Search results for: M/G/infinity

Authors: Muhammad Faraz, Talat Rafique, Jang Min Park

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In this article, rotational flow above a permeable surface with a variable free stream angular velocity is considered. Main interest is to solve the associated heat/mass transport equations under different situations. Firstly, heat transport phenomena occurring in generalized vortex flow are analyzed under two altered heating processes, namely, the (i) prescribed surface temperature and (ii) prescribed heat flux. The vortex motion imposed at infinity is assumed to follow a power-law form 〖(r/r_0)〗^((2n-1)) where r denotes the radial coordinate, r_0 the disk radius, and n is a power-law parameter. Assuming a similar solution, the governing Navier-Stokes equations transform into a set of coupled ODEs which are treated numerically for the aforementioned thermal conditions. Secondly, mass transport phenomena accompanied by activation energy are incorporated into the generalized vortex flow situation. After finding self-similar equations, a numerical solution is furnished by using MATLAB's built-in function bvp4c.

Keywords: bödewadt flow, vortex flow, rotating flows, prescribed heat flux, permeable surface, activation energy

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Authors: Nicolae Pascu

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Aside from being a fundamental tool in Complex analysis, Schwarz Lemma-which was finalized in its most complete form at the beginning of the last century-generated an important area of research in various fields of mathematics, which continues to advance even today. We present some properties of analytic functions in the half-plane which satisfy the conditions of the classical Schwarz Lemma (Carathéodory functions) and obtain a generalization of the well-known Aleksandrov-Sobolev Lemma for analytic functions in the half-plane (the correspondent of Schwarz-Pick Lemma from the unit disk). Using this Schwarz-type lemma, we obtain a characterization for the entire class of Carathéodory functions, which might be of independent interest. We prove two monotonicity properties for Carathéodory functions that do not depend upon their normalization at infinity (the hydrodynamic normalization). The method is based on conformal mapping arguments for analytic functions in the half-plane satisfying appropriate conditions, in the spirit of Schwarz lemma. According to the research findings in this paper, our main results give estimates for the modulus and the argument for the entire class of Carathéodory functions. As applications, we give several extensions of Julia-Wolf-Carathéodory Lemma in a half-strip and show that our results are sharp.

Keywords: schwarz lemma, Julia-wolf-caratéodory lemma, analytic function, normalization condition, caratéodory function

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Authors: Amir Hadi Ziaie

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In the present work, we revisit the collapse process of a spherically symmetric homogeneous scalar field (in FRW background) minimally coupled to gravity, when the phase-space deformations are taken into account. Such a deformation is mathematically introduced as a particular type of noncommutativity between the canonical momenta of the scale factor and of the scalar field. In the absence of such deformation, the collapse culminates in a spacetime singularity. However, when the phase-space is deformed, we find that the singularity is removed by a non-singular bounce, beyond which the collapsing cloud re-expands to infinity. More precisely, for negative values of the deformation parameter, we identify the appearance of a negative pressure, which decelerates the collapse to finally avoid the singularity formation. While in the un-deformed case, the horizon curve monotonically decreases to finally cover the singularity, in the deformed case the horizon has a minimum value that this value depends on deformation parameter and initial configuration of the collapse. Such a setting predicts a threshold mass for black hole formation in stellar collapse and manifests the role of non-commutative geometry in physics and especially in stellar collapse and supernova explosion.

Keywords: gravitational collapse, non-commutative geometry, spacetime singularity, black hole physics

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Authors: Alexandra Monteiro, K. Bousson, Fernando J. O. Moreira, Ricardo Reis

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Fixed-wing flying vehicles are usually controlled by means of control surfaces such as elevators, ailerons, and rudders. The failure of these systems may lead to severe or even fatal crashes. These failures resulted in increased popularity for research activities on propulsion control in the last decades. The present work deals with a hybrid control architecture in which the propulsion-controlled vehicle maintains its traditional control surfaces, addressing the issue of robust lateral-directional dynamics control. The challenges stem from the parameter uncertainties in the stability and control derivatives and some unknown terms in the flight dynamics model. Two approaches are implemented and tested: linear quadratic regulation with robustness characteristics and H∞ control. The problem is centered on roll-yaw controller design with full state-feedback, which is able to deal with a standalone propulsion control mode as well as a hybrid mode combining both propulsion control and conventional control surface concepts while maintaining the original flight maneuverability characteristics. The results for both controllers emphasized very good control performances; however, the H∞ controller showed higher stabilization rates and robustness albeit with a slightly higher control magnitude than using the linear quadratic regulator.

