiologically based pharmacokinetic (PBPK) modeling can be effectively used for predicting DDIs and guiding dose-selection, but requires development of PBPK models of cancer drugs. Among various types of cancer, metastatic prostate cancer is an area of high unmet medical need with minimal therapeutic options. Recently, enzalutamide was approved for treatment of metastatic prostate cancer and is often dosed as a combination in clinical practice. Enzalutamide is a potent CYP3A inducer and a model-based approach to guide dose-selection for enzalutamide combinations that are CYP3A substrates is needed. OBJECTIVE: A "fit for purpose" PBPK model of enzalutamide was developed to illustrate the CYP3A4 induction potential, understand the kinetics of de-induction of CYP3A4 following cessation of enzalutamide dosing and guide dose-selection of a co-administered CYP3A substrate. METHOD: The population-based simulator, Simcyp, was used for model building purposes. Model input parameters were obtained from public information, primarily from the FDA summaries. RESULTS: The simulated concentration time profiles of enzalutamide in healthy male subjects were comparable to observed profiles in male patients. Model predicted enzalutamide pharmacokinetic (PK) parameters, i.e. AUC, Cmax and half-life were within 1.5-fold of observed results obtained from two reported studies, supporting verification of the PBPK model. Model application was demonstrated by simulating a drug-drug interaction between enzalutamide and midazolam, a sensitive CYP3A4 substrate. Based on simulations, the midazolam AUC ratio ranged from 0.06 to 0.16 and was comparable to the observed ratio of 0.14. Based on modeling, upon cessation of enzalutamide dosing, it is predicted that at least 8 weeks are needed to re-attain baseline CYP3A4 activity. Based on PBPK modeling, dose adjustment of up to 3-fold for a co-administered CYP3A substrate was shown to re-attain baseline exposure. CONCLUSION: A "fit for purpose" PBPK model of enzalutamide was successfully developed using public information that recapitulated it's observed pharmacokinetics, CYP3A4 induction potential and the potential need for dose-adjustment of co-administered CYP3A substrates.

The Uremic Toxin Indoxyl-3-Sulfate Induces CYP1A2 In Primary Human Hepatocytes.

Chronic kidney disease (CKD) generally impacts clearance of renally eliminated drugs but growing evidence shows that it can influence clearance of hepatically eliminated drugs and a complete mechanistic understanding of this phenomenon is still lacking. CKD leads to accumulation of uremic toxins, including indoxyl- 3-sulfate (3-INDS) and indole-3-acetic acid (3-IAA). OBJECTIVE: In this study, we evaluated the potential of 3-INDS and 3-IAA (10, 30 and 100 µM) to induce liver cytochrome P450 (CYP) enzymes CYP1A2, 2B6 and 3A4/5 using cultured primary human hepatocytes following once daily treatment for 3 days. RESULTS: 3-INDS potently induced CYP1A2 mRNA and enzyme activity in a dose-dependent manner but did not induce CYP2B6 or 3A4. At 100 µM, a concentration observed in humans under uremic conditions, 3-INDS increased CYP1A2 mRNA and activity by 93% and 292% respectively when compared with prototypical inducer omeprazole. However, 3-IAA did not induce CYP1A2, 2B6 or 3A4. CONCLUSION: These results suggest that the uremic toxin, 3-INDS, is a potent CYP1A2 inducer and lends valuable mechanistic basis for how kidney disease can affect hepatic metabolism.