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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, with median 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 were 1.19, 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 required to validate optimal groupings for modern radiation therapy and investigate the contrasting prognostic capability of grade groups in surgical and radiation therapy patients.

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.

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., Environmental Science & Technology, 56 (7), ISSN:0013-936X, ISSN:1520-5851

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.

The Paris Agreement institutionalized decentralized and national approaches to climate change policy through Article 4 and the Nationally Determined Contributions (NDC) process. In this new context, what can be said about the prospects for a global carbon market, and how might that analysis benefit from a comparative political perspective? In this chapter, the authors argue that, given the shift to the NDC process and considering the history of carbon market linkage and diffusion, understanding the past and future of carbon markets requires an analysis of the variation in institutions and the political economies of countries. To illustrate this point, the authors unpack continuity and change in five cases: the European Union, China, Canada, South Korea, and Indonesia. The authors conclude that making sense of carbon markets requires an integrative view of the comparative institutional dynamics as well as the transnational processes of diffusion and learning that promotes policy ideas.

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.

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 ...

Introduction: CC-90009 is a novel cereblon E3 ligase modulator (CELMoD ®) agent that is a first-in-class degrader of translation termination factor G1 to S phase transition 1 (GSPT1). CC-90009 has demonstrated antileukemic activity as a single agent and is currently under investigation in patients with acute myeloid leukemia (AML; NCT02848001). Treatment with CC-90009 led to rapid reductions in peripheral and bone marrow blasts, and demonstrated preliminary promising efficacy, including several complete remissions, in patients with relapsed or refractory AML. Here, we describe the identification and preclinical activity of select anti-AML agents as potential combination partners of CC-90009 to further improve its efficacy and therapeutic index. Based on these results, the combination activity of CC-90009 with venetoclax (VEN)/azacitidine (AZA) is being evaluated in a phase 1/2 trial in patients with AML (NCT04336982). Methods: A high-throughput cell viability screen was performed to identify synergistic partners of CC-90009. AML cell lines (HL-60, HNT-34, KG-1, ML-2, NOMO-1, MOLM-13, MV4-11, F-36P, OCI-AML2, OCI-AML3) were treated with CC-90009 in combination with > 70 compounds, including standard anti-AML agents, tyrosine kinase inhibitors (TKIs), unfolded protein response inducers, transcription inhibitors, and epigenetic agents. MOLM-13 and MV4-11 are fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) cell lines. Hits were validated in a colony formation (CF) assay using primary AML cells and bone marrow mononuclear cells (BMMC) from healthy donors. Synergy of the combination partners with CC-90009 was further assessed in AML patient-derived xenograft (PDX) models. Synergy between the isocitrate dehydrogenase 2 (IDH2) inhibitor enasidenib and CC-90009 was evaluated in a TF-1 erythroleukemia cell line overexpressing IDH2 R140Q mutant, and an IDH2 R140Q PDX model, AM7577. Results: Our high-throughput combination screen revealed multiple TKIs, epigenetic agents, and pro-apoptotic agents as potential combination partners of CC-90009 in AML cell lines. FLT3 inhibitors, including sunitinib, pexidartinib, midostaurin, lestaurtinib, crenolanib, and gilteritinib, synergized with CC-90009 to reduce viability in FLT3-ITD AML cell lines MV4-11 and MOLM-13. Similarly, the B-cell lymphoma 2 (BCL2) inhibitor VEN potentiated CC-90009-induced apoptosis and accelerated cell-autonomous killing. Reduction in levels of MCL-1, an anti-apoptotic factor, by CC-90009 most likely contributed to the synergy with VEN. We prioritized the evaluation of FLT3, BCL2, and IDH2 inhibitors as partners of CC-90009. In CF assays, midostaurin enhanced the inhibitory effect of CC-90009 in primary AML cells, without augmenting the effect of CC-90009 in CD34+ BMMC from healthy donors. Similarly, VEN enhanced the reduction in CF by CC-90009 in AML patient-derived BMMC without exacerbating the decrease in CF by CC-90009 in BMMC from healthy donors. We characterized FLT3 inhibitor/CC-90009 and BCL2 inhibitor/AZA/CC-90009 combinations in a FLT3-ITD PDX murine model, PDX1. The FLT3 inhibitor quizartinib significantly prolonged survival when combined with CC-90009 compared with either agent alone (P < 0.001). Similarly, VEN/AZA/CC-90009 combination markedly extended survival compared with single agents or VEN/AZA doublets (P < 0.001). The synergy between CC-90009 and epigenetic modulators was validated and further characterized in customized cell differentiation assays. Addition of CC-90009 to enasidenib, a mutant IDH2 inhibitor, enhanced differentiation and killing of CD34+ stem and progenitor cells, and increased differentiated CD235a+ erythroblasts, compared with enasidenib alone in a TF-1 cell line overexpressing IDH2 R140Q. Enasidenib/CC-90009 combination treatment reduced CD45+ malignant populations and increased differentiated CD14+ cells, leading to significantly prolonged animal survival in an IDH2 R140Q PDX model, AM7577, compared with either agent alone (P < 0.0001). Conclusion: Using a high-throughput combination screen, we identified rational combination partners that synergize with CC-90009 in in vitro and in vivo AML models. Collectively, these results support the clinical evaluation of CC-90009 in combination with FLT3, BCL2, and IDH2 inhibitors to further improve treatment outcomes for patients with AML. Disclosures Pierce: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Yao: Bristol Myers Squibb: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months, Research Funding. Pace: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Wang: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Flandin-Blety: Bristol Myers Squibb: Current Employment. Benitez: Bristol Myers Squibb: Current Employment. Guarinos: Bristol Myers Squibb: Current Employment. Hoffmann: Bristol Myers Squibb: Current Employment. Carrancio: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Pourdehnad: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties.

