First-in-human study of naporafenib (LXH254) with or without spartalizumab in adult patients with advanced solid tumors harboring MAPK signaling pathway alterations.

BACKGROUND: We investigated naporafenib (LXH254), a pan-RAF kinase inhibitor, with or without spartalizumab, in patients with advanced solid tumors harboring MAPK pathway alterations. METHODS: This first-in-human phase 1 study had two dose-escalation arms: single-agent naporafenib (starting at 100 mg once-daily [QD]) and naporafenib (starting at the recommended dose/regimen)/spartalizumab (400 mg every 4 weeks). The naporafenib/spartalizumab dose-expansion part enrolled patients with KRAS-mutated non-small cell lung cancer (NSCLC) and NRAS-mutated melanoma. The primary objectives were to establish the maximum tolerated doses (MTD)/recommended doses for expansion (RDE) and evaluate tolerability and safety. RESULTS: A total of 142 patients were included in the naporafenib dose-escalation (n = 87), naporafenib/spartalizumab dose-escalation (n = 12) and naporafenib/spartalizumab dose-expansion (n = 43) arms. The MTD/RDE of naporafenib was 600 mg twice-daily (BID). In naporafenib escalation, five patients experienced 7 dose-limiting toxicities: decreased platelet count (1200 mg QD); neuralgia, maculopapular rash, pruritus (600 mg BID); increased blood bilirubin, hyponatremia, peripheral sensory neuropathy (800 mg BID). No DLTs occurred in the naporafenib/spartalizumab arm: the RDE was established at 400 mg BID. The most common treatment-related adverse events were rash and dermatitis acneiform (each 24.1%; naporafenib), nausea and pruritus (each 33.3%; naporafenib/spartalizumab; escalation) and rash (39.5%; naporafenib/spartalizumab; expansion). Naporafenib reduced DUSP6 expression in tumors. Two partial responses (PRs) occurred in naporafenib escalation, and 1 complete response and 3 PRs in the naporafenib/spartalizumab NRAS-mutated melanoma and KRAS-mutated NSCLC arms, respectively. CONCLUSIONS: Naporafenib, with or without spartalizumab, showed an acceptable safety profile, pharmacodynamic activity and limited antitumor activity. Additional naporafenib combination therapies are currently under investigation.

Streamlining Food Effect Assessment - Are Repeated Food Effect Studies Needed? An IQ Analysis.

Current regulatory guidelines on drug-food interactions recommend an early assessment of food effect to inform clinical dosing instructions, as well as a pivotal food effect study on the to-be-marketed formulation if different from that used in earlier trials. Study waivers are currently only granted for BCS class 1 drugs. Thus, repeated food effect studies are prevalent in clinical development, with the initial evaluation conducted as early as the first-in-human studies. Information on repeated food effect studies is not common in the public domain. The goal of the work presented in this manuscript from the Food Effect PBPK IQ Working Group was to compile a dataset on these studies across pharmaceutical companies and provide recommendations on their conduct. Based on 54 studies collected, we report that most of the repeat food effect studies do not result in meaningful differences in the assessment of the food effect. Seldom changes observed were more than twofold. There was no clear relationship between the change in food effect and the formulation change, indicating that in most cases, once a compound is formulated appropriately within a specific formulation technology, the food effect is primarily driven by inherent compound properties. Representative examples of PBPK models demonstrate that following appropriate validation of the model with the initial food effect study, the models can be applied to future formulations. We recommend that repeat food effect studies should be approached on a case-by-case basis taking into account the totality of the evidence including the use of PBPK modeling.

Initial Evidence for the Efficacy of Naporafenib in Combination With Trametinib in NRAS-Mutant Melanoma: Results From the Expansion Arm of a Phase Ib, Open-Label Study.

