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Intracellular adhesion molecule 1 (ICAM-1) is one of the most extensively studied inducible cell adhesion molecules which is responsible for several immune functions like T cell activation, extravasation, inflammation, etc. The molecule is constitutively expressed over the cell surface and is regulated up / down in response to inflammatory mediators like cellular stress, proinflammatory cytokines, viral infection. These stimuli modulate the expression of ICAM-1 primarily through regulating the ICAM-1 gene transcription. On account of the presence of various binding sites for NF-κB, AP-1, SP-1, and many other transcription factors, the architecture of the ICAM-1 promoter become complex. Transcription factors in union with other transcription factors, coactivators, and suppressors promote their assembly in a stereospecific manner on ICAM-1 promoter which mediates ICAM-1 regulation in response to different stimuli. Along with transcriptional regulation, epigenetic modifications also play a pivotal role in controlling ICAM-1 expression on different cell types. In this review, we summarize the regulation of ICAM-1 expression both at the transcriptional as well as post-transcriptional level with an emphasis on transcription factors and signaling pathways involved.

This work presents an end‐to‐end approach for assessing the absolute bioavailability of highly hydrophobic, poorly water‐soluble compounds that exhibit high nonspecific binding using venetoclax as a model drug. The approach utilizes a stable labeled i.v. microdose and requires fewer resources compared with traditional approaches that use radioactive 14C‐labeled compounds. The stable labeled venetoclax and internal standard were synthesized, then an i.v. formulation was developed. In the clinical study, female subjects received a single oral dose of venetoclax 100 mg followed by a 100‐µg i.v. dose of cold‐labeled 13C‐venetoclax at the oral time of maximum concentration (Tmax). The i.v. microdose was prepared as an extemporaneous, sterile compounded solution on the dosing day by pharmacists at the clinical site. Several measures were taken to ensure the sterility and safety of the i.v. preparation. A sensitive liquid chromatography‐tandem mass spectrometry method was developed to allow the detection of plasma levels from the i.v. microdose. Plasma samples were collected through 72 h, and pharmacokinetic parameters were estimated using noncompartmental methods. Postdosing sample analysis demonstrated the consistency of the preparations and allowed the precise calculation of the pharmacokinetic parameters based on the actual injected dose. The absolute bioavailability of venetoclax was estimated at 5.4% under fasting conditions. Venetoclax extraction ratio was estimated to be 0.06 suggesting that the fraction transferred from the enterocytes into the liver is limiting venetoclax bioavailability. The proposed framework can be applied to other highly hydrophobic, poorly water‐soluble compounds that exhibit high nonspecific binding to support the understanding of their absorption and disposition mechanisms and guide formulation development.

Veliparib (ABT‐888) is a poly(ADP‐ribose) polymerase inhibitor in development for the treatment of high‐grade ovarian cancer or BRCA‐mutated breast cancer in combination with carboplatin and paclitaxel. The population pharmacokinetics of veliparib were characterized using combined data from 1470 adult subjects with ovarian cancer, breast cancer, or other solid tumors enrolled in 6 phase 1 studies, 1 phase 2 study, and 2 phase 3 studies of veliparib oral doses of 10 to 400 mg twice daily as monotherapy or in combination with chemotherapy. A 1‐compartment model with linear clearance and first‐order absorption best characterized veliparib pharmacokinetics. The predicted apparent oral clearance (CL/F) and volume of distribution (Vc/F) were 479 L/day and 152 L, respectively. The significant covariates in the final model included albumin, creatinine clearance, strong inhibitors of cytochrome P450 (CYP) 2D6, and sex on CL/F and albumin, body weight, and sex on Vc/F. Mild and moderate renal impairment increased veliparib median (95%CI) steady‐state AUC (AUCss) by 27.3% (23.7%‐30.9%) and 65.4% (56.0%‐75.5%), respectively, compared with normal renal function. Male subjects had 16.5% (7.53%‐23.9%) lower AUCss compared with female subjects and coadministration with strong CYP2D6 inhibitors increased AUCss by 13.0% (6.11%‐20.8%). Race, age, region, cancer type, or enzyme (CYP3A4, CYP2C19) or transporter (P‐glycoprotein, multidrug and toxin extrusion protein 1/2, organic cation transporter 2) inhibiting/inducing comedications were not found to significantly impact veliparib pharmacokinetics. Other than baseline creatinine clearance and hence renal impairment effect on veliparib clearance, no other covariates had a clinically meaningful effect on veliparib exposure warranting dose adjustment.

Background Guggulu is an oleo gum resin obtained from the plant Commiphora wightii (Arn.) Bhand., used in Ayurved ic medicines for various ailments like anti-inflammatory conditions, hyperlipidemia, thyroid disorders etc. Guggulsterones E & Z are responsible for these broad ranges of pharmacological actions. It is recommended to do Shodhana (purification) before incorporating it into medicinal formulations. Sahasrayoga, an Ayurvedic text, emphasizes the purification of Guggulu in a particular media, which is a long run practice in Kerala. Objectives To compare the physicochemical and phytochemical parameters, quantitative estimation of Guggulsterone E & Z using high performance thin layer chromatography (HPTLC) and qualitative gas chromatography-mass spectrometry (GC-MS) analysis of Guggulu before and after purification. Methods Shodhana of Guggulu was performed in Water boiled with crushed fresh leaves of Neem (Azadirachta indica) and fresh rhizome of turmeric (Curcuma longa) using a special equipment (Dolayantra). Preliminary physicochemical and phytochemical evaluation, quantification of Guggulsterones E & Z using HPTLC and GC-MS analysis of raw and purified Guggulu were performed. Results Phytochemical evaluation of metabolites revealed marked variations. The mean concentrations of Guggulsterone E & Z showed significant differences before and after purification (pGuggulu. Conclusions Therapeutic efficacy of Guggulu might have enhanced after traditional purification.

Rotational Moulding (RM) is a versatile plastic processing method for the production of hollow products. Since the life expectancy of RM products are over several decades, prediction of mechanical properties like creep will be useful during the design phase of a product. In this research, an analytical model based on time hardening model was developed to predict and compare the creep behaviour of linear low-density polyethylene (LLDPE) and PP at 40 °C. The model uses some constants obtained from the experimental findings of a typical accelerated creep test using stepped isothermal method- time-temperature superposition (SIM-TTS). Based on the creep performance, the comparison of the two materials (LLDPE and PP) has been carried out and inferences have been made about their long term performance under constant stress.

We use density functional theory (DFT) to explore the physical properties of an $Er_{ W}$ point defect in monolayer $WS_{ 2}$. Our calculations indicate that electrons localize at the dangling bonds associated with a tungsten vacancy ($V_{W}$) and at the $Er^{ 3+}$ ion site, even in the presence of a net negative charge in the supercell. The system features a set of intra-gap defect states, some of which are reminiscent of those present in isolated $Er^{ 3+}$ ions. In both instances, the level of hybridization is low, i.e., orbitals show either strong Er or W character. Through the calculation of the absorption spectrum as a function of wavelength, we identify a broad set of transitions, including one possibly consistent with the $Er^{ 3+}$ $4I_{ 15/2} \rightarrow 4I_{ 13/2}$ observed in other hosts. Combined with the low native concentration of spin-active nuclei as well as the two-dimensional nature of the host, these properties reveal $Er:WS_{ 2}$ as a potential platform for realizing spin qubits that can be subsequently integrated with other nanoscale optoelectronic devices.

Strong light–matter coupling results in the formation of hybrid half-light half-matter excitations with modified energy levels. The strong coupling of excitons with photons in organic molecular sys...