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.

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.

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 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.

Yan Li,1 Liangang Liu,2 Lian Huang,3 Xiaomin Wang,4 Matthew Hoffmann,4 Josephine Reyes,1 Maria Palmisano,1 Simon Zhou1 1Translational Development and Clinical Pharmacology, 2Biometrics and Data Operations, 3Pharmaceutical Science Drug Product Development, 4Non-Clinical Development, Celgene Corporation, Summit, NJ, USA 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 4mg 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 48h postdose during each treatment period. Safety was evaluated throughout the study. Results: Pomalidomide exposures were comparable in healthy subjects administered with a single oral 4mg 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 3.0h 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 4mg of liquid suspension was bioequivalent to a single oral dose of 4mg of capsule formulation. There was no clinically relevant impact of food on pomalidomide liquid suspension. Single oral doses of 4mg pomalidomide were safe and well tolerated when administered as a liquid suspension under fed and fasted conditions or as a capsule under fasted conditions. Keywords: pomalidomide, liquid suspension, bioavailability, bioequivalence, food effect

1. The absorption, distribution, metabolism and excretion (ADME) 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% to 99% of the dose from rats in 168 hours post-dose and 82.4% from human volunteers in 504 hours post-dose. In rat bile, approximately 35% to 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.

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.

1. The disposition of tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, orally active c-Jun amino-terminal kinase inhibitor intended for treatment of fibrotic diseases was studied in rats, dogs and humans following a single oral dose of [(14)C]tanzisertib (Independent Investigational Review Board Inc., Plantation, FL). 2. Administered dose was quantitatively recovered in all species and feces/bile was the major route of elimination. Tanzisertib was rapidly absorbed (Tmax: 1-2 h) across all species with unchanged tanzisertib representing >83% of plasma radioactivity in dogs and humans, whereas