Keywords: robust propulsion control, h-infinity control, lateral-directional flight dynamics, parameter uncertainties

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Authors: Peter L. Varkonyi, Andras A. Sipos

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The quasi-static growth of elastic fibers is studied in the presence of distributed contact with an immobile surface, subject to isotropic dry or viscous friction. Unlike classical problems of elastic stability modelled by autonomous dynamical systems with multiple time scales (slowly varying bifurcation parameter, and fast system dynamics), this problem can only be formulated as a non-autonomous system without time scale separation. It is found that the fibers initially converge to a trivial, straight configuration, which is later replaced by divergence reminiscent of buckling phenomena. In order to capture the loss of stability, a new definition of exponential stability against infinitesimal perturbations for systems defined over finite time intervals is developed. A semi-analytical method for the determination of the critical length based on eigenvalue analysis is proposed. The post-critical behavior of the fibers is studied numerically by using variational methods. The emerging post-critical shapes and the asymptotic behavior as length goes to infinity are identified for simple spatial distributions of growth. Comparison with physical experiments indicates reasonable accuracy of the theoretical model. Some applications from modeling plant root growth to the design of soft manipulators in robotics are briefly discussed.

Keywords: buckling, elastica, friction, growth

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Authors: Michael Dreyfuss, Yahel Giat

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Limited battery range and long recharging times are the greatest obstacles to the successful adoption of electric cars. One of the suggestions to overcome these problems is that carmakers retain ownership of batteries and provide battery swapping service so that customers exchange their depleted batteries for recharged batteries. Motivated by this example, we consider the problem of optimal spares allocation in an exchangeable-item, multi-location repair system. We generalize the standard service measures of fill rate and average waiting time to reflect the fact that customers penalize the service provider only if they have to wait more than a ‘tolerable’ time window. These measures are denoted as the window fill rate and the truncated waiting time, respectively. We find that the truncated waiting time is convex and therefore a greedy algorithm solves the spares allocation problem efficiently. We show that the window fill rate is generally S-shaped and describe an efficient algorithm to find a near-optimal solution and detail a priori and a posteriori upper bounds to the distance from optimum. The theory is complemented with a large scale numerical example demonstrating the spare battery allocation in battery swapping stations.

Keywords: convex-concave optimization, exchangeable item, M/G/infinity, multiple location, repair system, spares allocation, window fill rate

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Authors: Mohammad Hossein Bayati Chaleshtari, Hadi Khoramishad

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Minimizing the stress concentration around triangular cutout in infinite perforated plates subjected to a uniform heat flux induces thermal stresses is an important consideration in engineering design. Furthermore, understanding the effective parameters on stress concentration and proper selection of these parameters enables the designer to achieve a reliable design. In the analysis of thermal stress, the effective parameters on stress distribution around cutout include fiber angle, flux angle, bluntness and rotation angle of the cutout for orthotropic materials. This paper was tried to examine effect of these parameters on thermal stress analysis of infinite perforated plates with central triangular cutout. In order to achieve the least amount of thermal stress around a triangular cutout using a novel swarm intelligence optimization technique called dragonfly optimizer that inspired by the life method and hunting behavior of dragonfly in nature. In this study, using the two-dimensional thermoelastic theory and based on the Likhnitskiiʼ complex variable technique, the stress analysis of orthotropic infinite plate with a circular cutout under a uniform heat flux was developed to the plate containing a quasi-triangular cutout in thermal steady state condition. To achieve this goal, a conformal mapping function was used to map an infinite plate containing a quasi- triangular cutout into the outside of a unit circle. The plate is under uniform heat flux at infinity and Neumann boundary conditions and thermal-insulated condition at the edge of the cutout were considered.