A quasi-one-dimensional organic semiconductor, hepta(p-phenylene vinylene) (HPV), was incorporated into a DNA tensegrity triangle motif using a covalent strategy. 3D arrays were self-assembled from an HPV-DNA pseudo-rhombohedron edge by rational design and characterized by X-ray diffraction. Templated by the DNA motif, HPV molecules exist as single-molecule fluorescence emitters at the concentration of 8 mM within the crystal lattice. The anisotropic fluorescence emission from HPV-DNA crystals indicates HPV molecules are well aligned in the macroscopic 3D DNA lattices. Sophisticated nanodevices and functional materials constructed from DNA can be developed from this strategy by addressing functional components with molecular accuracy.

Simple Summary This study aimed to explore the potential role of PPARγ–DNMT1 interaction through PPAR-responsive elements (PPREs), which we have found to be enriched with Alu repeats. Apart from protein–protein interactions and co-expression in multiple cancer types, we exclusively described a prognostic role for PPARγ in uveal melanoma (UM). Abstract Background: PPARγ (peroxisome proliferator-activated receptor gamma) is involved in the pathology of numerous diseases, including UM and other types of cancer. Emerging evidence suggests that an interaction between PPARγ and DNMTs (DNA methyltransferase) plays a role in cancer that is yet to be defined. Methods: The configuration of the repeating elements was performed with CAP3 and MAFFT, and the structural modelling was conducted with HDOCK. An evolutionary action scores algorithm was used to identify oncogenic variants. A systematic bioinformatic appraisal of PPARγ and DNMT1 was performed across 29 tumor types and UM available in The Cancer Genome Atlas (TCGA). Results: PPAR-responsive elements (PPREs) enriched with Alu repeats are associated with different genomic regions, particularly the promotor region of DNMT1. PPARγ–DNMT1 co-expression is significantly associated with several cancers. C-terminals of PPARγ and DNMT1 appear to be the potential protein–protein interaction sites where disease-specific mutations may directly impair the respective protein functions. Furthermore, PPARγ expression could be identified as an additional prognostic marker for UM. Conclusions: We hypothesize that the function of PPARγ requires an additional contribution of Alu repeats which may directly influence the DNMT1 network. Regarding UM, PPARγ appears to be an additional discriminatory prognostic marker, in particular in disomy 3 tumors.

Single photon sources (quantum emitters) are a key building block for emerging quantum technologies. Especially attractive for quantum photonic circuitry is the prospect of integrating such sources with conventional photonic structures such as resonators and waveguides. In this talk, we will first present our work on realizing single photon emitters (SPEs) in hexagonal boron nitride (hBN), a van der Waals material, via strain engineering. Following this we will discuss the coupling of such SPEs to silicon nitride microdisk resonators and to plasmonic surface lattice resonances. Prospects of realizing electrically driven SPEs using few layer hBN placed in van der Waals heterostructures will also be discussed.

Veliparib, a poly(ADP-ribose)-polymerase (PARP) 1 and 2 enzyme inhibitor, was administered at 120 mg twice daily (BID) for 7 days in a 21-day cycle with carboplatin/paclitaxel in the Phase 2 BROCADE study in patients with BRCA-deficient recurrent or metastatic breast cancer, a dose based on Phase 1 results. Population pharmacokinetic (PK) and exposure–response analyses were undertaken to retrospectively evaluate whether an optimal dose was used in BROCADE. A population PK analysis was performed using data from 168 patients in BROCADE along with data from 288 subjects in another 5 studies. The relationship between veliparib exposure and efficacy variables (including progression-free survival [PFS] and objective response rate [ORR]) and safety variables (selected grade 3 or greater hematological adverse events) were analyzed. Veliparib PK parameters in BROCADE were comparable to the previous studies. Creatinine clearance on veliparib apparent clearance and lean body weight on veliparib apparent volume of distribution were identified as covariates. A trend of better efficacy (PFS and ORR) in the veliparib arm compared to placebo was observed. However, veliparib exposure-efficacy response was relatively flat with higher veliparib exposures not showing better efficacy. No exposure–response relationship was observed in grade 3 or greater hematological toxicities (anemia, neutropenia, leukopenia, and thrombocytopenia). The exposure–response analysis suggested that intermittent 7-day veliparib 120 mg BID dosing in a 21-day cycle provided additional efficacy without meaningfully impacting the safety and tolerability when co-administered with carboplatin and paclitaxel in patients with BRCA-deficient breast cancer. A higher dose of veliparib is unlikely to provide greater benefit in this combination in patients with BRCA-deficient recurrent or metastatic breast cancer.

The objective of this research was to characterize the venetoclax exposure-efficacy and exposure-safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low-dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure-safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure-efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure-response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400-mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure-response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.

Background: Vibrio parahaemolyticus is a Gram-negative bacterium widely distributed in marine environments and a well-recognized invertebrate pathogen frequently isolated from seafood. V. parahaemolyticus may also spread into humans, via contaminated, raw, or undercooked seafood, causing gastroenteritis and diarrhea. Methods: A Nuclear Magnetic Resonance (NMR)-based detection system was used to detect pathogenic levels of this microorganism (105 CFU/ml) with Molecular Mirroring using iron nanoparticles coated with target-specific biomarkers capable of binding to DNA of the target microorganism. The NMR system generates a signal (in milliseconds) by measuring NMR spin–spin relaxation time T2, which correlates with the amount of microorganism DNA. Results: Compared with conventional microbiology techniques such as real-time PCR (qPCR), the NMR biosensor showed similar limits of detection (LOD) at different concentrations (105–108 CFU/ml) using two DNA extraction methods. In addition, the NMR biosensor system can detect a wide range of microorganism DNAs in different matrices within a short period of time. Conclusion: NMR biosensor represents a potential tool for diagnostic and quality control to ensure microbial pathogens such as V. parahaemolyticus are not the cause of infection. The “hybrid” technology (NMR and nanoparticle application) opens a new platform for detecting other microbial pathogens that have impacted human health, animal health and food safety. Keywords: Nuclear magnetic resonance (NMR), Vibrio parahaemolyticus, Food safety, Aquaculture, Biosensors

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Minimal residual disease (MRD) is an important emerging clinical end point in chronic lymphocytic leukemia (CLL). The objective of this research was to develop an integrated mechanistic model to evaluate the impact of venetoclax-rituximab combination therapy on MRD kinetics. Using data from 435 patients with relapsed or refractory CLL, an integrated model was developed and validated that accounted for venetoclax dosing and pharmacokinetics, rituximab treatment, absolute lymphocyte count, and blood and bone marrow (BM) MRD data. Simulations of venetoclax-rituximab (six cycles) combination predicted the proportion (90% confidence interval) of patients with BM MRD below 10-4 to be 57% (54-61%) and 63% (59-67%) at 12 and 24 months of treatment, respectively. Continued venetoclax treatment to 48 months only increased the predicted rate of negative BM MRD to 66% (63-70%). These results indicate that treatment with venetoclax-rituximab combination for a finite 2-year period would nearly maximize the rate of negative BM MRD (< 10-4 ). Preliminary clinical data agree with these predictions and more long-term follow-up data are awaited to confirm the same.

Venetoclax, a substrate of cytochrome P450 (CYP) 3A and P-glycoprotein (P-gp), is approved for the treatment of patients with chronic lymphocytic leukemia who have received at least one prior therapy. This study evaluated the effect of azithromycin, a commonly used antibiotic in cancer patients and a P-gp inhibitor, on the pharmacokinetics of venetoclax. In this single-center, open-label, nonfasting, two-period study, 12 healthy female subjects received a single 100 mg dose of venetoclax on day 1 of period 1 and day 3 of period 2. Subjects received azithromycin 500 mg on day 1 and 250 mg once daily on days 2 through 5. Serial blood samples for the determination of venetoclax concentrations were collected after dosing in both periods. Safety was evaluated throughout the study. Following coadministration of venetoclax with multiple doses of azithromycin, venetoclax maximum concentration and area under the curve to infinite time were 25% and 35% lower, respectively, compared to venetoclax administered alone. Venetoclax half-life and time to maximum concentration remained relatively unchanged when administered with azithromycin. Venetoclax was well tolerated with no serious adverse events reported. The modest changes in venetoclax exposures when given with azithromycin indicate that no dose adjustment would be needed when venetoclax is coadministered with azithromycin or other drugs with P-gp inhibitory potential. Azithromycin represents an alternative to other antimicrobial agents with higher potential to alter venetoclax pharmacokinetics such as clarithromycin, erythromycin, and ciprofloxacin. AbbVie in collaboration with Genentech/Roche.

