Prematurity and associated future paediatric airway pathology: experience from a single tertiary paediatric ENT centre.

PURPOSE: Enhanced management of the pre-term patient has resulted in improved survival rates in increasingly premature patients. Although prematurity predisposes to congenital airway pathology, there is also increased risk of endotracheal intubation, and therefore acquired subglottic pathology. We sought to evaluate airway pathology in children outside the neonatal period with a history of prematurity to explore the relationship between prematurity and upper airway pathologies. METHODS: Data for patients undergoing elective microlaryngobronchoscopy (MLB) at our centre were collected prospectively over a 5-year period. Patients identified as premature were sub-classified by the grade of prematurity. RESULTS: 339 patients over 1 month of age underwent MLB, of which 56 (16.5%) were born prematurely. Of those with identified airway pathology, 49 (23.4%) were born prematurely, accounting for 32.6% of subglottic stenosis (n = 30), 24% of laryngomalacia (n = 13) and 19% of laryngeal cleft diagnoses (n = 16). 49 premature patients (87.5%) had one or more airway pathologies diagnosed. Multi-level airway pathology was seen in twelve premature infants (21.4%), demonstrating a statistically significant association (odds ratio 3.396; 95% CI 1.697-6.842; p value < 0.0016). Incidence of airway pathology, the severity of airway disease and multi-level airway pathology were not related to the grade of prematurity. CONCLUSIONS: Premature patients account for a significant proportion of the workload within our tertiary centre due to improving neonatal care and survival in pre-term infants. We suggest early paediatric ENT evaluation for ex-premature patients with symptoms of airway pathology, with a low threshold for MLB. Improving neonatal survival rates in ever-increasing prematurity will require the further provision of specialist paediatric ENT services to manage their ongoing care.

Evaluation of covariate effects on pharmacokinetics of monoclonal antibodies in oncology.

AIMS: The development of monoclonal antibodies (mAbs) requires an understanding of the interindividual variability (IIV) in pharmacokinetics (PK) at the population level facilitated by population PK (PopPK) modelling. However, there is no clear rationale for selecting which covariates to screen during PopPK model development. Here, we compare the effect of covariates on PK parameters for mAbs in oncology and identify the most commonly used covariates affecting PK parameters. METHODS: All 25 mAbs approved for therapeutic use in oncology until December 2017 by the Food and Drug Administration and the European Medicines Agency were selected for study. Literature searches revealed 23 available PopPK models for these mAbs. To understand the magnitude and types of covariate effect on PK parameters, all covariates included in the final PopPK model for each mAb were summarized. RESULTS: The most commonly identified covariates were baseline body weight (BW; 17 mAbs), baseline serum albumin (8 mAbs), and sex (7 mAbs) on clearance; and BW (16 mAbs) and sex (12 mAbs) on central volume of distribution. A reduced PopPK model was developed for nivolumab and ipilimumab using these covariates, and the percentage of explained IIV from the reduced model (20.3% and 16.8%, respectively) was compared with that from the full model (24.5% and 27.9%, respectively). CONCLUSIONS: This analysis provides a uniform platform for selecting covariates and suggests that the effect of BW, albumin and sex should be included during the development of PopPK models for mAbs in oncology. The reduced model was able to explain IIV to a similar extent as the full model.

A multi-arm phase I dose escalating study of an oral NOTCH inhibitor BMS-986115 in patients with advanced solid tumours.

Background Inhibiting Notch is a promising anti-cancer strategy as it plays a critical role in cancer stem cells maintenance and tumour angiogenesis. BMS-986115 is an orally active, selective inhibitor of gamma-secretase mediated Notch signalling. Method Two dose escalation schedules (Arm-A continuous daily schedule and Arm-B intermittent 2 times weekly schedule) of BMS-986115 were evaluated in advanced solid tumour patients. The primary objective was to establish the safety, tolerability and Maximum Tolerated Dose (MTD) of BMS-986115. Results Thirty six patients (24 in Arm A and 12 in Arm B) were treated. The most frequent treatment related adverse advents were diarrhoea (72%), hypophosphataemia (64%), and nausea (61%). The MTD was 1.5 mg daily in Arm A but not established in Arm B. Four patients in Arm A and 2 in Arm B experienced dose limiting toxicities (grade 3 nausea, diarrhoea, pruritus/urticaria and ileus). BMS-986115 showed dose related increase in exposure within the dose range tested. Target inhibition of Notch pathway related genes was observed. Three patients in Arm A and 2 in Arm B achieved stable disease for more than 6 months. Conclusion The daily oral dosing of BMS-986115 is safe and tolerable with biological activity demonstrated by continuous target engagement and Notch signalling inhibition.