Keywords: infinite perforated plate, complex variable method, thermal stress, optimization method

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Authors: Luiz G. Véras, Felipe L. Medeiros, Lamartine F. Guimarães

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This work approaches the automatic planning of paths for Unmanned Aerial Vehicles (UAVs) through the application of the Rapidly Exploring Random Tree Star-Smart (RRT*-Smart) algorithm. RRT*-Smart is a sampling process of positions of a navigation environment through a tree-type graph. The algorithm consists of randomly expanding a tree from an initial position (root node) until one of its branches reaches the final position of the path to be planned. The algorithm ensures the planning of the shortest path, considering the number of iterations tending to infinity. When a new node is inserted into the tree, each neighbor node of the new node is connected to it, if and only if the extension of the path between the root node and that neighbor node, with this new connection, is less than the current extension of the path between those two nodes. RRT*-smart uses an intelligent sampling strategy to plan less extensive routes by spending a smaller number of iterations. This strategy is based on the creation of samples/nodes near to the convex vertices of the navigation environment obstacles. The planned paths are smoothed through the application of the method called quintic pythagorean hodograph curves. The smoothing process converts a route into a dynamically-viable one based on the kinematic constraints of the vehicle. This smoothing method models the hodograph components of a curve with polynomials that obey the Pythagorean Theorem. Its advantage is that the obtained structure allows computation of the curve length in an exact way, without the need for quadratural techniques for the resolution of integrals.

Keywords: path planning, path smoothing, Pythagorean hodograph curve, RRT*-Smart

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Authors: Marija Vitanova, Aleksandra Bogdanovic, Kemal Edip, Viktor Hristovski, Vlado Micov

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Bridges represent critical structures in lifeline systems. They provide reliable modes of transportation, so their failure can seriously obstruct relief and rehabilitation work. Earthquake ground motions can cause significant damages in bridges, so during the strong earthquakes, they can easily collapse. The base isolation technique has been quite effective in seismic response mitigation of the bridges in reducing the piers base shear. The effect of soil structure interaction on the dynamic responses of seismically isolated three span girder bridge with viscous dampers is investigated. Viscous dampers are installed in the mid span of the bridge to control bearing displacement. The soil surrounding the foundation of piers has been analyzed by applying different soil densities in order to consider the soil stiffness. The soil medium has been assumed as a four layered infill as dense and loose medium. The boundaries in the soil medium are considered as infinite elements in order to absorb the radiating waves. The formulation of infinite elements is the same as for the finite elements in addition to the mapping of the domain. Based on the iso-parametric concept, the infinite element in global coordinate is mapped onto an element in local coordinate system. In the formulation of the infinite element, only the positive direction extends to infinity thus allowing the waves to propagate outside of the soil medium. Dynamic analyses for two levels of earthquake intensity are performed in time domain using direct integration method. In order to specify the effects of the SSI, the responses of the isolated and controlled isolated bridges are compared. It is observed that the soil surrounding the piers has significant effects on the bearing displacement of the isolated RC bridges. In addition, it is observed that the seismic responses of isolated RC bridge reduced significantly with the installation of the viscous dampers.

Keywords: viscous dampers, reinforced concrete girder bridges, seismic response, SSI

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Authors: Andreea Halunga, Chris D. Orme, Takashi Yamagata