Strong optical nonlinearities play a central role in realizing quantum photonic technologies. Exciton-polaritons, which result from the hybridization of material excitations and cavity photons, are an attractive candidate to realize such nonlinearities. While the interaction between ground state excitons generates a notable optical nonlinearity, the strength of such interactions is generally not sufficient to reach the regime of quantum nonlinear optics. Excited states, however, feature enhanced interactions and therefore hold promise for accessing the quantum domain of single-photon nonlinearities. Here we demonstrate the formation of exciton-polaritons using excited excitonic states in monolayer tungsten diselenide (WSe2) embedded in a microcavity. The realized excited-state polaritons exhibit an enhanced nonlinear response ∼$${g}_{{pol}-{pol}}^{2s} \sim 46.4\pm 13.9\,\mu {eV}\mu {m}^{2}$$ g p o l − p o l 2 s ~ 46.4 ± 13.9 μ e V μ m 2 which is ∼4.6 times that for the ground-state exciton. The demonstration of enhanced nonlinear response from excited exciton-polaritons presents the potential of generating strong exciton-polariton interactions, a necessary building block for solid-state quantum photonic technologies.

Color centers in wide bandgap semiconductors are attracting broad attention as platforms for quantum technologies relying on room-temperature single-photon emission (SPE), and for nanoscale metrology applications building on the centers' response to electric and magnetic fields. Here, we demonstrate room-temperature SPE from defects in cubic boron nitride (cBN) nanocrystals, which we unambiguously assign to the cubic phase using spectrally resolved Raman imaging. These isolated spots show photoluminescence (PL) spectra with zero-phonon lines (ZPLs) within the visible region (496-700 nm) when subject to sub-bandgap laser excitation. Second-order autocorrelation of the emitted photons reveals antibunching with $g^{2}$ ~ 0.2 and a decay constant of 2.75 ns that is further confirmed through fluorescence lifetime measurements. The results presented herein prove the existence of optically addressable isolated quantum emitters originating from defects in cBN, making this material an interesting platform for opto-electronic devices and quantum applications., 7 pages, 3 figures

Atomically thin transition metal dichalcogenides (TMDs) possess a number of properties that make them attractive for realizing room-temperature polariton devices. An ideal platform for manipulating polariton fluids within monolayer TMDs is that of Bloch surface waves, which confine the electric field to a small volume near the surface of a dielectric mirror. Here we demonstrate that monolayer tungsten disulfide ($\text{WS}_2$) can sustain Bloch surface wave polaritons (BSWPs) with a Rabi splitting of 43 meV and propagation constants reaching 33 $\mu$m. In addition, we evidence strong polariton-polariton nonlinearities within BSWPs, which manifest themselves as a reversible blueshift of the lower polariton resonance by up to 12.9$\pm$0.5 meV. Such nonlinearities are at the heart of polariton devices and have not yet been demonstrated in TMD polaritons. As a proof of concept, we use the nonlinearity to implement a nonlinear polariton source. Our results demonstrate that BSWPs using TMDs can support long-range propagation combined with strong nonlinearities, enabling potential applications in integrated optical processing and polaritonic circuits., Comment: 7 pages, 4 figures

The 3 direct-acting antiviral (3D) regimen of ombitasvir/paritaprevir/ritonavir plus dasabuvir has recently been approved in several Asian geographic regions for the treatment of hepatitis C virus (HCV) genotype (GT) 1 infection. The pharmacokinetics of the components of the 3D regimen with or without ribavirin were evaluated in healthy Chinese subjects and HCV GT1b-infected Chinese, South Korean, and Taiwanese patients, with or without cirrhosis, to determine how the drug exposures in Asian populations compare with historical data in Western populations. Participants received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily plus dasabuvir 250 mg twice daily for 14 days (healthy subjects, n = 36) or 12 weeks (HCV patients, n = 754). Patients with compensated cirrhosis also received ribavirin 1000 or 1200 mg divided twice daily, per the local label. Intensive or sparse pharmacokinetic sampling was performed for assessments of plasma drug concentrations. The exposures [maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC)] of the components of the 3D regimen were comparable (

The clinical development program of the direct-acting antiviral (DAA) combination therapy of paritaprevir (coadministered with ritonavir) and ombitasvir, with and without dasabuvir (3-DAA [3D] and 2-DAA [2D] regimens, respectively) used in the treatment of chronic hepatitis C infection has generated a robust dataset across various dosing regimens and patient populations. The current analysis aimed to characterize the population pharmacokinetics in patients without cirrhosis (‘non-cirrhotic’) and with compensated cirrhosis (‘cirrhotic’), while accounting for differences across hepatitis C virus (HCV) genotypes (GT) 1, 2, and 4, multiple regimens (3D regimen ± ribavirin for GT1 in global studies, 2D regimen for subgenotype 1b in Japan, 2D regimen + ribavirin for GT2 in Japan, and 2D regimen + ribavirin for GT4), and ethnicities. Pharmacokinetic data from nine clinical studies (~ 1850 patients) were used to model the population pharmacokinetics of each component of the DAA regimens. Model development was performed in stages, starting with an initial base model. Covariate–parameter relationships were then assessed using forward inclusion/backward elimination procedures. Model development was guided by goodness-of-fit plots, likelihood ratio tests, plausibility of parameter estimates, and knowledge of DAA, ritonavir, and ribavirin pharmacokinetics. Paritaprevir, ombitasvir, and ritonavir pharmacokinetics were described by a one-compartment model, while dasabuvir and ribavirin pharmacokinetics were characterized by a two-compartment model. The analysis showed generally overlapping exposures between compensated cirrhotic and non-cirrhotic patients or between subgroups of the identified significant covariates. The largest differences were the approximately 30–60% higher dasabuvir and paritaprevir exposures in compensated cirrhotic patients. These differences did not warrant dose adjustments for the DAAs when used in HCV-infected patients with compensated cirrhosis.

Color centers in hexagonal boron nitride (hBN) are presently attracting broad interest as a novel platform for nanoscale sensing and quantum information processing. Unfortunately, their atomic structures remain largely elusive and only a small percentage of the emitters studied thus far have the properties required to serve as optically addressable spin qubits. Here, we use confocal fluorescence microscopy at variable temperatures to study a new class of point defects produced via cerium ion implantation in thin hBN flakes. We find that, to a significant fraction, emitters show bright room-temperature emission, and good optical stability suggesting the formation of Ce-based point defects. Using density functional theory (DFT) we calculate the emission properties of candidate emitters, and single out the CeVB center—formed by an interlayer Ce atom adjacent to a boron vacancy—as one possible microscopic model. Our results suggest an intriguing route to defect engineering that simultaneously exploits the singular properties of rare-earth ions and the versatility of two-dimensional material hosts.