Identification of an atypical calcium-dependent calmodulin binding site on the C-terminal domain of GluN2A.

N-methyl-D-aspartate (NMDA) receptors are calcium-permeable ion channels assembled from four subunits that each have a common membrane topology. The intracellular carboxyl terminal domain (CTD) of each subunit varies in length, is least conserved between subunits, and binds multiple intracellular proteins. We defined a region of interest in the GluN2A CTD, downstream of well-characterized membrane-proximal motifs, that shares only 29% sequence similarity with the equivalent region of GluN2B. GluN2A (amino acids 875-1029) was fused to GST and used as a bait to identify proteins from mouse brain with the potential to bind GluN2A as a function of calcium. Using mass spectrometry we identified calmodulin as a calcium-dependent GluN2A binding partner. Equilibrium fluorescence spectroscopy experiments indicate that Ca(2+)/calmodulin binds GluN2A with high affinity (5.2±2.4 nM) in vitro. Direct interaction of Ca(2+)/calmodulin with GluN2A was not affected by disruption of classic sequence motifs associated with Ca(2+)/calmodulin target recognition, but was critically dependent upon Trp-1014. These findings provide new insight into the potential of Ca(2+)/calmodulin, previously considered a GluN1-binding partner, to influence NMDA receptors by direct association.

Considerations for the prediction of survival time in pancreatic cancer based on registry data.

Semi-parametric and parametric survival models in patients with pancreatic adenocarcinoma (PC) using data from Surveillance, Epidemiology, and End Result (SEER) registry were developed to identify relevant covariates affecting survival, verify against external patient data and predict disease outcome. Data from 82,251 patients was extracted using site and histology codes for PC in the SEER database and refined based on specific cause of death. Predictors affecting survival were selected from SEER database; the analysis dataset included 2,437 patients. Survival models were developed using both semi-parametric and parametric approaches, evaluated using Cox-Snell and deviance residuals, and predictions were assessed using an external dataset from Saint Louis University (SLU). Prediction error curves (PECs) were used to evaluate prediction performance of these models compared to Kaplan-Meier response. Median overall survival time of patients from SEER data was 5 months. Our analysis shows that the PC data from SEER was best fitted by both semi-parametric and the parametric model with log-logistic distribution. Predictors that influence survival included disease stage, grade, histology, tumor size, radiation, chemotherapy, surgery, and lymph node status. Survival time predictions from the SLU dataset were comparable and PECs show that both semi-parametric and parametric models exhibit similar predictive performance. PC survival models constructed from registry data can provide a means to classify patients into risk-based subgroups, to predict disease outcome and aide in the design of future prospective randomized trials. These models can evolve to incorporate predictive biomarker and pharmacogenetic correlates once adequate causal data is established.

The changing face of paediatric airway endoscopic surgery: An 8-year single surgeon review.

INTRODUCTION: As a recently established division, we sought to reflect on the development of our paediatric airway surgery service, and prospectively examine the diagnoses that underwent microlaryngobronchoscopy (MLB) to help quantify the evolving population demographics of paediatric airway disorders. MATERIAL AND METHODS: This was a prospective longitudinal study conducted of all paediatric MLBs performed by a single surgeon in a tertiary paediatric ENT centre between 2012 and 2019. RESULTS: A total of 1040 MLBs were performed in 498 patients at the paediatric ENT centre of the Royal London Hospital. Median age at first procedure was 19 months. Median follow-up was 48 months. Primary diagnoses were laryngomalacia (21%), subglottic stenosis (SGS - 18%), laryngeal cleft (13%), and normal anatomy (28.3%). Repeat procedures were needed in 39.1% patients, who underwent a median of 2 repeat procedures. SGS (57.7%) constituted majority of the repeat category, followed by laryngeal cleft (12.36%), laryngomalacia (10.15%), unilateral/bilateral vocal cord palsy(4.24%) and laryngeal papilloma(4.24%). Laryngeal papilloma constituted largest number of procedures per patient (Median = 4, IQR = 5.75), followed by subglottic web and SGS. Mean length of stay(LOS) was 0.67 ± 0.96 days(d), with laryngeal cleft cases recording longest mean LOS. There was a steady increase in proportion of day-surgeries across study period [6.9% (2012) vs 59%(2019)]. CONCLUSION: SGS constitutes the major bulk of paediatric airway surgery, reflective of increasing number of premature births and prolonged intubation among neonates. Day-case MLB is a safe and feasible option in selected patients. This long-term data provides useful information to accurately prognosticate patients regarding potential number of repeat procedures for each diagnosis.