1. In vitro metabolism of Tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, selective c-Jun amino-terminal kinase (JNK) inhibitor, was investigated in mouse, rat, rabbit, dog, monkey and human hepatocytes over 4 h. The extent of metabolism of [(14)C]tanzisertib was variable, with10% metabolized in dog and human,20% metabolized in rabbit and monkey and75% metabolized in rat and mouse. Primary metabolic pathways in human and dog hepatocytes, were direct glucuronidation and oxidation of cyclohexanol to a keto metabolite, which was subsequently reduced to parent or cis-isomer, followed by glucuronidation. Rat and mouse produced oxidative metabolites and cis-isomer, including direct glucuronides and sulfates of tanzisertib and cis-isomer. 2. Enzymology of oxido-reductive pathways revealed that human aldo-keto reductases AKR1C1, 1C2, 1C3 and 1C4 were responsible for oxido-reduction of tanzisertib, CC-418424 and keto tanzisertib. Characterizations of enzyme kinetics revealed that AKR1C4 had a high affinity for reduction of keto tanzisertib to tanzisertib compared to other isoforms. These results demonstrate unique stereoselectivity of the reductive properties documented by human AKR1C enzymes for the same substrate. 3. Characterization of UGT isoenzymes in glucuronidation of tanzisertib and CC-418424 revealed that, tanzisertib glucuronide was catalyzed by: UGT1A1, 1A4, 1A10 and 2B4, while CC-418424 glucuronidation was catalyzed by UGT2B4 and 2B7.

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 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.

Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors.

Studies in pregnant rabbits were conducted to evaluate if there are any differences in the uptake of thalidomide into the intrauterine compartment and developmental toxicity risk following oral and intravaginal administration. Thalidomide concentrations in maternal plasma, yolk sac cavity (YSC) fluid and embryo following intravaginal administration were 2- to 7-fold lower than their respective levels after oral administration. Ratios of thalidomide concentration in YSC fluid to maternal plasma were similar between these two routes, indicating no difference in uptake into the intrauterine compartment. A rabbit embryo-fetal development study using oral and intravaginal thalidomide administration at 2mg/kg/day (a dose >10,000-fold higher than the expected amount of thalidomide in human semen) did not result in any developmental abnormalities. These data demonstrated no preferential transfer mechanism of thalidomide from vagina to conceptus, and no additional embryo-fetal developmental toxicity risks with thalidomide exposure via the vaginal route.

Pomalidomide, a potent novel immunomodulatory agent, has been developed as a racemic mixture of its R- and S-isomers. Pharmacokinetic (PK) analyses were conducted to determine the PK disposition of the isomers from their PK profiles in humans and monkeys. Modeling and simulation were performed to describe the observed PK profiles and explore potential differences in isomer disposition and exposure. PK profiles of S- and R-isomers were measured in a human absorption, distribution, metabolism, and excretion study after oral administration of racemate. PK profiles of S- and R-isomers were measured in monkeys after intravenous and oral administration of S- or R-isomers and pomalidomide racemate. Modeling and simulation were performed using NONMEM 7.2 (Globomax, Ellicott City, MD) to describe the observed PK profiles of S- and R-isomers in humans and monkeys. The results showed that in humans, the in vivo elimination rate of pomalidomide isomers was lower than the R-/S-interconversion rate, resulting in no clinically relevant difference in overall exposure to the two isomers. However, in monkeys, the in vivo elimination rate was higher than the R-/S-interconversion rate, resulting in 1.72- and 1.55-fold differences in R- versus S-isomer exposures. Monte Carlo simulation indicated that exposure to R- and S-enantiomers in humans should be comparable even if single isomers are administered. Thus, in humans, rapid isomeric interconversion of pomalidomide isomers results in comparable exposure to R- and S-enantiomers regardless of whether pomalidomide is administered as a single enantiomer or as a racemate, therefore justifying the clinical development of pomalidomide as a racemate.