Venetoclax is a first in class BCL-2 inhibitor that is approved for treatment of CLL and AML. It is currently under evaluation in other indications in adult and pediatric populations. Venetoclax is available as 10 mg, 50 mg, and 100 mg film-coated tablets. While the 100 mg tablet is most commonly used, the smaller size of the lower strength tablets is preferred by patients experiencing difficulty swallowing large tablets. Moreover, two powder formulations for suspension (0.72% and 7.2%) to be mixed with delivery vehicles were developed. In this abstract we present data from clinical studies that evaluated the bioavailability of the different venetoclax formulations relative to the commercially available 100 mg tablet. Three open-label, single-dose, crossover bioavailability studies in healthy female subjects were conducted. The first study evaluated the bioavailability of the commercially available 10 and 50 mg tablets relative to the 100 mg tablet. Forty subjects received a 100 mg dose of venetoclax (1x100 mg tablet, 2x50 mg tablets or 10x10 mg tablets) at the start of each period after a low-fat breakfast. The second study evaluated the bioavailability of the two powder formulations relative to the 100 mg tablet. Sixteen subjects received a 100 mg dose of venetoclax (1x100 mg film-coated tablet; 100 mg 0.72% powder formulation; 100 mg 7.2% powder formulation; and 4x25 mg dispersible tablets for oral suspension used in the Phase 1 study) in each of the 4 periods after a high fat breakfast. The third study evaluated the bioavailability of the two powder formulations when administered with different dosing vehicles relative to water. Twenty-four subjects (12 per cohort) received 100 mg of venetoclax (0.72% powder formulation or the 7.2% powder formulation) with either water, apple juice, apple sauce or yogurt in each of the 4 periods after a moderate fat breakfast. Bioavailability assessment of the commercial tablets demonstrated that ten 10 mg tablets were bioequivalent to one 100 mg tablet, two 50 mg tablets were bioequivalent to one 100 mg tablet, and two 50 mg tablets were bioequivalent to ten 10 mg tablets. The two powder formulations for oral suspension (0.72% and 7.2%) met the bioequivalence criteria (0.80-1.25) to the commercial 100 mg tablet with respect to AUCt and AUC∞, but the lower bound of the 90% CI of the Cmax extended slightly below 0.80. The delivery vehicles (water, apple juice, apple sauce and yogurt) did not affect the bioavailability of venetoclax 0.72% or 7.2% oral suspensions Citation Format: Mohamed Badawi, Bo Tong, Xin Chen, Tammy Palenski, Su Young Kim, Divya Samineni, David Hoffman, Rajeev Menon, Ahmed Hamed Salem. Clinical assessment of the bioavailability of venetoclax tablet and powder formulations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 641.

1. Venetoclax is a novel, small molecule B-cell lymphoma-2 (BCL-2) inhibitor that has demonstrated clinical efficacy in a variety of haematological malignancies. Since venetoclax is an inhibitor of P glycoprotein (P-gp) transporter, a study was conducted in healthy, female volunteers to evaluate the effect of venetoclax on the pharmacokinetics of digoxin, a P-gp probe substrate. 2. Volunteers received a single oral dose of digoxin (0.5 mg) with or without a single oral dose of venetoclax (100 mg). Serial blood samples were obtained for pharmacokinetic assessments of digoxin and venetoclax and serial urine samples were obtained for measurement of digoxin concentrations. Safety was assessed throughout the study. 3. Coadministration of digoxin and venetoclax increased digoxin maximum observed plasma concentration (Cmax) by 35% and area under the plasma-concentration time curve (AUC0-∞) by 9%. Digoxin half-life, renal clearance and the fraction excreted unchanged in urine remained relatively similar. The results of this study indicate that venetoclax can increase the concentrations of P-gp substrates. Narrow therapeutic index P-gp substrates should be administered six hours prior to venetoclax to minimise the potential interaction.

Exposure-response analyses were performed for a venetoclax monotherapy study in 106 patients with varying subtypes of non-Hodgkin lymphoma (NHL) (NCT01328626). Logistic regression, time-to-event, and progression-free survival (PFS) analyses were used to evaluate the relationship between venetoclax exposure, NHL subtype and response, PFS, or occurrence of serious adverse events. Trends for small increases in the probability of response with increasing venetoclax exposures were identified, and became more evident when assessed by NHL subtype. Trends in exposure-PFS were shown for the mantle cell lymphoma (MCL) subtype, but not other subtypes. There was no increase in the probability of experiencing a serious adverse event with increasing exposure. Overall, the results indicate that venetoclax doses of 800-1200 mg as a single agent may be appropriate to maximize efficacy in MCL, follicular lymphoma, and diffuse large B-cell lymphoma subtypes with no expected negative impact on safety.

The triple direct-acting antiviral (3-DAA) regimen (two co-formulated tablets of ombitasvir/paritaprevir/ritonavir once daily and one tablet of dasabuvir twice daily) for patients with hepatitis C virus (HCV) genotype 1 infection has been reformulated for once-daily administration containing all three active DAAs (3QD regimen). Two bioequivalence studies compared the 3-DAA and 3QD regimens. In study 1, fed, single-, and multiple-dose crossover comparisons revealed exposures for drug components that were slightly outside the bioequivalence criteria, i.e., 21 to 29% lower dasabuvir C trough, paritaprevir C max, and ritonavir C max. In study 2, fed and fasted single-dose crossover comparisons demonstrated a large impact of food on exposures, confirming the product’s labeling requirement for administration only with food, and revealed a lack of bioequivalence under fasting conditions. Exposure-response analyses using efficacy data from phase 2/3 studies of the 3-DAA regimen demonstrated that the lower dasabuvir C trough for the 3QD regimen (under fed condition) would have minimal impact on sustained virologic response at week 12 post-treatment (SVR12). Thus, the pharmacodynamic similarity between the regimens was established and the analyses provided the basis for regulatory approval of the 3QD regimen to treat patients with chronic HCV genotype 1 infection.

All-oral direct-acting antiviral regimens that include combinations of ombitasvir, paritaprevir, ritonavir, and dasabuvir with or without ribavirin were evaluated in hepatitis C virus-infected patients in phase II/III clinical studies. The objective of these analyses was to quantify the relationship between exposures of the components of the regimen and laboratory values and to determine covariates that could influence the relationship. Exposure–safety response relationships between individual components of the direct-acting antiviral regimens and clinically important laboratory values were explored using data from 2998 patients from 11 phase II/III clinical studies. Multivariate logistic regression analyses were used to identify significant relationships between predictor variables and response variables. No statistically significant associations were observed between ombitasvir, dasabuvir, or ritonavir exposures and maximum post-baseline alanine aminotransferase (ALT) or total bilirubin grade or minimum hemoglobin grade. A two-fold increase in paritaprevir exposure from therapeutic exposure was predicted to increase the probability of experiencing a grade 3 or higher increase in ALT by 0.5% and bilirubin by 1.1%. In the phase II/III clinical studies, ALT and bilirubin increases were reversible with continued dosing or after treatment cessation. Other correlates with adverse events of clinical importance included concomitant ribavirin treatment, sex, race, and presence of cirrhosis, consistent with previous observations. Exposure–response analyses from phase II/III studies with the combination direct-acting antiviral regimen indicated no statistically significant relationships with ombitasvir, dasabuvir, or ritonavir exposure, but a statistically significant association was observed between paritaprevir exposure and the probability of experiencing a grade 3 or higher increase in ALT or bilirubin.

We evaluated the performance of an early prototype core molecular mirroring nuclear magnetic resonance detection platform (Mentor-100) to detect toxigenic Clostridium difficile from stool. This technology uses customized nanoparticles bound to target specific oligonucleotide probes that form binaries in the presence of nucleic acid from the target microorganism. Liquid patient stool specimens were seeded with C. difficile or other Clostridium species to determine the analytical sensitivity and specificity. Samples underwent nucleic acid extraction and target amplification with probes conjugated with iron nanoparticles. Signal from nuclear magnetic resonance spin–spin relaxation time was measured to detect the presence or absence of toxigenic C. difficile. The limit of detection was

AbbVie's 3 direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with and without ribavirin is approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Safe and efficacious antiviral regimens resulting in minimal to no drug-drug interactions (DDIs) with antiretrovirals are needed to ensure that patients coinfected with HCV and the human immunodeficiency virus (HIV) achieve 12-week sustained virologic response rates similar to HCV-monoinfected patients. Also, the prevalence of injection drug use history is high in both monoinfected and HIV/HCV-coinfected patients. This review summarizes results from phase 1 DDI studies of the 3D regimen and antiretrovirals or drugs to treat substance abuse. Data suggest the 3D regimen is a viable option for HIV/HCV-coinfected patients on antiretroviral therapy containing tenofovir/emtricitabine, abacavir/lamivudine, dolutegravir, raltegravir, or atazanavir. HCV-infected patients receiving medications for substance abuse, particularly methadone or buprenorphine/naloxone, can also be treated with the 3D regimen.