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This paper proposes a heteroskedasticity-robust Breusch-Pagan test of the null hypothesis of zero cross-section (or contemporaneous) correlation in linear panel-data models, without necessarily assuming independence of the cross-sections. The procedure allows for either fixed, strictly exogenous and/or lagged dependent regressor variables, as well as quite general forms of both non-normality and heteroskedasticity in the error distribution. The asymptotic validity of the test procedure is predicated on the number of time series observations, T, being large relative to the number of cross-section units, N, in that: (i) either N is fixed as T→∞; or, (ii) N²/T→0, as both T and N diverge, jointly, to infinity. Given this, it is not expected that asymptotic theory would provide an adequate guide to finite sample performance when T/N is "small". Because of this, we also propose and establish asymptotic validity of, a number of wild bootstrap schemes designed to provide improved inference when T/N is small. Across a variety of experimental designs, a Monte Carlo study suggests that the predictions from asymptotic theory do, in fact, provide a good guide to the finite sample behaviour of the test when T is large relative to N. However, when T and N are of similar orders of magnitude, discrepancies between the nominal and empirical significance levels occur as predicted by the first-order asymptotic analysis. On the other hand, for all the experimental designs, the proposed wild bootstrap approximations do improve agreement between nominal and empirical significance levels, when T/N is small, with a recursive-design wild bootstrap scheme performing best, in general, and providing quite close agreement between the nominal and empirical significance levels of the test even when T and N are of similar size. Moreover, in comparison with the wild bootstrap "version" of the original Breusch-Pagan test our experiments indicate that the corresponding version of the heteroskedasticity-robust Breusch-Pagan test appears reliable. As an illustration, the proposed tests are applied to a dynamic growth model for a panel of 20 OECD countries.

Keywords: cross-section correlation, time-series heteroskedasticity, dynamic panel data, heteroskedasticity robust Breusch-Pagan test

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Authors: Li Chun Zhao, Zhi Chao Hu, Xi Qiang Liu, Man Lai Lee, Chak Shing Yeung, Man Fei Xu, Yuen Yee Kwan, Alan H. M. Ho, Nickie W. K. Chan, Bin Deng, Zhong Zhen Zhao, Min Xu

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Background: Chuangxiong Rhizoma (Chuangxion, CX) is one of the most frequently used herbs in Chinese medicine because of its wide therapeutic effects such as vasorelaxation and anti-inflammation. Aim: The purposes of this study are (1) to perform non-targeted / targeted analyses of CX methanol extract and water extract, and compare the present data with previously LC-MS or GC-MS fingerprints; (2) to examine the difference between CX methanol extract and water extract for preliminarily evaluating whether current compound markers of methanol extract from crude CX materials could be suitable for quality control of CX water extract. Method: CX methanol extract was prepared according to the Hong Kong Chinese Materia Medica Standards. DG water extract was prepared by boiling with pure water for three times (one hour each). UHPLC-Q-TOF-MS/MS fingerprint analysis was performed by C18 column (1.7 µm, 2.1 × 100 mm) with Agilent 1290 Infinity system. Experimental data were analyzed by Agilent MassHunter Software. A database was established based on 13 published LC-MS and GC-MS CX fingerprint analyses. Total 18 targeted compounds in database were selected as markers to compare present data with previous data, and these markers also used to compare CX methanol extract and water extract. Result: (1) Non-targeted analysis indicated that there were 133 compounds identified in CX methanol extract, while 325 compounds in CX water extract that was more than double of CX methanol extract. (2) Targeted analysis further indicated that 9 in 18 targeted compounds were identified in CX methanol extract, while 12 in 18 targeted compounds in CX water extract that showed a lower lose-rate of water extract when compared with methanol extract. (3) By comparing CX methanol extract and water extract, Senkyunolide A (+1578%), Ferulic acid (+529%) and Senkyunolide H (+169%) were significantly higher in water extract when compared with methanol extract. (4) Other bioactive compounds such as Tetramethylpyrazine were only found in CX water extract. Conclusion: Many new compounds in both CX methanol and water extracts were found by using UHPLC Q-TOF MS/MS analysis when compared with previous published reports. A new standard reference including non-targeted compound profiling and targeted markers functioned especially for quality control of CX water extract (herbal decoction) should be established in future. (This project was supported by Hong Kong Baptist University (FRG2/14-15/109) & Natural Science Foundation of Guangdong Province (2014A030313414)).