Preclinical Characterization and Phase I Trial Results of a Bispecific Antibody Targeting PD-L1 and 4-1BB (GEN1046) in Patients with Advanced Refractory Solid Tumors.

Checkpoint inhibitors (CPI) have revolutionized the treatment paradigm for advanced solid tumors; however, there remains an opportunity to improve response rates and outcomes. In preclinical models, 4-1BB costimulation synergizes with CPIs targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis by activating cytotoxic T-cell-mediated antitumor immunity. DuoBody-PD-L1×4-1BB (GEN1046) is an investigational, first-in-class bispecific immunotherapy agent designed to act on both pathways by combining simultaneous and complementary PD-L1 blockade and conditional 4-1BB stimulation in one molecule. GEN1046 induced T-cell proliferation, cytokine production, and antigen-specific T-cell-mediated cytotoxicity superior to clinically approved PD-(L)1 antibodies in human T-cell cultures and exerted potent antitumor activity in transplantable mouse tumor models. In dose escalation of the ongoing first-in-human study in heavily pretreated patients with advanced refractory solid tumors (NCT03917381), GEN1046 demonstrated pharmacodynamic immune effects in peripheral blood consistent with its mechanism of action, manageable safety, and early clinical activity [disease control rate: 65.6% (40/61)], including patients resistant to prior PD-(L)1 immunotherapy. SIGNIFICANCE: DuoBody-PD-L1×4-1BB (GEN1046) is a first-in-class bispecific immunotherapy with a manageable safety profile and encouraging preclinical and early clinical activity. With its ability to confer clinical benefit in tumors typically less sensitive to CPIs, GEN1046 may fill a clinical gap in CPI-relapsed or refractory disease or as a combination therapy with CPIs. See related commentary by Li et al., p. 1184. This article is highlighted in the In This Issue feature, p. 1171.

MDR1 function is sensitive to the phosphorylation state of myosin regulatory light chain.

Multiple drug resistance protein 1 (MDR1) is composed of two homologous halves separated by an intracellular linker region. The linker has been reported to bind myosin regulatory light chain (RLC), but it is not clear how this can occur in the context of a myosin II complex. We characterized MDR1-RLC interactions and determined that binding occurs via the amino terminal of the RLC, a domain that typically binds myosin heavy chain. MDR1-RLC interactions were sensitive to the phosphorylation state of the light chain in that phosphorylation by myosin light chain kinase (MLCK) resulted in a loss of binding in vitro. We used ML-7, a specific inhibitor of MLCK, to study the functional consequences of disrupting RLC phosphorylation in intact cells. Pretreatment of polarized Madin-Darby canine kidney cells stably expressing MDR1 with ML-7 produced a significant increase in apical to basal permeability and a corresponding decrease in the efflux ratio (threefold; p<0.01) of [(3)H]-digoxin, a classic MDR1 substrate. Together these data show that MDR1-mediated transport of [(3)H]-digoxin can be modulated by pharmacological manipulation of myosin RLC, but direct MDR1-RLC interactions are atypical and not explained by the structure of the myosin II holoenzyme.

Zwitterionic chitosan derivatives for pH-sensitive stealth coating.