Introduction: Venetoclax is a selective BCL2 inhibitor approved for the treatment of CLL and AML in adults and is currently being evaluated in several hematologic and solid malignancies. While plasma pharmacokinetics (PK) of venetoclax is well documented, data regarding the accumulation of venetoclax into the central nervous system (CNS) are limited. Venetoclax has a molecular weight of 868.44 which was hypothesized to limit its passage through the tight junctions of the blood brain barrier (BBB). Moreover, venetoclax is a substrate of the P- glycoprotein (P-gp) and breast cancer resistance protein (BCRP) efflux transporters, expressed by endothelial cells at the BBB, which presents an extra hurdle for penetration into the CNS. In this analysis we characterized the passage of venetoclax into the CNS using PK samples collected during a phase 1 study (NCT03236857) of pediatric patients with relapsed and refractory acute leukemia receiving venetoclax in combination with chemotherapy. Methods: PK samples from cerebrospinal fluid (CSF) were collected at screening and if a lumbar puncture was performed as standard of care during treatment. Plasma PK samples were collected throughout the study. CSF and plasma concentrations of venetoclax were determined using liquid-liquid extraction followed by liquid chromatography (LC) with tandem mass spectrometric detection (MS/MS). The lower limit of quantitation for venetoclax was 2.14 ng/mL in plasma and 0.1ng/mL in CSF. Results: There was a total of 66 samples from 33 patients with relapsed or refractory AML or ALL. The venetoclax concentration in CSF ranged between Conclusion: To our knowledge this is the first study reporting venetoclax CSF pharmacokinetics in the AML and ALL setting. The lower disposition observed in humans is contrary to our expectation, given the significantly higher expression of P-gp in mice BBB compared to humans and suggests that other factors are involved in venetoclax disposition to the CSF. The ability of venetoclax to cross the blood brain barrier may explain the reported activity of venetoclax in treatment of hematologic malignancies with CNS involvement1,2. References: Reda G, Cassin R, Dovrtelova G, et al. Venetoclax penetrates in cerebrospinal fluid and may be effective in chronic lymphocytic leukemia with central nervous system involvement. Haematologica. 2019;104(5):e222-e223. doi:10.3324/haematol.2018.213157 Beziat G, Gauthier M, Protin C, et al. Venetoclax with high-dose methotrexate and rituximab seem effective and well-tolerated in the treatment of central nervous system involvement of chronic lymphocytic leukemia: A case report. Clin Case Rep. 2020;8(2):269-273. Published 2020 Jan 10. doi:10.1002/ccr3.2580 Disclosures Salem: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Badawi:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Place:Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Palenski:AbbVie: Current Employment, Other: may hold stock or other options. Arrendale:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Kim:AbbVie, Inc.: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: may hold stock or other options. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options.

Context: Myelodysplastic syndromes (MDS) represent a group of bone marrow disorders involving cytopenia, hypercellular bone marrow, and dysplastic hematopoietic progenitors. Death is commonly caused by the effects of cytopenia, leading to infections or bleeding [1]. Finding efficacious treatment regimens in MDS remains a challenge as it involves understanding of both disease induced and treatment related cytopenias. Objective: The objective was to develop a semi-mechanistic model of disease progression in MDS based on clinical data, involving relevant hematopoietic cells that can describe the effect of drug intervention with venetoclax azacitidine combination therapy. The model was subsequently used to simulate different treatment regimens (with respect to dose, dosing duration in a cycle, and number of cycles) and compare the outcomes. Study Design and Data: Data from an ongoing Phase 1b study evaluating the safety and efficacy of venetoclax (400 mg or 800 mg for 28 days or 100 mg to 400 mg for 14 days in each 28-day cycle) with azacitidine (75 mg/m2 on days 1-7 of each cycle) in treatment-naive patients with higher-risk MDS were used for the analysis. The data contained venetoclax concentrations, neutrophil, red blood cell, and platelet count in the blood and blasts in the bone marrow. Methods: An integrated semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model was developed that accounted for venetoclax PK and azacitidine treatment to describe time dynamics of neutrophils, red blood cells, and platelets. The model also included crowding in the bone marrow due to excess stem cells, MDS blasts, and progenitor cells, and its effect on hematopoiesis. Results: The model described the observed clinical data well and showed predictive ability across considered cell types. Complete remission (CR) and marrow complete remission (mCR) rates were predicted close to observed rates in the study. Simulated efficacy (recovery of blast count, CR, and mCR rates) and safety (neutropenia and thrombocytopenia) endpoints are comparable to the expected outcomes from various dosing regimens. Conclusions: A model describing drug-disease interactions in MDS was developed that integrates multiple end points and differentiates disease driven from drug-induced cytopenia. Reference: [1] Dayyani, F, et al. Cause of death in patients with lower-risk myelodysplastic syndrome. Cancer. 2010 May 1; 116.9:2174-2179. Disclosures: The analysis presented was funded by AbbVie. AbbVie contributed to the design, research, and interpretation of data, writing, reviewing, and approving the publication. NT, JZ, RM, BE, JW, SM, and SG are employees of AbbVie and may hold stock. AHW receives honoraria from Novartis, Astellas, Pfizer, Macrogenics, Abbvie, Genentech, Servier, Celgene, Amgen, Astra Zeneca and Janssen. AHW also receives research funding from Novartis, Celgene, Abbvie, Servier, Astra Zeneca and Amgen. AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax. G-GM is an investigator in AbbVie funded Clinical Trials. DM is a Genentech employee and may own stock. C.M. performed the analysis at AbbVie during an internship. C.M. also receives research funding from an industry consortium (AbbVie Deutschland GmbH & Co. KG, Boehringer Ingelheim Pharma GmbH & Co. KG, Grunenthal GmbH, F. Hoffmann-La Roche Ltd., Merck KGaA and Sanofi) for the PharMetrX program

Generation of an accurate humoral and a cell mediated adaptive immune responsesare dictated by binding of an antigen to a T- and a B-cell receptor, respectively (first signal) followed by ligation of costimulatory molecules (second signal). CD40, a costimulatory receptor molecule, expressed mainly on antigen presenting cells, some non-immune cells and tumors, binds to CD40 ligand molecule expressed transiently on T-cells and non-immune cells under inflammatory conditions. In the past decade, the CD40-CD40L interaction has emerged as an immune-potentiating system that governs and regulates host immune response against various diseases and pathogens, failing of which results in detrimental patho-physiologies including cancer and autoimmune disorders. CD40-CD40L transduces immune signals intracellularly via TRAF-dependent and independent mechanisms and further downstream by different MAPK pathways and transcription factors such as NF-κB, p38 etc. While CD40 signaling pathway through its cognate interaction between B and T cells promotes activation and proliferation of B-cells, Ig class switching, and generation of B cell memory; however, CD40-CD40L interaction involving other APCs and non-immune cells relay distinct cell signaling resulting in production of a variety of cytokines/chemokines and cell adhesion molecules ultimately conferring host defense against pathogen. In cancer and autoimmune disorders, CD40-CD40L interaction is also responsible for aberrant expression of many disease specific markers, class I/II MHC molecules and other co-stimulatory molecules such as B7 and CD28 in cell- and disease-specific manner. In the present review, the current state of understanding about the CD40-CD40L mediated regulation of immune and non-immune cells is presented. The current paradigm is to target CD40 using agonist anti-CD40 mAbs alone or in synergistic combination with chemotherapy in order to harness or confer anti-tumor and anti-inflammatory immunity.