PURPOSE: No approved targeted therapy for the treatment of patients with neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS)-mutant melanoma is currently available. PATIENTS AND METHODS: In this phase Ib escalation/expansion study (ClinicalTrials.gov identifier: NCT02974725), the safety, tolerability, and preliminary antitumor activity of naporafenib (LXH254), a BRAF/CRAF protein kinases inhibitor, were explored in combination with trametinib in patients with advanced/metastatic KRAS- or BRAF-mutant non-small-cell lung cancer (escalation arm) or NRAS-mutant melanoma (escalation and expansion arms). RESULTS: Thirty-six and 30 patients were enrolled in escalation and expansion, respectively. During escalation, six patients reported grade ≥3 dose-limiting toxicities, including dermatitis acneiform (n = 2), maculopapular rash (n = 2), increased lipase (n = 1), and Stevens-Johnson syndrome (n = 1). The recommended doses for expansion were naporafenib 200 mg twice a day plus trametinib 1 mg once daily and naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. During expansion, all 30 patients experienced a treatment-related adverse event, the most common being rash (80%, n = 24), blood creatine phosphokinase increased, diarrhea, and nausea (30%, n = 9 each). In expansion, the objective response rate, median duration of response, and median progression-free survival were 46.7% (95% CI, 21.3 to 73.4; 7 of 15 patients), 3.75 (95% CI, 1.97 to not estimable [NE]) months, and 5.52 months, respectively, in patients treated with naporafenib 200 mg twice a day plus trametinib 1 mg once daily, and 13.3% (95% CI, 1.7 to 40.5; 2 of 15 patients), 3.75 (95% CI, 2.04 to NE) months, and 4.21 months, respectively, in patients treated with naporafenib 400 mg twice a day plus trametinib 0.5 mg once daily. CONCLUSION: Naporafenib plus trametinib showed promising preliminary antitumor activity in patients with NRAS-mutant melanoma. Prophylactic strategies aimed to lower the incidence of skin-related events are under investigation.

A single- and multiple-dose study to characterize the pharmacokinetics, safety, and tolerability of ceftolozane/tazobactam in healthy Chinese participants.

Ceftolozane/tazobactam (C/T) is approved in several countries to treat complicated urinary tract infections, complicated intra-abdominal infections, and nosocomial pneumonia. There is a paucity of pharmacokinetics and safety data for C/T in Chinese participants. This study evaluated the pharmacokinetics, safety, and tolerability of C/T in 12 healthy Chinese participants after three single administrations of increasing doses (0.75 g, 1.5 g, and 3 g) and multiple administrations of 1.5 g C/T every 8 h for 3 days. After single doses, maximum concentrations of ceftolozane and tazobactam were reached by the end of the 1-h infusion and declined in a biphasic manner thereafter, with mean half-lives of 1.9-2.2 h and 0.74-0.95 h, respectively. Volume of distribution (Vd) and renal clearance (CL) were consistent across the three single-dose levels for ceftolozane (Vd, 15.8-19.5 L; CL, 5.68-6.09 L/h) and tazobactam (Vd, 23.3-28.6 L; CL, 20.8-23.5 L/h). Area under the concentration-time curve (AUC) extrapolated to infinity (ceftolozane, 88.1-328 h∙µg/mL; tazobactam, 10.7-48.0 h∙µg/mL) increased in a dose-dependent manner. After multiple doses over 3 days, AUC from time 0 to 8 h, and concentration at the end of infusion were similar to single-dose measurements (geometric mean ratios, 0.87-1.01 for both drugs). C/T was well tolerated, with no serious adverse events or discontinuations reported; all adverse events were mild. The pharmacokinetics and safety/tolerability of C/T in healthy Chinese participants was comparable to that in previous studies in other populations, supporting the use of C/T for the treatment of Chinese patients.

A Comparison of Wearable Tonometry, Photoplethysmography, and Electrocardiography for Cuffless Measurement of Blood Pressure in an Ambulatory Setting.