Zwitterionic chitosan, a chitosan derivative with a unique pH-dependent charge profile, was employed to create a stealth coating on the cationic surface of drug carriers. Zwitterionic chitosans were synthesized by amidation of chitosan with succinic anhydride. The succinic anhydride-conjugated chitosan had an isoelectric point, which could be easily tuned from pH 4.9 to 7.1 and showed opposite charges below and above the isoelectric point. The succinic anhydride-conjugated chitosan was able to inhibit the protein adsorption to the cationic surface at physiological pH, compatible with blood components and well tolerated upon intraperitoneal injection. The succinic anhydride-conjugated chitosan has the potential to serve as a coating material to prevent protein adsorption to cationic surfaces, which can be removed in a pH-responsive manner.

Drug delivery systems for intraperitoneal therapy.

Disorders associated with the peritoneal cavity include peritoneal adhesions and intraperitoneal (IP) malignancies. To prevent peritoneal adhesions, physical barrier devices are used to prevent organs from contacting other structures in the abdomen and forming adhesions, or pharmacological agents that interfere with adhesion formation are administered intraperitoneally. IP malignancies are other disorders confined to the peritoneal cavity, which are treated by combination of surgical removal and chemotherapy of the residual tumor. IP drug delivery helps in the regional therapy of these disorders by providing relatively high concentration and longer half-life of a drug in the peritoneal cavity. Various studies suggest that IP delivery of anti-neoplastic agents is a promising approach for malignancies in the peritoneal cavity compared to the systemic administration. However, IP drug delivery faces several challenges, such as premature clearance of a small molecular weight drug from the peritoneal cavity, lack of target specificity, and poor drug penetration into the target tissues. Previous studies have proposed the use of micro/nanoparticles and/or hydrogel-based systems for prolonging the drug residence time in the peritoneal cavity. This commentary discusses the currently used IP drug delivery systems either clinically or experimentally and the remaining challenges in IP drug delivery for future development.

Safety, Tolerability, and Potential Clinical Activity of a Glucocorticoid-Induced TNF Receptor-Related Protein Agonist Alone or in Combination With Nivolumab for Patients With Advanced Solid Tumors: A Phase 1/2a Dose-Escalation and Cohort-Expansion Clinical Trial.

IMPORTANCE: Multiple immunostimulatory agonist antibodies have been clinically tested in solid tumors to evaluate the role of targeting glucocorticoid-induced tumor necrosis factor (TNF) receptor-related protein in anticancer treatments. OBJECTIVE: To evaluate the safety and activity of the fully human glucocorticoid-induced TNF receptor-related protein agonist IgG1 monoclonal antibody BMS-986156 with or without nivolumab in patients with advanced solid tumors. DESIGN, SETTING, AND PARTICIPANTS: This global, open-label, phase 1/2a study of BMS-986156 with or without nivolumab enrolled 292 patients 18 years or older with advanced solid tumors and an Eastern Cooperative Oncology Group performance status of 1 or less. Prior checkpoint inhibitor therapy was allowed. Monotherapy and combination dose-escalation cohorts ran concurrently to guide expansion doses beginning October 16, 2015; the study is ongoing. INTERVENTIONS: The protein agonist BMS-986156 was administered intravenously at a dose of 10, 30, 100, 240, or 800 mg every 2 weeks as monotherapy, and in the combination group 30, 100, 240, or 800 mg plus 240 mg of nivolumab every 2 weeks; same-dose cohorts were pooled for analysis. One cohort also received 480 mg of BMS-986156 plus 480 mg of nivolumab every 4 weeks. MAIN OUTCOMES AND MEASURES: The primary end points were safety, tolerability, and dose-limiting toxic effects. Additional end points included antitumor activity per Response Evaluation Criteria in Solid Tumors, version 1.1, and exploratory biomarker analyses. RESULTS: With a follow-up range of 1.4 to 101.7 weeks (follow-up ongoing), 34 patients (16 women and 18 men; median age, 56.6 years [range, 28-75 years]) received monotherapy (4 patients completed initial treatment), and 258 patients (140 women and 118 men; median age, 60 years [range, 21-87 years]) received combination therapy (65 patients completed initial treatment). No grade 3 to 5 treatment-related adverse events occurred with BMS-986156 monotherapy; grade 3 to 4 treatment-related adverse events occurred in 24 patients (9.3%) receiving BMS-986156 plus nivolumab, with no grade 5 treatment-related adverse events. One dose-limiting toxic effect (grade 4 elevated creatine phosphokinase levels) occurred in a patient receiving 800 mg of BMS-986156 plus 240 mg of nivolumab every 2 weeks; BMS-986156 with or without nivolumab exhibited linear pharmacokinetics with dose-related increase after a single dose. Peripheral T-cell and natural killer-cell proliferation increased after administration of BMS-986156 with or without nivolumab. No consistent and significant modulation of intratumoral CD8+ T cells and FoxP3+ regulatory T cells was observed. No responses were seen with BMS-986156 alone; objective response rates ranged from 0% to 11.1% (1 of 9) across combination therapy cohorts, with a few responses observed in patients previously treated with anti-programmed death receptor (ligand) 1 therapy. CONCLUSIONS AND RELEVANCE: Based on this cohort, BMS-986156 appears to have had a manageable safety profile, and BMS-986156 plus nivolumab demonstrated safety and efficacy comparable to historical data reported for nivolumab monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02598960.