Venetoclax is a selective B cell lymphoma-2 inhibitor. It is approved for treatment of chronic lymphocytic leukemia and is being investigated for other hematological malignancies. Venetoclax is predominantly eliminated by the liver; therefore, there is a need to investigate the effect of hepatic insufficiency on venetoclax pharmacokinetics. A phase I study was carried out in 24 women with normal hepatic function or mild, moderate, or severe hepatic impairment (based on Child–Pugh scores), who received a single 50 mg dose of venetoclax with a low-fat meal. Blood samples were collected up to 120 h after venetoclax administration. Pharmacokinetic parameters were estimated using non-compartmental methods. Venetoclax maximum observed plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) in subjects with mild or moderate hepatic impairment were similar to subjects with normal hepatic function. Mean venetoclax AUC in subjects with severe hepatic impairment was 2.3- to 2.7-fold higher than in subjects with normal hepatic function. The half-life of venetoclax in subjects with severe hepatic impairment was approximately two-fold longer than in subjects with normal hepatic function and subjects with mild or moderate hepatic impairment. Unbound fractions of venetoclax in subjects with mild, moderate, and severe hepatic impairment were similar to the subjects with normal hepatic function. No significant adverse safety events were reported. No venetoclax dosage adjustment is required in subjects with mild or moderate hepatic impairment. In subjects with severe hepatic impairment, a 50% dose reduction of venetoclax is recommended to account for higher exposures and the longer half-life.

Optical waveguides are vital components of data communication system technologies, but their scaling down to the nanoscale has remained challenging despite advances in nano-optics and nanomaterials. Recently, we theoretically predicted that the ultimate limit of visible photon guiding can be achieved in monolayer-thick transition metal dichalcogenides. Here, we present an experimental demonstration of light guiding in an atomically thick tungsten disulfide membrane patterned as a photonic crystal structure. In this scheme, two-dimensional tungsten disulfide excitonic photoluminescence couples into quasi-guided photonic crystal modes known as resonant-type Wood’s anomalies. These modes propagate via total internal reflection with only a small portion of the light diffracted to the far field. Such light guiding at the ultimate limit provides more possibilities to miniaturize optoelectronic devices and to test fundamental physical concepts. A monolayer WS2 membrane patterned as a photonic crystal sustains guided optical modes that propagate via total internal reflection.

Aim To characterize the population pharmacokinetics of a triple direct-acting antiviral (DAA) regimen (3D) (ombitasvir, paritaprevir-ritonavir, and dasabuvir) and adjunctive ribavirin and estimate covariate effects in a broad spectrum of subjects with hepatitis C virus (HCV) genotype 1 infection. Methods Pharmacokinetic data from six phase 3 studies and one phase 2 study in subjects receiving the currently approved doses of the 3D ± ribavirin regimen for treating HCV genotype 1 infection for 12 or 24 weeks were characterized using separate population pharmacokinetic models built using each component of the regimen from non-linear mixed-effects methodology in NONMEM 7.3. In the models, demographic and clinical covariates were tested. Models were assessed via goodness-of-fit plots, visual predictive checks, and bootstrap evaluations. Results The population pharmacokinetic models for each component of the 3D ± ribavirin regimen (DAAs and ritonavir, N = 2348) and ribavirin (N = 1841) adequately described their respective plasma-concentration-time data. Model parameter estimates were precise and robust, and all models showed good predictive performance. Significant covariate effects associated with apparent clearance and volume of distribution included age, body weight, sex, cirrhosis, HCV subtype, opioid or antidiabetic agent use, and creatinine clearance. Conclusion Population pharmacokinetics of the 3D ± ribavirin regimen components in HCV-infected patients were characterized using phase 3 and 2 HCV clinical trial data. Although several statistically significant covariates were identified, their effects were modest and not clinically meaningful to necessitate dose adjustments for any component of the 3D regimen. This article is protected by copyright. All rights reserved.

The direct-acting antiviral regimen of 25 mg ombitasvir–150 mg paritaprevir–100 mg ritonavir once daily (QD) plus 250 mg dasabuvir twice daily (BID) is approved for the treatment of hepatitis C virus genotype 1 infection, including patients coinfected with human immunodeficiency virus. This study was performed to evaluate the pharmacokinetic, safety, and tolerability effects of coadministering the regimen of 3 direct-acting antivirals with two antiretroviral therapies (dolutegravir or abacavir plus lamivudine). Healthy volunteers ( n = 24) enrolled in this phase I, single-center, open-label, multiple-dose study received 50 mg dolutegravir QD for 7 days or 300 mg abacavir plus 300 mg lamivudine QD for 4 days, the 3-direct-acting-antiviral regimen for 14 days, followed by the 3-direct-acting-antiviral regimen with dolutegravir or abacavir plus lamivudine for 10 days. Pharmacokinetic parameters were calculated to compare combination therapy with 3-direct-acting-antiviral or antiretroviral therapy alone, and safety/tolerability were assessed throughout the study. Coadministration of the 3-direct-acting-antiviral regimen increased the geometric mean maximum plasma concentration ( C max ) and the area under the curve (AUC) of dolutegravir by 22% (central value ratio [90% confidence intervals], 1.219 [1.153, 1.288]) and 38% (1.380 [1.295, 1.469]), respectively. Abacavir geometric mean C max and AUC values decreased by 13% (0.873 [0.777, 0.979]) and 6% (0.943 [0.901, 0.986]), while those for lamivudine decreased by 22% (0.778 [0.719, 0.842]) and 12% (0.876 [0.821, 0.934]). For the 3-direct-acting-antiviral regimen, geometric mean C max and AUC during coadministration were within 18% of measurements made during administration of the 3-direct-acting-antiviral regimen alone, although trough concentrations for paritaprevir were 34% (0.664 [0.585, 0.754]) and 27% (0.729 [0.627, 0.847]) lower with dolutegravir and abacavir-lamivudine, respectively. All study treatments were generally well tolerated, with no evidence of increased rates of adverse events during combination administration. These data indicate that the 3-direct-acting-antiviral regimen can be administered with dolutegravir or abacavir plus lamivudine without dose adjustment.

The low quantum yield observed in two-dimensional semiconductors of transition metal dichalcogenides (TMDs) has motivated the quest for approaches that can enhance the light emission from these systems. Here, we demonstrate broadband enhancement of spontaneous emission and increase in Raman signature from archetype two-dimensional semiconductors: molybdenum disulfide (MoS2) and tungsten disulfide (WS2) by placing the monolayers in the near field of a photonic hypercrystal having hyperbolic dispersion. Hypercrystals are characterized by a large broadband photonic density of states due to hyperbolic dispersion while having enhanced light in/out coupling by a subwavelength photonic crystal lattice. This dual advantage is exploited here to enhance the light emission from the 2D TMDs and can be utilized for developing light emitters and solar cells using two-dimensional semiconductors.

The direct-acting antiviral agent (DAA) combination of ombitasvir and paritaprevir (administered with ritonavir) with (3D regimen) or without (2D regimen) dasabuvir has shown very high efficacy rates in the treatment of chronic hepatitis C virus (HCV) infection. Renal impairment, a common comorbidity in patients with chronic HCV infection, can influence the pharmacokinetics of antiviral agents and hence their efficacy and safety profiles. The aim of this study was to evaluate the influence of renal impairment on the pharmacokinetics and tolerability of the 3D and 2D regimens. Overall, 24 subjects, six in each of four renal function groups (normal, mild, moderate, and severe), received a single dose of the 3D and 2D regimens in separate dosing periods. Plasma and urine were analyzed to assess the effect of renal impairment on drug exposure. DAA exposures changed by up to 21, 37, and 50 % in subjects with mild, moderate, and severe renal impairment, respectively, versus subjects with normal renal function. Ritonavir exposure increased with the degree of renal impairment (maximum 114 %). The half-lives of DAAs and ritonavir in subjects with renal impairment were generally comparable with those in healthy subjects. No safety or tolerability concerns arose in this study. The 3D and 2D regimens do not require dose adjustment for patients with HCV infection and concomitant renal impairment.