Introduction There is substantial interest in implementation of image-guided intensity-modulated radiotherapy (IG-IMRT) in the post-prostatectomy setting. We describe our implementation of IG-IMRT, and examine how often published organ-at-risk (OAR) constraints were met. Furthermore, we evaluate the incidence of acute genitourinary and gastrointestinal toxicities when patients were treated according to our protocol. Methods Patients were eligible if they received post-prostatectomy radiotherapy (PPRT). Planning data were collected prospectively, and toxicity assessments were collected before, during and after treatment. Results Seventy-five eligible patients received either 64 Gy (19%) or 66 Gy (81%) in a single phase to the prostate bed. Suggested rectal dose-constraints of V40Gy

Background: 4β-hydroxycholesterol (4βHC) has recently been proposed as a potential endogenous biomarker for CYP3A activity. Developing bioanalytical assays for 4βHC is challenging for several reasons, including endogenous background levels in plasma; the presence of free and ester forms; the inherent lack of MS sensitivity; and the presence of multiple positional isomers. Results: Bioanalytical assays in mouse, rat, dog and human plasma were adapted and modified from a previous published human plasma assay for 4βHC by using alkaline de-esterification, picolinic derivatization, a surrogate analyte (d7-4βHC) in authentic matrices and chromatographic conditions that showed good separation from isobaric, positional isomers. Conclusion: These assays were applied to multiple studies and demonstrated potential applications of 4βHC as a CYP3A biomarker across preclinical and clinical settings.

Apremilast is a novel, orally available small molecule that specifically inhibits PDE4 and thus modulates multiple pro- and anti-inflammatory mediators, and is currently under clinical development for the treatment of psoriasis and psoriatic arthritis. The pharmacokinetics and disposition of [(14)C]apremilast was investigated following a single oral dose (20 mg, 100 μCi) to healthy male subjects. Approximately 58% of the radioactive dose was excreted in urine, while faeces contained 39%. Mean C(max), AUC(0-∞) and t(max) values for apremilast in plasma were 333 ng/mL, 1970 ng*h/mL and 1.5 h. Apremilast was extensively metabolized via multiple pathways, with unchanged drug representing 45% of the circulating radioactivity and7% of the excreted radioactivity. The predominant metabolite was O-desmethyl apremilast glucuronide, representing 39% of plasma radioactivity and 34% of excreted radioactivity. The only other radioactive components that represented4% of the excreted radioactivity were O-demethylated apremilast and its hydrolysis product. Additional minor circulating and excreted compounds were formed via O-demethylation, O-deethylation, N-deacetylation, hydroxylation, glucuronidation and/or hydrolysis. The major metabolites were at least 50-fold less pharmacologically active than apremilast. Metabolic clearance of apremilast was the major route of elimination, while non-enzymatic hydrolysis and excretion of unchanged drug were involved to a lesser extent.

Intravenous (i.v.) temsirolimus, a novel inhibitor of mammalian target of rapamycin (mTOR), is approved for treatment of renal cell carcinoma. In vitro studies with pooled human liver microsomes showed that temsirolimus and its principal metabolite, sirolimus, inhibit the CYP2D6 isozyme (K(i) = 1.5 and 5 microM, respectively), indicating potential for pharmacokinetic interaction with agents that are substrates of CYP2D6.This 2-period study in healthy subjects investigated the pharmacokinetics of a single oral 50-mg dose of the CYP2D6 substrate desipramine, first without and subsequently with a single coadministered i.v. 25-mg dose of temsirolimus.The study population consisted of 25 males and 1 female; 10 were black, 12 were white, and 4 were of other races. Plasma and whole blood samples were available from all 26 subjects in period 1 following oral desipramine and from 23 subjects in period 2 following oral desipramine and i.v. temsirolimus coadministration. The 90% confidence intervals for least squares geometric mean ratios of desipramine and 2-hydroxy-desipramine C(max), AUC(T), and AUC were within 80-125%, indicating that parameter differences did not manifest into clinically relevant exposure changes. A single i.v. 25-mg dose of temsirolimus, alone or with desipramine, was well tolerated in healthy subjects.A single i.v. 25-mg dose of temsirolimus did not alter disposition of desipramine. Temsirolimus i.v. 25 mg may be safely administered with agents metabolized through the CYP2D6 pathway, but vigilance for drug interaction is warranted in patients with advanced malignancies.