Nivolumab Clearance Is Stationary in Patients With Resected Melanoma on Adjuvant Therapy: Implications of Disease Status on Time-Varying Clearance.

Nivolumab clearance (CL) in patients with advanced melanoma (MEL) decreases over the treatment duration, with change in CL associated with improved disease status, measured by reduced tumor burden. Here, we characterize the pharmacokinetics of nivolumab administered as adjuvant therapy for patients with MEL (AdjMEL) whose tumors were removed by surgical resection. A population pharmacokinetic model was developed using data from 1,773 patients with AdjMEL, MEL, non-small cell lung cancer, and other solid tumors who received nivolumab over a dose range of 0.1-20 mg/kg every 2 weeks. In patients with AdjMEL, the geometric mean nivolumab CL of 6.0 mL/hour was 40% lower at baseline and did not vary with time and 20% lower at steady state compared with patients with MEL. Lower nivolumab CL in patients with AdjMEL and absence of time dependence support the hypothesis that changes in nivolumab CL in the metastatic setting are associated with disease status after treatment.

Challenges and Opportunities With Oncology Drug Development in China.

Cancer is a growing public health problem in China. Despite the high unmet medical need of patients with cancer in China, oncology drug approvals have historically lagged behind those in the West, mainly the United States and Europe. China is currently undertaking regulatory reforms at a fast pace in order to mitigate this lag.

Co-expression of myosin II regulatory light chain and the NMDAR1 subunit in neonatal and adult mouse brain.

Movement of glutamate receptors in neurons likely involves direct and indirect association of receptor subunits with microtubule- and actin-based motor proteins. We have previously shown that myosin II regulatory light chain (RLC) binds directly to subunits of the NMDA-type glutamate receptor (NR), suggesting that NMDA receptors are closely associated with a myosin II motor complex. Using a polyclonal antibody predicted to recognize all RLC isoforms previously described in rodent brain, we report the expression of RLC and the NR1 subunit in cortex, hippocampus and cerebellum of postnatal day 0 (P0) and adult mouse. Although myosin RLC was not exclusively localized with NR1 by immunohistochemistry, co-staining was striking in the neuronal soma of deep cortical neurons and Purkinje neurons of the cerebellum which showed a punctate, perinuclear pattern of immunoreactivity. These neuronal populations were identified using a monoclonal antibody directed against a nuclear-specific, transcriptional repressor, chicken ovalbumin upstream promoter-transcription factor (COUP-TF)-interacting protein 2 (CTIP2). Co-expression of NR1 and a myosin II motor was validated using an isoform specific anti-nonmuscle myosin II-B heavy chain (NMHC II-B) antibody. Our findings support the idea that there is regional heterogeneity in the molecular composition of the NMDA receptor-associated cytoskeleton, and suggest that NR subunits may be associated with an actin-based, myosin II-B motor within the endomembrane system of some neuronal populations. Differential staining patterns observed with light and heavy chain antibodies, however, suggest that there is also heterogeneity in the composition of myosin II complexes in brain.

Evaluation of Immunogenicity of Nivolumab Monotherapy and Its Clinical Relevance in Patients With Metastatic Solid Tumors.