Surface-enhanced Raman scattering (SERS) is commonly associated with noble metal substrates. However, over the years modest Raman enhancements ( 3 × 105 enhancement in SERS signal from an organic molecule (4-mercaptopyridine) placed in the near field of a two-dimensional semiconductor molybdenum disulfide (MoS2) monolayer. This large enhancement in the SERS signal is attributed to the charge transfer (CT) state formed at the interface of the 2D semiconductor and organic molecule and is found to occur when the excitation source is chosen to be in resonance with the CT state. This approach provides a new strategy for carrying out SERS experiments on molecules with very weak Raman sig...

Ombitasvir (also known as ABT-267) is a potent inhibitor of hepatitis C virus (HCV) nonstructural protein 5A (NS5A), which has been developed in combination with paritaprevir/ritonavir and dasabuvir in a three direct-acting antiviral oral regimens for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of ombitasvir in humans without coadministration of paritaprevir/ritonavir and dasabuvir. Following the administration of a single 25-mg oral dose of [(14)C]ombitasvir to four healthy male volunteers, the mean total percentage of the administered radioactive dose recovered was 92.1% over the 192-hour sample collection in the study. The recovery from the individual subjects ranged from 91.4 to 93.1%. Ombitasvir and corresponding metabolites were primarily eliminated in feces (90.2% of dose), mainly as unchanged parent drug (87.8% of dose), but minimally through renal excretion (1.9% of dose). Biotransformation of ombitasvir in human involves enzymatic amide hydrolysis to form M23 (dianiline), which is further metabolized through cytochrome P450-mediated oxidative metabolism (primarily by CYP2C8) at the tert-butyl group to generate oxidative and/or C-desmethyl metabolites. [(14)C]Ombitasvir, M23, M29, M36, and M37 are the main components in plasma, representing about 93% of total plasma radioactivity. The steady-state concentration measurement of ombitasvir metabolites by liquid chromatography-mass spectrometry analysis in human plasma following multiple doses of ombitasvir, in combination with paritaprevir/ritonavir and dasabuvir, confirmed that ombitasvir is the main component (51.9% of all measured drug-related components), whereas M29 (19.9%) and M36 (13.1%) are the major circulating metabolites. In summary, the study characterized ombitasvir metabolites in circulation, the metabolic pathways, and the elimination routes of the drug.

Paritaprevir (also known as ABT-450), a potent NS3-4A serine protease inhibitor [identified by AbbVie (North Chicago, IL) and Enanta Pharmaceuticals (Watertown, MA)] of the hepatitis C virus (HCV), has been developed in combination with ombitasvir and dasabuvir in a three-direct-acting antiviral agent (DAA) oral regimen for the treatment of patients infected with HCV genotype 1. This article describes the mass balance, metabolism, and disposition of paritaprevir in humans. After the administration of a single 200-mg oral dose of [(14)C]paritaprevir coadministered with 100 mg of ritonavir to four male healthy volunteers, the mean total percentage of the administered radioactive dose recovered was 96.5%, with recovery in individual subjects ranging from 96.0% to 96.9%. Radioactivity derived from [(14)C]paritaprevir was primarily eliminated in feces (87.8% of the dose). Radioactivity recovered in urine accounted for 8.8% of the dose. The biotransformation of paritaprevir in humans involves: 1) P450-mediated oxidation on the olefinic linker, the phenanthridine group, the methylpyrazinyl group, or combinations thereof; and 2) amide hydrolysis at the acyl cyclopropane-sulfonamide moiety and the pyrazine-2-carboxamide moiety. Paritaprevir was the major component in plasma [90.1% of total radioactivity in plasma, AUC from time 0 to 12 hours (AUC0-12hours) pool]. Five minor metabolites were identified in plasma, including the metabolites M2, M29, M3, M13, and M6; none of the metabolites accounted for greater than 10% of the total radioactivity. Paritaprevir was primarily eliminated through the biliary-fecal route followed by microflora-mediated sulfonamide hydrolysis to M29 as a major component in feces (approximately 60% of dose). In summary, the biotransformation and clearance pathways of paritaprevir were characterized, and the structures of metabolites in circulation and excreta were elucidated.

The combination of ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A inhibitor) coadministered with ritonavir (r), and dasabuvir (an NS5B nonnucleoside polymerase inhibitor), referred to as the 3D regimen, and the combination of ombitasvir-paritaprevir-r, referred to as the 2D regimen, have demonstrated high efficacy with and without ribavirin in hepatitis C virus (HCV)-infected subjects. These regimens have potential for coadministration with sofosbuvir (nucleoside NS5B inhibitor) in the treatment of HCV. This phase 1, drug-drug interaction, open-label, multiple-dose study enrolled 32 healthy subjects to receive the 3D or 2D regimen in combination with sofosbuvir. Doses of study drugs were as follows: ombitasvir-paritaprevir-r, 25/150/100 mg daily (QD); dasabuvir, 250 mg twice daily (BID); and sofosbuvir, 400 mg QD. Blood samples were collected on study days 7, 14, and 21 for evaluating drug interaction at steady state. The effect of the 3D and 2D regimens on the pharmacokinetics of sofosbuvir and its circulating metabolite GS-331007 and vice versa was assessed by a repeated-measures analysis. Exposures of the 3D and 2D regimens were similar (≤20% change) during coadministration with sofosbuvir and during administration alone. Sofosbuvir exposures were 61% to 112% higher with the 3D regimen and 64% to 93% higher with the 2D regimen than with sofosbuvir alone. GS-331007 total exposures were 27% and 32% higher with the 3D and 2D regimens, respectively, than with sofosbuvir alone. Increases in sofosbuvir and GS-331007 exposures likely resulted from breast cancer resistance protein (BCRP) and/or P glycoprotein (P-gp) transporter inhibition by paritaprevir and ritonavir. No subjects discontinued the study due to study drug-related adverse events. No dose adjustment is recommended for 3D, 2D, or sofosbuvir in clinical trials exploring the safety and efficacy of the combination. (This study has been registered at ClinicalTrials.gov under registration no. NCT02356562 and NCT02292719.)