OBJECTIVE: While non-invasive, cuffless blood pressure (BP) measurement has demonstrated relevancy in controlled environments, ambulatory measurement is important for hypertension diagnosis and control. We present both in-lab and ambulatory BP estimation results from a diverse cohort of participants. METHODS: Participants (N=1125, aged 21-85, 49.2% female, multiple hypertensive categories) had BP measured in-lab over a 24-hour period with a subset also receiving ambulatory measurements. Radial tonometry, photoplethysmography (PPG), electrocardiography (ECG), and accelerometry signals were collected simultaneously with auscultatory or oscillometric references for systolic (SBP) and diastolic blood pressure (DBP). Predictive models to estimate BP using a variety of sensor-based feature groups were evaluated against challenging baselines. RESULTS: Despite limited availability, tonometry-derived features showed superior performance compared to other feature groups and baselines, yieldingprediction errors of 0.32 ±9.8 mmHg SBP and 0.54 ±7.7 mmHg DBP in-lab, and 0.86 ±8.7 mmHg SBP and 0.75 ±5.9 mmHg DBP for 24-hour averages. SBP error standard deviation (SD) was reduced in normotensive (in-lab: 8.1 mmHg, 24-hr: 7.2 mmHg) and younger (in-lab: 7.8 mmHg, 24-hr: 6.7 mmHg) subpopulations. SBP SD was further reduced 15-20% when constrained to the calibration posture alone. CONCLUSION: Performance for normotensive and younger participants was superior to the general population across all feature groups. Reference type, posture relative to calibration, and controlled vs. ambulatory setting all impacted BP errors. SIGNIFICANCE: Results highlight the need for demographically diverse populations and challenging evaluation settings for BP estimation studies. We present the first public dataset of ambulatory tonometry and cuffless BP over a 24-hour period to aid in future cardiovascular research.

Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial.

BACKGROUND: The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. METHODS: Baseline renal function was categorized as normal renal function (creatinine clearance 80-130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. RESULTS: A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [- 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; - 2.6 [- 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; - 2.1 [- 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [- 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [- 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [- 8.7 to 19.0]). CONCLUSIONS: C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

Calibrating surface hyperelastic constitutive models in soft solids.

Soft solids such as silicone gels, with bulk shear modulus ranging from ∼10 to 1000kPa, exhibit strongly strain-dependent surface stresses. Moreover, unlike conventional stiffer materials, the effects of surface stress in these materials manifest at length scales of tens of micrometers rather than nanometers. However, the calibration of constitutive parameters for surface hyperelasticity has proved to be challenging. Using a reasonably general surface constitutive model, we explore the possibility of obtaining its parameters from force-twist, torque-twist, and force-extension (force-compression) responses of a soft cylinder held between two inert, rigid plates. The motivation behind using these responses is derived from the fact that the roles of the surface constitutive parameters, under suitably ideal conditions, are neatly separated from each other and the three responses easily yield values of the three parameters. Moreover, through large deformation finite-element simulations with coupled bulk and surface hyperelasticity, we delineate the extent to which deviation from the ideal conditions may be tolerated. Using an example with previously reported material parameters, we estimate that, for cylindrical specimens with a radius of the order of 100µm, the capability to measure forces and torques of the order of 1-100µN and 10^{3}-10^{5}µN-µm, respectively, will be required to determine the parameters accurately.

Physiologically-based pharmacokinetics modeling to investigate formulation factors influencing the generic substitution of dabigatran etexilate.

The exposure-response relationship of direct acting oral anti-coagulants (DOACs) for bleeding risk is steep relative to ischemic stroke reduction. As a result, small changes in exposure may lead to bleeding events. The overall goal of this project was to determine the effect of critical formulation parameters on the pharmacokinetics (PKs) and thus safety and efficacy of generic DOACs. In this first installment of our overall finding, we developed and verified a physiologically-based PK (PBPK) model for dabigatran etexilate (DABE) and its metabolites. The model was developed following a middle out approach leveraging available in vitro and in vivo data. External validity of the model was confirmed by overlapping predicted and observed PK profiles for DABE as well as free and total dabigatran for a dataset not used during model development. The verified model was applied to interrogate the impact of modulating the microenvironment pH on DABE systemic exposure. The PBPK exploratory analyses highlighted the high sensitivity of DABE exposure to supersaturation ratio and precipitation kinetics.

Understanding Mechanisms of Food Effect and Developing Reliable PBPK Models Using a Middle-out Approach.

Over the last 10 years, 40% of approved oral drugs exhibited a significant effect of food on their pharmacokinetics (PK) and currently the only method to characterize the effect of food on drug absorption, which is recognized by the authorities, is to conduct a clinical evaluation. Within the pharmaceutical industry, there is a significant effort to predict the mechanism and clinical relevance of a food effect. Physiologically based pharmacokinetic (PBPK) models combining both drug-specific and physiology-specific data have been used to predict the effect of food on absorption and to reveal the underlying mechanisms. This manuscript provides detailed descriptions of how a middle-out modeling approach, combining bottom-up in vitro-based predictions with limited top-down fitting of key model parameters for clinical data, can be successfully used to predict the magnitude and direction of food effect when it is predicted poorly by a bottom-up approach. For nefazodone, a mechanistic clearance for the gut and liver was added, for furosemide, an absorption window was introduced, and for aprepitant, the biorelevant solubility was refined using multiple solubility measurements. In all cases, these adjustments were supported by literature data and showcased a rational approach to assess the factors limiting absorption and exposure.