Pomalidomide offers an alternative for patients with relapsed/refractory multiple myeloma who have exhausted treatment options with lenalidomide and bortezomib. Little is known about pomalidomide's potential for drug-drug interactions (DDIs); as pomalidomide clearance includes hydrolysis and cytochrome P450 (CYP450)-mediated hydroxylation, possible DDIs via CYP450 and drug-transporter proteins were investigated in vitro and in a clinical study. In vitro pomalidomide was neither an inducer nor inhibitor of CYP450, nor an inhibitor of transporter proteins P glycoprotein (P-gp), BCRP, OAT1, OAT3, OCT2, OATP1B1, and OATP1B3. Oxidative metabolism of pomalidomide was predominately mediated by CYP1A2 and CYP3A4, and pomalidomide was shown to be a P-gp substrate. In healthy males, co-administration of oral (4 mg) pomalidomide with ketoconazole (CYP3A/P-gp inhibitor) or carbamazepine (CYP3A/P-gp inducer) did not result in clinically relevant changes in pomalidomide exposure. Co-administration of pomalidomide with fluvoxamine (CYP1A2 inhibitor) in the presence of ketoconazole approximately doubled pomalidomide exposure. Pomalidomide appears to have low potential for clinically relevant DDI and is unlikely to affect the clinical exposure of other drugs. Avoid co-administration of strong CYP1A2 inhibitors unless medically necessary. Pomalidomide dose should be reduced by 50% if co-administered with strong CYP1A2 inhibitors and strong CYP3A/P-gp inhibitors.

Background Pelvic radiation disease (PRD) also widely known as "radiation proctopathy" is a well recognised late side-effect following conventional prostate radiotherapy. However, endoscopic evaluation and/or specialist referral for new or persistent post-prostate radiotherapy bowel symptoms is not routine and serious diagnoses may potentially be missed. Here we report a policy of endoscopic evaluation of bowel symptoms persisting >90days post radiotherapy for prostate cancer. Methods and materials A consecutive series of 102 patients who had radical prostate intensity-modulated radiotherapy (IMRT)/image-guided radiotherapy (IGRT) and who had new or ongoing bowel symptoms or positive faecal occult blood tests (FOBT) on follow up visits more than three months after treatment, were referred for endoscopic examination. All but one (99%) had full colonoscopic investigation. Results Endoscopic findings included gastric/colonic/rectal polyps (56%), diverticular disease (49%), haemorrhoids (38%), radiation proctopathy (29%), gastritis/oesophagitis (8%) and rarer diagnoses, including bowel cancer which was found in 3%. Only four patients (4%) had radiation proctopathy without associated pathology and 65 patients (63%) had more than one diagnosis. If flexible sigmoidoscopy alone were used, 36.6% of patients and 46.6% patients with polyp(s) would have had their diagnoses missed. Conclusions Our study has shown that bowel symptoms following prostate IMRT/IGRT are due to numerous diagnoses other than PRD, including malignancy. Routine referral pathways should be developed for endoscopic evaluation/specialist review for patients with new or persistent bowel symptoms (or positive FOBT) following prostate radiotherapy. This recommendation should be considered for incorporation into national guidelines.

