Saturable Absorption Process Research Articles

Solid state light emitting polyaromatic luminogens containing pyrazoline chromophore

A series of polyaromatic luminophores based on pyrene pyrazoline containing donor-acceptor π-conjugation extended through naphthalene (PPN), anthracene (PPA) and pyrene (PPP) were designed and synthesized. They exhibited high glass transition temperatures and high thermal stability. Fluorescence shifted to longer wavelength while moving from solution state emission (blue to greenish yellow) to solid state and thin film emission (yellow, orange, red), further, electron accepting ability also increased with polyaryl substituents. PPN exhibited dual emission in solution, solid state and thin film. The purity of color emission was confirmed from CIE values. The luminogens reveal typical AIE (PPN, PPA) and AIBSE (PPP) features of twisted molecular conformation into aggregation of molecules arranged in J and H type aggregations. Solvatochromism observed as prominent blue to yellow emission shift, large Stokes shift in D-A of twisted molecular geometry and intramolecular charge transfer in various solvents. They demonstrate dual emission in nonpolar solvents with twisted intramolecular charge transfer process. The lifetime analysis of TCSPC revealed longer and shorter lifetime values in the excited state. Powder X-ray diffraction and differential scanning calorimetry disclosed phase transition between crystalline and amorphous states. The single beam Z-scan analysis revealed third order nonlinear optical properties of the materials. They exhibited nonlinear absorption owing to saturable absorption process while negative nonlinear refraction led to self defocusing nature. DFT and TD-DFT calculations established that these luminogens are highly twisted in nature. Charge transport properties were calculated through reorganization energy and reveals that these molecules could act as electron transporting materials. Computed IP and EA values along with reorganization energy reveal that they could be used as trifunctional materials (electron, hole and emitter). The changing of polyaromatic groups in 3, 5 position of pyrazoline ring was demonstrated that it could lead to new solid state light emitters that these molecules have potential in organic optoelectronics as OLED and down conversion solar cell applications.

Nonlinear spectroscopy of three-level cascade systems in the act of saturable and reverse saturable absorption

In the process of nonlinear absorption study using ultra-short laser pulses, it is imperative to know the population dynamics of excited molecules/atoms as a function of time. Using rate equation approach, we have numerically demonstrated the time-dependent population dynamics of three-level cascade systems under single photon resonant excitation by 125 fs single shot laser pulse with central wavelength at 532 nm. We present the effect of life-times, absorption cross-sections and photon flux on population redistribution among the energy levels by considering the saturable absorption (SA) and reverse saturable absorption process (RSA) in the wide range of spectroscopic parameters such as life-times and absorption cross-sections. In cascade energy level systems, ultra-short laser pulses have to be used to investigate higher energy levels absorption cross-section and life-times. Our results can be extended to higher energy levels of cascade systems by incorporating them into the rate equation models.

Nonlinear absorption and optical limiting of Ag–CdSe nano-hybrids of different growth times

Metal-semiconductor Nano-composites have enormous applications due to Plasmon –exciton coupling. Open aperture Z-scan is investigated for Ag–CdSe hybrid nanostructure, a toggle from saturable absorption process SA to reverse saturable absorption RSA is observed upon laser power increment. Proofs of crystal and morphological structure are given by selected area electron diffraction (SAED) and high resolution transmission electron microscope (HRTEM). Red shifting in photoluminescence spectra PL is observed which is ascribed to the particle size increment. Intriguing nonlinear findings can be used to engineer optical switching devices and optical limiters.

Nonlinear optical response of graphene/silicon nanocomposites

In this experimental investigation, silicon nanoparticles and graphene nanosheets suspensions were produced by the pulsed laser ablation in distilled water separately. Then graphene and silicon were mixed in different volumetric ratio and irradiated by UV radiation to produced graphene/silicon nanocomposites. In order to characterize the structural and optical properties of samples, UV–Vis–NIR spectroscopy, Raman spectrum, and transmission electron microscopy were carried out. According to Raman spectra the defects introduced into the graphene nanosheets are more than the defects in the graphene/silicon nanocomposites. The extinction coefficients and bandgap energies of graphene/Si nanocomposites were decreased with increasing the amount of graphene suspension. The z-scan method was employed to estimate the role of the volume ratio of graphene nanosheets to silicon nanoparticles in changing the nonlinear responses of the graphene/silicon nanocomposites. Results of z-scan show that the nonlinear optical properties of graphene/silicon nanocomposites enhanced by increasing the concentration of Si nanoparticles. Furthermore, the measured values of third order nonlinear optical susceptibility, $$\chi^{\left( 3 \right)}$$ of the graphene/silicon nanocomposites were from the order of 10−15 SI. Results show that the origin of optical nonlinearity of suspensions is due to the saturable absorption process.

Fe induced optical limiting properties of Zn1−xFexS nanospheres

Zn1−xFexS (x=0.00, 0.01, 0.03, 0.05) nanospheres were synthesized by polyethylene glycol assisted hydrothermal method. XRD studies revealed that samples of all concentrations exhibited cubic structure with crystallite grain size 7–9nm. TEM and SEM show the formation of nanospheres by dense aggregation of smaller particles. Increasing Zn/Fe ratio tune the band gap from 3.4 to 3.2eV and also quenches the green luminescence. FTIR spectra reveal the presence of capping agent, intensity variation and shifting of LO and TO phonon modes confirm the presence of Fe ions. Nonlinear optical properties were measured using open and closed aperture z-scan techniques, employing frequency doubled 532nm pumping sources which indicated reverse saturable absorption (RSA) process. The nonlinear optical coefficients are obtained by two photon absorption (2PA). Composition dependent nonlinear optical coefficients “β”, nonlinear refractive index, third order susceptibility and optical limiting threshold were estimated. The sample shows good nonlinear absorption and enhancement of optical limiting behavior with increasing Fe volume fraction. Contribution of RSA on optical nonlinearity of Zn1−xFexS nanospheres are also investigated using three different input energies. Zn1−xFexS with comparatively small limiting threshold value is a promising candidate for optical power limiting applications.