Correction to: Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective.

An Erratum to this paper has been published: https://doi.org/10.1208/s12248-020-00535-z.

Use of Physiologically Based Pharmacokinetic (PBPK) Modeling for Predicting Drug-Food Interactions: an Industry Perspective.

The effect of food on pharmacokinetic properties of drugs is a commonly observed occurrence affecting about 40% of orally administered drugs. Within the pharmaceutical industry, significant resources are invested to predict and characterize a clinically relevant food effect. Here, the predictive performance of physiologically based pharmacokinetic (PBPK) food effect models was assessed via de novo mechanistic absorption models for 30 compounds using controlled, pre-defined in vitro, and modeling methodology. Compounds for which absorption was known to be limited by intestinal transporters were excluded in this analysis. A decision tree for model verification and optimization was followed, leading to high, moderate, or low food effect prediction confidence. High (within 0.8- to 1.25-fold) to moderate confidence (within 0.5- to 2-fold) was achieved for most of the compounds (15 and 8, respectively). While for 7 compounds, prediction confidence was found to be low (> 2-fold). There was no clear difference in prediction success for positive or negative food effects and no clear relationship to the BCS category of tested drug molecules. However, an association could be demonstrated when the food effect was mainly related to changes in the gastrointestinal luminal fluids or physiology, including fluid volume, motility, pH, micellar entrapment, and bile salts. Considering these findings, it is recommended that appropriately verified mechanistic PBPK modeling can be leveraged with high to moderate confidence as a key approach to predicting potential food effect, especially related to mechanisms highlighted here.

Physiologically Based Pharmacokinetic Modeling of Monoclonal Antibodies in Pediatric Populations Using PK-Sim.

Physiologically based pharmacokinetic (PBPK) models are increasingly used to support pediatric dose selection for small molecule drugs. In contrast, only a few pediatric PBPK models for therapeutic antibodies have been published recently, and the knowledge on the maturation of the processes relevant for antibody pharmacokinetics (PK) is limited compared to small molecules. The aim of this study was, thus, to evaluate predictions from antibody PBPK models for children which were scaled from PBPK models for adults in order to identify respective knowledge gaps. For this, we used the generic PBPK model implemented in PK-Sim without further modifications. Focusing on general clearance and distribution mechanisms, we selected palivizumab and bevacizumab as examples for this evaluation since they show simple, linear PK which is not governed by drug-specific target mediated disposition at usual therapeutic dosages, and their PK has been studied in pediatric populations after intravenous application. The evaluation showed that the PK of palivizumab was overall reasonably well predicted, while the clearance for bevacizumab seems to be underestimated. Without implementing additional ontogeny for antibody PK-specific processes into the PBPK model, bodyweight normalized clearance increases only moderately in young children compared to adults. If growth during aging at the time of the simulation was considered, the apparent clearance is approximately 20% higher compared to simulations for which growth was not considered for newborns due to the long half-life of antibodies. To fully understand the differences and similarities in the PK of antibodies between adults and children, further research is needed. By integrating available information and data, PBPK modeling can contribute to reveal the relevance of involved processes as well as to generate and test hypothesis.

Mechanics of reversible wrinkling in a soft dielectric elastomer.

A parallel array of wrinkles can be generated in a simple parallel plate capacitor arrangement with a soft dielectric elastomer plate constrained all around its periphery and coated with flexible electrodes. The direction of the wrinkles is predetermined and the phenomenon is reversible in a range of applied potentials. A model of the wrinkled plate as a prestretched neo-Hookean membrane with superposed small out-of-plane bending displacements yields good estimates of the potential range for wrinkling as well as the number of parallel wrinkles. The mechanics is controlled by the thickness and aspect ratios, prestretch, and a nondimensional electric potential.

Characterization of entanglements in glassy polymeric ensembles using the Gaussian linking number.