There is substantial interest in implementation of image-guided intensity-modulated radiotherapy (IG-IMRT) in the post-prostatectomy setting. We describe our implementation of IG-IMRT, and examine how often published organ-at-risk (OAR) constraints were met. Furthermore, we evaluate the incidence of acute genitourinary and gastrointestinal toxicities when patients were treated according to our protocol.Patients were eligible if they received post-prostatectomy radiotherapy (PPRT). Planning data were collected prospectively, and toxicity assessments were collected before, during and after treatment.Seventy-five eligible patients received either 64 Gy (19%) or 66 Gy (81%) in a single phase to the prostate bed. Suggested rectal dose-constraints of V40Gy 60% and V60Gy 40% were met in 64 (85%) and 75 (100%) patients, respectively. IMRT-specific rectal dose-constraints of V40Gy 35% and V65Gy 17% were achieved in 5 (7%) and 57 (76%) of patients. Bladder dose-constraint (V50Gy 50%) was met in 58 (77%) patients. Two patients (3%) experienced new grade 3 genitourinary toxicity and one patient (1%) experienced new grade 3 gastroinestinal toxicity. All grade 3 toxicities had improved by 3-month review. Overall deterioration in urinary and gastrointestinal symptoms occurred in 33 (44%) and 35 (47%) of patients respectively.We report on our implementation of PPRT which takes into account nationally adopted guidelines, with a margin reduction supported by use of daily image guidance. Non-IMRT OAR constraints were met in most cases. IMRT-specific constraints were less often achieved despite margin reductions, suggesting the need for review of guidelines. Severe toxicity was rare, and most patients did not experience deterioration in urinary or bowel function attributable to radiotherapy.

Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3−5%), prodrug derivatives (3a−h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.

Tigecycline, a novel, first-in-class glycylcycline antibiotic, has been approved for the treatment of complicated intra-abdominal infections and complicated skin and skin structure infections. The pharmacokinetics, metabolism, and excretion of [(14)C]tigecycline were examined in healthy male volunteers. Tigecycline has been shown to bind to bone; thus, to minimize the amount of radioactivity binding to bone and to maximize the recovery of radioactivity, tigecycline was administered intravenously (30-min infusion) as a single 100-mg dose, followed by six 50-mg doses, every 12 h, with the last dose being [(14)C]tigecycline (50 microCi). After the final dose, the pharmacokinetics of tigecycline in serum showed a long half-life (55.8 h) and a large volume of distribution (21.0 l/kg), whereas radioactivity in serum had a shorter half-life (6.9 h) and a smaller volume of distribution (3.3 l/kg). The major route of elimination was feces, containing 59% of the radioactive dose, whereas urine contained 32%. Unchanged tigecycline was the predominant drug-related compound in serum, urine, and feces. The major metabolic pathways identified were glucuronidation of tigecycline and amide hydrolysis followed by N-acetylation to form N-acetyl-9-aminominocycline. The glucuronide metabolites accounted for 5 to 20% of serum radioactivity, and approximately 9% of the dose was excreted as glucuronide conjugates within 48 h. Concentrations of N-acetyl-9-aminominocycline were approximately 6.5% and 11% of the tigecycline concentrations in serum and urine, respectively. Excretion of unchanged tigecycline into feces was the primary route of elimination, and the secondary elimination pathways were renal excretion of unchanged drug and metabolism to glucuronide conjugates and N-acetyl-9-aminominocycline.