Keywords: Chuanxiong rhizoma, fingerprint analysis, targeted analysis, quality control

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Authors: Omer Burak Iskender, Keck Voon Ling, Vincent Dubanchet, Luca Simonini

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This paper presents Guidance and Control (G&C) strategy to approach and synchronize with potentially rotating targets. The proposed strategy generates and tracks a safe trajectory for space servicing missions, including tasks like approaching, inspecting, and capturing. The main objective of this paper is to validate the G&C laws using a Hardware-In-the-Loop (HIL) setup with realistic rendezvous and docking equipment. Throughout this work, the assumption of full relative state feedback is relaxed by onboard sensors that bring realistic errors and delays and, while the proposed closed loop approach demonstrates the robustness to the above mentioned challenge. Moreover, G&C blocks are unified via the Model Predictive Control (MPC) paradigm, and the coupling between translational motion and rotational motion is addressed via dual quaternion based kinematic description. In this work, G&C is formulated as a convex optimization problem where constraints such as thruster limits and the output constraints are explicitly handled. Furthermore, the Monte-Carlo method is used to evaluate the robustness of the proposed method to the initial condition errors, the uncertainty of the target's motion and attitude, and actuator errors. A capture scenario is tested with the robotic test bench that has onboard sensors which estimate the position and orientation of a drifting satellite through camera imagery. Finally, the approach is compared with currently used robust H-infinity controllers and guidance profile provided by the industrial partner. The HIL experiments demonstrate that the proposed strategy is a potential candidate for future space servicing missions because 1) the algorithm is real-time implementable as convex programming offers deterministic convergence properties and guarantee finite time solution, 2) critical physical and output constraints are respected, 3) robustness to sensor errors and uncertainties in the system is proven, 4) couples translational motion with rotational motion.

Keywords: dual quaternion, model predictive control, real-time experimental test, rendezvous and docking, spacecraft autonomy, space servicing

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Authors: Glenn Auld Knierim

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Automated robotic winding of high-temperature superconductors (HTS) addresses precision, efficiency, and reliability critical to the commercialization of products. Today’s HTS materials are mature and commercially promising but require manufacturing attention. In particular to the exaggerated rectangular cross-section (very thin by very wide), winding precision is critical to address the stress that can crack the fragile ceramic superconductor (SC) layer and destroy the SC properties. Damage potential is highest during peak operations, where winding stress magnifies operational stress. Another challenge is operational parameters such as magnetic field alignment affecting design performance. Winding process performance, including precision, capability for geometric complexity, and efficient repeatability, are required for commercial production of current HTS. Due to winding limitations, current HTS magnets focus on simple pancake configurations. HTS motors, generators, MRI/NMR, fusion, and other projects are awaiting robotic wound solenoid, planar, and spherical magnet configurations. As with conventional power cables, full transposition winding is required for long length alternating current (AC) and pulsed power cables. Robotic production is required for transposition, periodic swapping of cable conductors, and placing into precise positions, which allows power utility required minimized reactance. A full transposition SC cable, in theory, has no transmission length limits for AC and variable transient operation due to no resistance (a problem with conventional cables), negligible reactance (a problem for helical wound HTS cables), and no long length manufacturing issues (a problem with both stamped and twisted stacked HTS cables). The Infinity Physics team is solving manufacturing problems by developing automated manufacturing to produce the first-ever reliable and utility-grade commercial SC cables and magnets. Robotic winding machines combine mechanical and process design, specialized sense and observer, and state-of-the-art optimization and control sequencing to carefully manipulate individual fragile SCs, especially HTS, to shape previously unattainable, complex geometries with electrical geometry equivalent to commercially available conventional conductor devices.