We propose a method for enumerating entanglements between long chained, linear polymers that is based on the Gaussian linking number. The linking number is calculated between closely approaching segments of the macromolecular chains. Topological features of an entanglement, i.e., the extent to which one open segment winds around another, are reflected by the linking number. We show that using this measure, we can track disentanglement events through a deformation history and gain insights into how large scale disentanglements lead to failure. Incorporating an additional step where the topological entanglements identified along each chain are optimally clustered using standard clustering algorithms, we can also obtain a measure of the average number of rheological constraints that exist along each chain in an ensemble. Comparisons with other methods of enumerating entanglements, especially the primitive path analysis, are also made. Our results indicate that the linking number between two entangled segments in the undeformed state is a good indicator of the strength of the entanglement. Also, disentanglements occurring overwhelmingly around chain ends are an important cause of failure when a triaxial stress state exists in the polymer.

Von Recklinghausen's Disease Presenting as Otolaryngologic Emergency: A Rare Occurrence.

Type 1 Neurofibromatosis (NF1) is a rare autosomal dominant genetic disorder. There are seven clinical features of which two are necessary to diagnose it. Another important feature is plexiform neurofibroma which commonly presents as painful expansile lesion. Here we present a case of NF1 with huge swelling of left hemiface and chin following trauma over pre-existing swelling and presented as life threatening emergency and managed surgically.

Xiao-Chai-Hu-Tang (XCHT) Intervening Irinotecan's Disposition: The Potential of XCHT in Alleviating Irinotecan-Induced Diarrhea.

BACKGROUND: Diarrhea is a severe side effect of irinotecan, a pro-drug of SN-38 used for the treatment of many types of cancers. Pre-clinical and clinical studies showed that decreasing the colonic exposure of SN-38 can mitigate irinotecan-induced diarrhea. OBJECTIVE: The purpose of this study is to evaluate the anti-diarrhea potential of Xiao-Chai-Hu-Tang (XCHT), a traditional Chinese herbal formula, against irinotecan-induced diarrhea by determining if and how XCHT alters the disposition of SN-38. METHODS: LC-MS/MS was used to quantify the concentrations of irinotecan and its major metabolites (i.e., SN-38, SN-38G). An Intestinal perfusion model was used to determine the effect of XCHT on the biliary and intestinal secretions of irinotecan, SN-38, and SN-38G. Pharmacokinetic (PK) studies were performed to determine the impact of XCHT on the blood and fecal concentrations of irinotecan, SN-38, and SN-38G. RESULTS: The results showed that XCHT significantly inhibits both biliary and intestinal excretions of irinotecan, SN-38, and SN-38G (range: 35% to 95%). PK studies revealed that the fecal concentrations of irinotecan and SN-38 were significantly decreased from 818.35 ± 120.2 to 411.74 ± 138.83 µg/g or from 423.95 ± 76.44 to 245.63 ± 56.72 µg/g (p<0.05) by XCHT, respectively, suggesting the colonic exposure of SN-38 is significantly decreased by XCHT. PK studies also showed that the plasma concentrations of irinotecan, SN-38, and SN-38G were not affected by XCHT. CONCLUSION: In conclusion, XCHT significantly decreased the exposure of SN-38 in the gut without affecting its plasma level, thereby possessing the potential of alleviating irinotecan-induced diarrhea without negatively impacting its therapeutic efficacy.

Physiologically Based Pharmacokinetic Modeling to Evaluate Formulation Factors Influencing Bioequivalence of Metoprolol Extended-Release Products.

The University of Florida Center for Pharmacometrics and Systems Pharmacology and the Food and Drug Administration Office of Generic Drugs have collaborated on a research project to develop a mechanism- and risk-based strategy that systematically investigates postmarketing reports of therapeutic inequivalence following the switch between brand and generic drug products. In this study we developed and qualified a physiologically based pharmacokinetic model to systematically investigate the influence of drug- and formulation-related properties on the oral absorption and bioequivalence of modified-release products using metoprolol as an example. Our findings show that the properties of the release-controlling polymer are the critical attributes for in vitro dissolution, in vivo absorption, and systemic exposure (ie, pharmacokinetics) and, thus, the bioequivalence of metoprolol extended-release products rather than the properties of the drug itself. Differences in dissolution rate can result in significant differences in maximum plasma concentration but not in area under the concentration-time curve.