Nivolumab is a fully human IgG4 monoclonal antibody targeting the programmed death-1 (PD-1) receptor that blocks interactions between PD-1 and its ligands on tumor cells to prevent T-cell exhaustion in patients with cancer. It has demonstrated efficacy in multiple tumor types, including melanoma, non-small-cell lung cancer, and renal cell carcinoma. This analysis assessed the immunogenicity of nivolumab and its impact on pharmacokinetics, safety, and efficacy in patients with solid tumors enrolled in 6 clinical studies. The incidence and prevalence of antidrug antibodies (ADAs) were determined by validated electrochemiluminescence assays in samples collected during nivolumab treatment and up to 100 days after the last dose. Confirmed positive samples from the 6 studies were also tested for presence of neutralizing antibodies (NAbs). Among 1086 nivolumab-treated patients, 138 patients (12.7%) were ADA positive (relative to baseline), only 3 (0.3%) of whom were persistently positive for ADA, and 9 (0.8%) were NAb positive at 1 time point. The presence of ADAs was not associated with hypersensitivity, infusion reactions, or loss of efficacy and had minimal impact on nivolumab clearance. Additionally, the presence of NAbs was not associated with loss of efficacy. In conclusion, immunogenicity of nivolumab is not clinically meaningful.

Nivolumab Exposure-Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non-Small Cell Lung Cancer.

Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients with previously treated, advanced non-small cell lung cancer (NSCLC). Exposure-response (E-R) analyses for efficacy and safety were conducted to inform the benefit-risk assessment of nivolumab in this patient population.Experimental Design: The analyses used clinical trial data from patients with squamous (n = 293) or nonsquamous (n = 354) NSCLC from four clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E-R efficacy analyses were performed by investigating the relationship between time-averaged nivolumab concentration after the first dose (Cavg1) and the probability of overall survival by histology. E-R safety analyses examined relationships between nivolumab Cavg1 and hazards of adverse events leading to discontinuation or death (AEs-DC/D).Results: Nivolumab exposure was not associated with overall survival [the 95% confidence interval (CI) of effect included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555-1.16) or nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683-1.29). Similarly, nivolumab exposure was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI, 0.644-1.31). The risk of AEs-DC/D was similar among patients with squamous or nonsquamous histology.Conclusions: Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E-R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC. Clin Cancer Res; 23(18); 5394-405. ©2017 AACR.

Challenges and considerations for development of therapeutic proteins in pediatric patients.

Target specificity and generally good tolerability of therapeutic proteins (TPs) present desirable treatment opportunities for pediatric patients. However, little is known on the ontogeny of processes related to the pharmacokinetics (PK) and disposition of TPs. The science, regulatory requirements and strategy of developing TPs for children are evolving. Our current review of TPs, (with focus on monoclonal antibodies and fusion proteins) that were approved for pediatric use indicates that dose-selection for pediatric pivotal studies is often based on adult PK information alone. This approach might not be sufficient if more complex PK properties than simple linear PK are present. Body weight-based dosing for pediatric patients directly scaled down from adult dosing can lead to under-exposure in young pediatric patients who are usually in the lowest body-weight range. Tiered-fixed dosing can be reasonably effective for TPs in achieving comparable exposure in children over a wide age range. The uniqueness of the pediatric population, the practical challenges in conducting clinical studies in this population, as well as regulations from health authorities warrant including pharmacometrics as an integral component of pediatric drug development. We propose a framework distinct from previous proposals, to guide clinical pharmacology strategy for pediatric drug development specifically for TPs.

Modeling and simulation approach to support dosing and study design requirements for treating HIV-related neuropsychiatric disease with the NK1-R antagonist aprepitant.