Introduction Pomalidomide (POM) is an IMiD® immunomodulatory agent recently approved by the FDA for the treatment of patients with relapsed/refractory multiple myeloma. The prevalence of polypharmacy in disease treatment raises the possibilities of drug-drug interactions. Therapies that are CYP450 inhibitors, inducers, or transporter inhibitors, may alter the clinical exposure of substrates of these enzymes and transporters when they are administered concomitantly. POM is known to be predominantly metabolized via CYP450-mediated hydroxylation.1 The aim was to investigate the inhibition/induction potential of POM and its sensitivity as a CYP450 substrate in vitro, and to evaluate the impact of strong CYP450 inhibitors/inducers and a P-glycoprotein (P-gp) inhibitor on the pharmacokinetics (PK) of POM in healthy male subjects. Methods In vitro analyses were conducted using standard published methodologies.2-7 The in vitro data were followed up with a phase 1, open-label, non-randomized study in healthy men with single doses (SD) of POM. The study comprised a screening phase, 2 parallel treatment groups and a safety follow-up. Subjects in Part 1 received POM (4 mg SD) alone; ketoconazole (KETO 200 mg twice daily [BID] for 7 days) + POM (4 mg SD on day 5); and KETO (200 mg BID) + fluvoxamine (FLUV 50 mg BID) for 7 days + POM (4 mg SD on day 5) in three sequential periods to evaluate the effect of CYP3A4 and P-gp (KETO) and CYP1A2 (FLUV) inhibition on POM PK. Subjects in Part 2 received POM (4 mg SD) alone followed by carbamazepine (CARB 200 mg BID) for 11 days + POM (4 mg SD on day 10) in two sequential periods to evaluate the effect of CYP3A4 induction on POM PK. Serial blood samples were collected to determine the plasma concentrations of POM, FLUV, KETO, CARB and CARB-10, 11-epoxide by validated LC-MS/MS assay. PK and safety data were summarized using descriptive statistics. An analysis of variance model was performed on natural log transformed PK data, and used to estimate the ratio of geometric means between POM and the other drugs with treatments as fixed effects and subjects as random effect. Results In vitro, POM did not inhibit or induce CYP450 enzymes, nor the transporters P-gp, BCRP, OAT1, OAT2, OAT3, OATP1B1, or OATP1B3. The in vitro oxidative metabolism of POM was predominately mediated by CYP3A4 and CYP1A2. In the clinical trial, all 32 enrolled subjects (age 20–54 years; BMI 19.3–30.3 kg/m2) were included in the PK and safety analyses. Statistical comparison showed that the mean exposure of POM administered after multiple doses of KETO was increased by ∼19% (AUC0-inf) and 7% (Cmax) compared to exposure of POM alone (Table). Addition of FLUV to the POM + KETO regimen increased mean exposure of POM by ∼107% (AUC0-inf) and 13% (Cmax) compared to POM + KETO. Overall, co-administration of POM + KETO + FLUV increased mean exposure of POM by ∼146% (AUC0-inf) and 21% (Cmax) compared to POM alone. The mean exposure of POM when administered after multiple doses of CARB decreased by ∼20% (AUC0-inf) and 25% (Cmax) compared to exposure of POM alone. The mean estimated terminal half-life of POM was similar with or without KETO or CARB (range 5.85 to 6.77 h), but increased in the presence of KETO + FLUV (12.37 h), suggesting that the predominant interaction may be on the clearance (CL/F) rather than the absorption phase of POM. POM CL/F was decreased by ∼16% in the presence of KETO (6.96 L/h), and decreased by ∼56% in the presence of KETO + FLUV (3.64 L/h), compared to POM alone (8.27 L/h). In contrast, POM + CARB increased POM CL/F compared to POM alone (9.49 versus 7.56 L/h). POM 4 mg SD was generally well tolerated either alone or with the other drugs. The most common POM-related adverse event (AE) was nausea (6.3% of subjects). No deaths or serious AEs were reported. Conclusions POM appears to have a low potential for drug-drug interactions. POM is not a CYP450 inhibitor, inducer, or transporter inhibitor, in vitro and is therefore unlikely to affect the exposure of other drugs clinically. Co-administration of POM with the strong CYP3A4/5 and P-gp inhibitor KETO, or the strong CYP3A4/5 inducer CARB, had no clinically relevant effect on exposure to POM. Co-administration of POM with a strong CYP1A2 inhibitor (FLUV) will likely increase systemic exposure to POM and subjects receiving these concomitantly should be closely monitored for the occurrence of side-effects. POM 4 mg was generally well tolerated. Disclosures: Kasserra: Celgene: Employment, Equity Ownership. Assaf:Celgene Corporation: Employment, Equity Ownership. Hoffmann:Celgene Corporation: Employment, Equity Ownership. Li:Celgene Corporation: Employment, Equity Ownership. Liu:Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Kumar:Celgene Corporation: Employment, Equity Ownership. Palmisano:Celgene Corporation: Employment, Equity Ownership.