Keywords: automated winding manufacturing, high temperature superconductor, magnet, power cable

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Authors: Joao Barbosa

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After an intense dispute between the big bang cosmology and its big rival, the steady-state cosmology, some important experimental observations, such as the determination of helium abundance in the universe and the discovery of the cosmic background radiation in the 1960s were decisive for the progressive and wide acceptance of big bang cosmology and the inevitable abandonment of steady-state cosmology. But, despite solid theoretical support and those solid experimental observations favorable to big bang cosmology, Fred Hoyle, one of the proponents of the steady-state and the main opponent of the idea of the big bang (which, paradoxically, himself he baptized), never gave up and continued to fight for the idea of a stationary (or quasi-stationary) universe until the end of his life, even after decades of widespread consensus around the big bang cosmology. We can try to understand this persistent attitude of Hoyle by applying Holton’s thematic analysis to cosmology. Holton recognizes in the scientific activity a dimension that, even unconscious or not assumed, is nevertheless very important in the work of scientists, in implicit articulation with the experimental and the theoretical dimensions of science. This is the thematic dimension, constituted by themata – concepts, methodologies, and hypotheses with a metaphysical, aesthetic, logical, or epistemological nature, associated both with the cultural context and the individual psychology of scientists. In practice, themata can be expressed through personal preferences and choices that guide the individual and collective work of scientists. Thematic analysis shows that big bang cosmology is mainly based on a set of themata consisting of evolution, finitude, life cycle, and change; the cosmology of the steady-state is based on opposite themata: steady-state, infinity, continuous existence, and constancy. The passionate controversy that these cosmological views carried out is part of an old cosmological opposition: the thematic opposition between an evolutionary view of the world (associated with Heraclitus) and a stationary view (associated with Parmenides). Personal preferences seem to have been important in this (thematic) controversy, and the thematic analysis that was developed shows that Hoyle is a very illustrative example of a life-long personal commitment to some themata, in this case to the opposite themata of the big bang cosmology. His struggle against the big bang idea was strongly based on philosophical and even religious reasons – which, in a certain sense and in a Holtonian perspective, is related to thematic preferences. In this personal and persistent struggle, Hoyle always refused the way how some experimental observations were considered decisive in favor of the big bang idea, arguing that the success of this idea is based on sociological and cultural prejudices. This Hoyle’s attitude is a personal thematic attitude, in which the acceptance or rejection of what is presented as proof or scientific fact is conditioned by themata: what is a proof or a scientific fact for one scientist is something yet to be established for another scientist who defends different or even opposites themata.

Keywords: cosmology, experimental observations, fred hoyle, interpretation, life-long personal commitment, Themata

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Authors: Vitor M. Vilas Boas, Cleison D. Silva, Gustavo S. Mafra, Alexandre Trofino Neto

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Motor imagery (MI) based brain-computer interfaces (BCI) uses event-related (de)synchronization (ERS/ ERD), typically recorded using electroencephalography (EEG), to translate brain electrical activity into control commands. To mitigate undesirable artifacts and noise measurements on EEG signals, methods based on band-pass filters defined by a specific frequency band (i.e., 8 – 30Hz), such as the Infinity Impulse Response (IIR) filters, are typically used. Spatial techniques, such as Common Spatial Patterns (CSP), are also used to estimate the variations of the filtered signal and extract features that define the imagined motion. The CSP effectiveness depends on the subject's discriminative frequency, and approaches based on the decomposition of the band of interest into sub-bands with smaller frequency ranges (SBCSP) have been suggested to EEG signals classification. However, despite providing good results, the SBCSP approach generally increases the computational cost of the filtering step in IM-based BCI systems. This paper proposes the use of the Fast Fourier Transform (FFT) algorithm in the IM-based BCI filtering stage that implements SBCSP. The goal is to apply the FFT algorithm to reduce the computational cost of the processing step of these systems and to make them more efficient without compromising classification accuracy. The proposal is based on the representation of EEG signals in a matrix of coefficients resulting from the frequency decomposition performed by the FFT, which is then submitted to the SBCSP process. The structure of the SBCSP contemplates dividing the band of interest, initially defined between 0 and 40Hz, into a set of 33 sub-bands spanning specific frequency bands which are processed in parallel each by a CSP filter and an LDA classifier. A Bayesian meta-classifier is then used to represent the LDA outputs of each sub-band as scores and organize them into a single vector, and then used as a training vector of an SVM global classifier. Initially, the public EEG data set IIa of the BCI Competition IV is used to validate the approach. The first contribution of the proposed method is that, in addition to being more compact, because it has a 68% smaller dimension than the original signal, the resulting FFT matrix maintains the signal information relevant to class discrimination. In addition, the results showed an average reduction of 31.6% in the computational cost in relation to the application of filtering methods based on IIR filters, suggesting FFT efficiency when applied in the filtering step. Finally, the frequency decomposition approach improves the overall system classification rate significantly compared to the commonly used filtering, going from 73.7% using IIR to 84.2% using FFT. The accuracy improvement above 10% and the computational cost reduction denote the potential of FFT in EEG signal filtering applied to the context of IM-based BCI implementing SBCSP. Tests with other data sets are currently being performed to reinforce such conclusions.