Psychiatric illness is common in HIV-infected patients and underlines the importance for screening not only for cognitive impairment but also for co-morbid mental disease. The rationale for combining immunomodulatory neurokinin- 1 receptor (NK1-R) antagonists with combined antiretroviral therapy (cART) is based on multimodal pharmacologic mechanisms. The NK1-R antagonist aprepitant's potential utility as a drug for depression is complicated by >99.9% protein binding and both enzyme inhibition and induction of CYP3A4. A population-based PK model developed from a pilot Phase 1B trial in 19 HIV-infected patients (125 or 250 mg/d aprepitant for 2 weeks) was modified to account for enzyme induction and impact of an exposure enhancer on CYP3A4 metabolism. Likelihood of clinical success in depression was assessed based on achievement of target trough plasma concentration and evaluated using Monte Carlo simulation. Scenarios were generated for varying daily dose (375, 625, 750 and 875 mg), pharmacokinetic variability, exposure enhancement (EE), duration (2 and 6 months) and sample size (n=12 and 24/arm). Daily dosing of ≥ 625 mg with EE yielded desirable troughs (based on in vitro infectivity experiments) of > 2.65 ug/mL for the majority of virtual patients simulated. Results are dependent on the degree of exposure enhancement and extent of enzyme induction. Actual threshold exposure requirements for aprepitant in HIV-associated depression are unknown though preclinical evidence supports trough levels > 2.65 ug/mL. If 100% NK1r blockage is necessary for efficacy, doses of 875 mg (625 mg with EE) or higher may be required. The benefit of aprepitant on innate immunity(natural killer cells) and absence of negative effects onex vivo neutrophil chemotaxis alleviates concerns regarding drug dependent inhibition (DDI)-mediated infection risk.

Risk assessment of drug interaction potential and concomitant dosing pattern on targeted toxicities in pediatric cancer patients.

This investigation evaluated the impact of potential drug interactions on the incidence of reported toxicities seen with common dosing patterns in children with cancer, with the intent of being able to screen and reduce the incidence of adverse drug reactions (ADRs) in the future. Toxicity reported in pediatric cancer patients treated at the Children's Hospital of Philadelphia from 2004 to 2010 were abstracted from a cancer tumor registry and merged with drug order profiles from the medical record system. Analysis datasets were created in SAS and permutation algorithms were used to identify pairwise drug combinations associated with specific toxicity occurrence. Relative risk of toxicity based on dosing pattern was assessed via comparison to control patients. A total of 326 of 1,713 patients (19%) had reportable toxicities. Neutrophil count decreases and alanine aminotransferase increases represented the highest occurring, corresponding to 28.8% and 31.9% prevalence among patients reporting toxicity, respectively. Of coadministered drug pairs, acetaminophen-diphenhydramine occurred most frequently; however, methotrexate-vincristine was the highest occurring pair linked to a single toxicity (hepatotoxicity). Toxicity was highly associated with the diagnoses of leukemia (52.1%) or neuroblastoma (28.5%). Comparison of the dosing interval (≤30 versus >30 min) suggested that risk of toxicity can be associated with the timing of coadministration, with ≤30 min increasing the risk of hepatotoxicity with fentanyl-midazolam and methotrexate-midazolam combinations. Knowledge of drug interactions in children with cancer may help reduce the incidence of ADRs by providing pharmacotherapy options that may reduce the likelihood of toxicity.

Hyaluronic acid-based hydrogel for regional delivery of paclitaxel to intraperitoneal tumors.

Intraperitoneal (IP) chemotherapy is an effective way of treating local and regional malignancies confined in the peritoneal cavity such as ovarian cancer. However, a persistent major challenge in IP chemotherapy is the need to provide effective drug concentrations in the peritoneal cavity for an extended period of time. We hypothesized that hyaluronic acid (HA)-based in-situ crosslinkable hydrogel would serve as a carrier of paclitaxel (PTX) particles to improve their IP retention and therapeutic effects. In-vitro gel degradation and release kinetics studies demonstrated that HA gels could entrap microparticulate PTX (>100 µm) and release the drug over 10 days, gradually degraded by hyaluronidase, but had limited effect on retention of Taxol, a 14-nm micelle form of PTX. When administered IP to tumor-bearing nude mice, PTX was best retained in the peritoneal cavity as PTX-gel (microparticulate PTX entrapped in the HA gel), whereas Taxol-gel and other Taxol-based formulations left negligible amount of PTX in the cavity after 14 days. Despite the increase in IP retention of PTX, PTX-gel did not further decrease the tumor burdens than Taxol-based formulations, presumably due to the limited dissolution of PTX. This result indicates that spatial availability of a drug does not necessarily translate to the enhanced anti-tumor effect unless it is accompanied by the temporal availability.