Glucuronidation: driving factors and their impact on glucuronide disposition.

Glucuronidation is a well-recognized phase II metabolic pathway for a variety of chemicals including drugs and endogenous substances. Although it is usually the secondary metabolic pathway for a compound preceded by phase I hydroxylation, glucuronidation alone could serve as the dominant metabolic pathway for many compounds, including some with high aqueous solubility. Glucuronidation involves the metabolism of parent compound by UDP-glucuronosyltransferases (UGTs) into hydrophilic and negatively charged glucuronides that cannot exit the cell without the aid of efflux transporters. Therefore, elimination of parent compound via glucuronidation in a metabolic active cell is controlled by two driving forces: the formation of glucuronides by UGT enzymes and the (polarized) excretion of these glucuronides by efflux transporters located on the cell surfaces in various drug disposition organs. Contrary to the common assumption that the glucuronides reaching the systemic circulation were destined for urinary excretion, recent evidences suggest that hepatocytes are capable of highly efficient biliary clearance of the gut-generated glucuronides. Furthermore, the biliary- and enteric-eliminated glucuronides participate into recycling schemes involving intestinal microbes, which often prolong their local and systemic exposure, albeit at low systemic concentrations. Taken together, these recent research advances indicate that although UGT determines the rate and extent of glucuronide generation, the efflux and uptake transporters determine the distribution of these glucuronides into blood and then to various organs for elimination. Recycling schemes impact the apparent plasma half-life of parent compounds and their glucuronides that reach intestinal lumen, in addition to prolonging their gut and colon exposure.

Role of Toll-like receptor 4 in drug-drug interaction between paclitaxel and irinotecan in vitro.

The bacterial receptor, Toll-like receptor (TLR) 4 mediates inflammatory responses and has been linked to a broad array of diseases. TLR4 agonists are being explored as potential treatments for cancer and other diseases. We have previously shown that activation of TLR4 by lipopolysaccharide (LPS) leads to down-regulation of drug metabolizing enzymes/transporters (DMETs), and altered pharmacokinetics/pharmacodynamics (PK/PD) of drugs. These changes can increase the risk of drug-drug interactions (DDIs) in patients on multiple medications. Clinically, DDI was observed for combination chemotherapy of paclitaxel (TLR4 ligand) and irinotecan. To determine the role of TLR4 in DDI between paclitaxel and irinotecan in vitro, primary hepatocytes from TLR4-wild-type (WT) and mutant mice were pre-treated with paclitaxel, followed by irinotecan. Gene expression of DMETs was determined. Paclitaxel treatment increased the levels of irinotecan metabolites, SN-38 and SN-38 glucuronide (SN-38G) in TLR4-dependent manner. Paclitaxel-mediated induction of genes involved in irinotecan metabolism such as Cyp3a11 and Ugt1a1 was TLR4-dependent, while induction of the transporter Mrp2 was TLR4-independent. These novel findings demonstrate that paclitaxel can affect irinotecan metabolism by a TLR4-dependent mechanism. This provides a new perspective towards evaluation of marketed drugs according to their potential to exert DDIs in TLR4-dependent manner.

Correlations between axial stiffness and microstructure of a species of bamboo.

Bamboo is a ubiquitous monocotyledonous flowering plant and is a member of the true grass family Poaceae. In many parts of the world, it is widely used as a structural material especially in scaffolding and buildings. In spite of its wide use, there is no accepted methodology for standardizing a species of bamboo for a particular structural purpose. The task of developing structure-property correlations is complicated by the fact that bamboo is a hierarchical material whose structure at the nanoscopic level is not very well explored. However, we show that as far as stiffness is concerned, it is possible to obtain reliable estimates of important structural properties like the axial modulus from the knowledge of certain key elements of the microstructure. Stiffness of bamboo depends most sensitively on the size and arrangement of the fibre sheaths surrounding the vascular bundles and the arrangement of crystalline cellulose microfibrils in their secondary cell walls. For the species of bamboo studied in this work, we have quantitatively determined the radial gradation that the arrangement of fibres renders to the structure. The arrangement of the fibres gives bamboo a radially graded property variation across its cross section.