Keywords: brain-computer interfaces, fast Fourier transform algorithm, motor imagery, sub-band common spatial patterns

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Authors: Suliman Al-Fayoumi, Sherri Amberg, Huafeng Zhou, Jack W. Singer, James P. Dean

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Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1, and CSF1R. In clinical studies, pacritinib was well tolerated with clinical activity in patients with myelofibrosis. The most frequent adverse events (AEs) observed with pacritinib are gastrointestinal (diarrhea, nausea, and vomiting; mostly grade 1-2 in severity) and typically resolve within 2 weeks. A human ADME mass balance study demonstrated that pacritinib is predominantly cleared via hepatic metabolism and biliary excretion (>85% of administered dose). The major hepatic metabolite identified, M1, is not thought to materially contribute to the pharmacological activity of pacritinib. Hepatic diseases are known to impair hepatic blood flow, drug-metabolizing enzymes, and biliary transport systems and may affect drug absorption, disposition, efficacy, and toxicity. This phase 1 study evaluated the pharmacokinetics (PK) and safety of pacritinib and the M1 metabolite in study subjects with mild, moderate, or severe hepatic impairment (HI) and matched healthy subjects with normal liver function to determine if pacritinib dosage adjustments are necessary for patients with varying degrees of hepatic insufficiency. Study participants (aged 18-85 y) were enrolled into 4 groups based on their degree of HI as defined by Child-Pugh Clinical Assessment Score: mild (n=8), moderate (n=8), severe (n=4), and healthy volunteers (n=8) matched for age, BMI, and sex. Individuals with concomitant renal dysfunction or progressive liver disease were excluded. A single 400 mg dose of pacritinib was administered to all participants. Blood samples were obtained for PK evaluation predose and at multiple time points postdose through 168 h. Key PK parameters evaluated included maximum plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration time curve (AUC) from hour zero to last measurable concentration (AUC0-t), AUC extrapolated to infinity (AUC0-∞), and apparent terminal elimination half-life (t1/2). Following treatment, pacritinib was quantifiable for all study participants at 1 h through 168 h postdose. Systemic pacritinib exposure was similar between healthy volunteers and individuals with mild HI. However, there was a significant difference between those with moderate and severe HI and healthy volunteers with respect to peak concentration (Cmax) and plasma exposure (AUC0-t, AUC0-∞). Mean Cmax decreased by 47% and 57% respectively in participants with moderate and severe HI vs matched healthy volunteers. Similarly, mean AUC0-t decreased by 36% and 45% and mean AUC0-∞ decreased by 46% and 48%, respectively in individuals with moderate and severe HI vs healthy volunteers. Mean t1/2 ranged from 51.5 to 74.9 h across all groups. The variability on exposure ranged from 17.8% to 51.8% across all groups. Systemic exposure of M1 was also significantly decreased in study participants with moderate or severe HI vs. healthy participants and individuals with mild HI. These changes were not significantly dissimilar from the inter-patient variability in these parameters observed in healthy volunteers. All AEs were grade 1-2 in severity. Diarrhea and headache were the only AEs reported in >1 participant (n=4 each). Based on these observations, it is unlikely that dosage adjustments would be warranted in patients with mild, moderate, or severe HI treated with pacritinib.

Keywords: pacritinib, myelofibrosis, hepatic impairment, pharmacokinetics

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