Introduction: Venetoclax (VEN), an orally bioavailable selective BCL-2 inhibitor, was granted accelerated approval by the FDA for the treatment of acute myeloid leukemia (AML) in combination with a hypomethylating agent (HMA) or low-dose cytarabine (LDAC). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships using data from the nonrandomized Phase 1/2 studies and the confirmatory Phase 3 studies in subjects with treatment-naïve AML who are ineligible for intensive chemotherapy. Methods: A population pharmacokinetic (PK) model for VEN was characterized using data from 771 AML subjects across 5 Phase 1 - 3 studies including subjects with relapsed/refractory AML and subjects with treatment-naïve AML who were ineligible for intensive chemotherapy. PK parameters from this model were used to calculate the exposure metric, the area under the plasma concentration-time curve at steady-state (AUCss), for exposure-efficacy and exposure-safety analyses. Logistic regression and Cox proportional-hazards models were used to characterize the exposure-response relationships for overall survival, event-free survival, and conversion to post-baseline transfusion independence for red blood cells or platelets as well as key safety endpoints of treatment-emergent Grade ≥ 3 neutropenia, thrombocytopenia, and infections. Additionally, best overall response of complete remission (CR), CR + CR with incomplete blood count recovery (CRi), and CR + CR with partial hematological recovery (CRh) were also characterized in the exposure-response analyses. Separate analyses were performed for VEN + HMA and VEN + LDAC, including subjects taking placebo (PBO) + HMA or PBO + LDAC, respectively, to inform the intercepts. A total of 575 subjects with treatment-naïve AML were included in the exposure-response analyses for VEN + HMA and 279 subjects with treatment-naïve AML were included in the exposure-response analyses for VEN + LDAC. Results: VEN + HMA: For all efficacy endpoints studied, there was a clear trend for higher efficacy in subjects treated with VEN + HMA as compared to PBO in combination with azacitidine (AZA). When PBO patients were included, significant exposure-response relationships between VEN exposure and overall survival and event-free survival were identified, and a maximal effect (Emax) model best described the statistically significant positive relationships between VEN exposure and best overall response of CR + CRi and CR + CRh. However, there were no apparent relationships between VEN exposure and any efficacy endpoint without the inclusion of PBO subjects, suggesting that the beneficial effect of VEN is already maximized in the dose range studied (400 to 1200 mg daily [QD]). No exposure-response relationship was identified between VEN exposure and treatment-emergent Grade ≥ 3 thrombocytopenia or infections. An Emax model best described the statistically significant relationship between VEN exposure and treatment-emergent Grade ≥ 3 neutropenia, consistent with the clinical finding that subjects in the VEN + HMA treatment arms had higher rates of reported neutropenia than those in the PBO + AZA arm. VEN + LDAC: For all efficacy endpoints studied, there was a clear trend for higher efficacy in subjects treated with VEN + LDAC as compared to PBO + LDAC. With PBO subjects included, an Emax model best described the statistically significant relationships between VEN exposure and best overall response of CR, CR + CRi, and CR + CRh, with probability of response plateauing at exposures corresponding to 600 mg QD of VEN. There were no apparent relationships between VEN exposure and any efficacy endpoint when the PBO subjects were excluded from analysis, indicating that the beneficial effect of VEN is already maximized at 600 mg QD. Although reported rates of treatment-emergent Grade ≥ 3 neutropenia were higher in the VEN + LDAC treatment arms as compared to PBO + LDAC, no significant exposure-response relationships were found between VEN exposure and treatment-emergent Grade ≥ 3 neutropenia, thrombocytopenia, or infections. Conclusion: The VEN exposure-efficacy and exposure-safety analyses confirm the benefit of adding VEN to either HMA or LDAC and support the dose regimens of VEN 400 mg QD in combination with an HMA and VEN 600 mg QD in combination with LDAC in treatment-naïve AML patients who are ineligible for intensive chemotherapy. Disclosures Eckert: AbbVie Inc.: Current Employment, Other: may hold stock or other options. Brackman:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Menon:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Salem:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Potluri:AbbVie: Current Employment, Other: may hold stock or stock options. Smith:Pfizer: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy. Wei:AbbVie Inc.: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; MacroGenics: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Walter and Eliza Hall Institute: Other: former employee and receives a fraction of its royalty stream related to venetoclax; Pfizer: Honoraria; Genentech: Honoraria; Astra Zeneca: Honoraria, Research Funding. Hayslip:Abbvie Inc: Current Employment, Other: may hold stock or other options. Miles:Genentech Inc.: Current Employment, Current equity holder in publicly-traded company. Mensing:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Gopalakrishnan:AbbVie Inc.: Current Employment, Other: may hold stock or other options. Zha:AbbVie Inc.: Current Employment, Other: may hold stock or other options.

Minimal residual disease (MRD) is an important clinical endpoint in chronic lymphocytic leukemia (CLL) because it correlates with progression free survival and overall survival. The objective of this work is to investigate the impact of venetoclax (VEN) exposures on undetectable MRD rates in blood and bone marrow (BM) in relapsed/refractory (R/R) CLL patients receiving VEN monotherapy or combination therapy with rituximab (RTX). Data from a total of 708 patients from four VEN monotherapy studies and one combination Phase 1b study (VEN + 6-9 cycles of RTX) in R/R CLL patients were utilized to perform this analysis. The median number of prior therapies in these studies was 3, 42% of the patients had 17p chromosomal deletion and 28% had prior B-Cell Receptor inhibitor (BCRi) therapy. Blood and BM MRD assessments were available for 70% and 38%, respectively, of patients included in the analysis. Absence of an MRD measurement was assumed as detectable MRD for the purposes of this analysis. The average concentration (Cavg) of VEN was computed for each patient by fitting a population pharmacokinetic model to the observed VEN concentration data. The model was used to calculate area under the curve and compute Cavg accounting for VEN dose ramp-ups, reductions and interruptions. The relationships between venetoclax Cavg and undetectable MRD rates were assessed by using quartile plots. Logistic regression analyses were also conducted to quantify the exposure-response relationship. With VEN monotherapy, the undetectable MRD rates in blood and BM increased with the increase in VEN exposures. With VEN + RTX combination treatment, the undetectable MRD rates in blood and BM showed an increase with increasing VEN average concentration, but the benefit saturated with limited increase at exposures beyond 400mg. Logistic regression analyses indicated statistically significant (p These results demonstrate that higher venetoclax concentrations are associated with higher undetectable MRD rates in both blood and BM. When VEN is combined with RTX, an increase in VEN dose beyond 400mg is unlikely to result in higher undetectable MRD rates. Citation Format: Sathej Gopalakrishnan, Rajeev Menon, Brenda Chyla, Divya Samineni, Amanda Jacobson, Su Young Kim, Sven Mensing, Ahmed Hamed Salem. Relationship between venetoclax concentrations and undetectable MRD in patients with chronic lymphocytic leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3024.

We have observed directional spontaneous emission of rhodamine 6G dye deposited on top of a silver grating and found that its angular distribution patterns were very different in TE and TM polarizations. The latter was related to the dispersion curves determined based on the polarized reflection spectra measured at multiple incidence angles. The most intriguing finding of this Letter was a resonance, which was coupled with TE-polarized light and determined the characteristic double-crescent patterns in the TE-polarized spontaneous emission. This observation, as well as nearly similar resonance observed in TM polarization, was tentatively explained in terms of leaky waveguide modes supported by a film of dye-doped polymer.

To characterize the pharmacokinetics of ombitasvir, paritaprevir, ritonavir, dasabuvir, and ribavirin in hepatitis C virus (HCV)-infected patients with chronic kidney disease stage 4 (CKD4) or end-stage renal disease (ESRD), including those on dialysis, in the open-label phase 3 RUBY-I and RUBY-II studies. Patients (n = 18 CKD4, n = 68 ESRD) received ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily ± dasabuvir 250 mg twice daily ± ribavirin 200 mg once daily for 12 or 24 weeks. Intensive pharmacokinetic samples were collected from ten patients; sparse samples were collected from all patients. Arterial and venous samples were collected from three patients during hemodialysis. Area under the plasma concentration-time curve (AUC) was estimated using noncompartmental analyses for intensive data, and steady-state trough concentrations (Ctrough) were obtained from the sparse data. Pharmacokinetic results from RUBY-I and RUBY-II were compared empirically to historical data. The AUC values of ombitasvir, paritaprevir, ritonavir, and dasabuvir were comparable between CKD4 and ESRD patients and were within the range of values observed in historical studies; dialysis had no effect on drug exposures. Ribavirin was extracted during hemodialysis but had similar exposures on dialysis and non-dialysis days. Individual steady-state Ctrough values for each drug overlapped between CKD4 and ESRD patients, and values in both groups were similar to historical values. Plasma concentrations of ombitasvir, paritaprevir, ritonavir, and dasabuvir were not altered by renal impairment or dialysis, suggesting these agents can be administered to HCV-infected CKD4 or ESRD patients, including those on dialysis, without dose adjustment. Clinicaltrials.gov identifiers: NCT02207088 (RUBY-I) and NCT02487199 (RUBY-II)

We demonstrate redistribution of the spectral intensities of the luminescence associated with different vibronic transitions in organic molecule, Diindenoperylene through strong coupling of excitons to surface plasmons.

Room temperature quantum emitter arrays are created in hexagonal Boron Nitride (hBN) by deterministic activation via strain engineering on a nanopillar substrate. Emitters are localized at pillar edges where the hBN film undergoes maximum strain.

We have observed double crescent patterns in the TE polarized spontaneous emission of rhodamine 6G dye deposited onto silver grating metasurface. It originates from the surface wave characterized by the effective index of refraction n=1.03.