All-optical switching and limiting properties of a Ru (II) Schiff-base complex for nonlinear optical applications

A salen-based ruthenium (Ru) (II) complex was synthesized for possible use in nonlinear optical device applications. The Ru complex was doped in a polymer matrix to fabricate films using a low-cost spin-coating technique. The third-order nonlinear optical parameters of the complex were investigated by Z-scan and degenerate four-wave mixing techniques. The study reveals two-order enhancement of third-order optical susceptibility χ(3) and exhibits superior limiting capability due to a reverse saturable absorption process. All-optical switching action for the films indicates that the sample can function as an optical inverter or a NOT gate. Hence, the Ru (II) Schiff-base complex materializes as a possible candidate for use in nonlinear optical devices.

Influence of sintering time on switching of the femtosecond nonlinear optical properties of CuNb2O6

Transition of mixed phases (monoclinic and orthorhombic) to pure orthorhombic phase was achieved during the synthesis process of CuNb2O6 by varying the sintering time. The suppression of monoclinic phase and dominant formation of orthorhombic CuNb2O6 was confirmed from the XRD and FTIR data analysis. FESEM studies demonstrated that due to increase in sintering time, coarsening process initiated the grain growth and trapping of pores leading to pore-free structures. The nonlinear optical (NLO) properties of mixed and pure copper niobate were studied by the Z-scan technique using near-infrared (800 nm, ∼150 fs, 80 MHz) laser excitation. Mixed phases exhibited saturable absorption and self-defocusing behaviour while pure orthorhombic demonstrated reverse saturable absorption and self-focusing process. The switching of nonlinearity along with increase in NLO coefficient of O-CuNb2O6 was attributed to the decreased metal-oxygen bond length and pore free structure. The increase in nonlinear absorption coefficient with input irradiance suggests the occurrence of effective 3 PA (2 PA followed by ESA) process. The magnitudes of nonlinear absorption coefficient (2.14 × 10−23m3/W2) and nonlinear refractive index (6.0 × 0−17 m2/W) of O-CuNb2O6 were found to be higher than well-known NLO materials. Orthorhombic CuNb2O6 exhibited optical limiting action with low limiting threshold of 38.26 μJ/cm2 and favouring NLO properties suggesting that the material to be an entrant candidate for safety devices against ultrashort pulsed lasers.

Dosing and Switching Strategies for Paliperidone Palmitate 3-Month Formulation in Patients with Schizophrenia Based on Population Pharmacokinetic Modeling and Simulation, and Clinical Trial Data.

Paliperidone palmitate 3-month formulation (PP3M), a long-acting injectable atypical antipsychotic, was recently approved in the US and Europe for the treatment of schizophrenia in adult patients who have already been treated with paliperidone palmitate 1-month formulation (PP1M) for ≥4months. This article reviews the pharmacokinetic rationale for the approved dosing regimens for PP3M, dosing windows, management of missed doses and treatment discontinuation, switching to other formulations, and dosing in special populations. Approved PP3M dosing regimens are based on the comparisons of simulations with predefined dosing regimens using paliperidone palmitate and oral paliperidone extended release (ER) population pharmacokinetic models (one-compartment model with two saturable absorption processes for PP3M; one-compartment model with parallel zero- and first-order absorption for PP1M; two-compartment model with sequential zero- and first-order absorption for ER) versus clinical trial data. Covariates were obtained by resampling subject covariates from the pharmacokinetics database for PP1M and PP3M. Simulation scenarios with varying doses and covariate values were generated. The population median and 90% prediction interval of the simulated concentration-time profiles were plotted for simulation outcomes evaluation. Simulations described in this paper provide (a) simulated plasma exposures for switching from PP1M to PP3M, (b) support for a once-every-3-months injection cycle, (c) information on dosing windows and managing missed doses of PP3M, (d) important guidance on PP3M dosing in special patient populations, and (e) key PP3M pharmacokinetic exposure metrics based on the population pharmacokinetic PP3M model. Population pharmacokinetics provided practical guidance to establish dosing regimens for PP3M.

Population pharmacokinetics of exenatide.

AimThe aim of the present analysis was to develop a core population pharmacokinetic model for the pharmacokinetic properties of immediate‐release (IR) exenatide, which can be used in subsequent analyses of novel sustained‐release formulations.MethodsData from eight clinical trials, evaluating a wide range of doses and different administration routes, were available for analysis. All modelling and simulations were conducted using the nonlinear mixed‐effect modelling program NONMEM. External model validation was performed using data from the phase III clinical trials programme through standard visual predictive checks.ResultsThe pharmacokinetics of IR exenatide was described by a two‐compartment model, and the absorption of subcutaneous exenatide was described with a sequential zero‐order rate constant followed by a saturable nonlinear absorption process. Drug elimination was characterized by two parallel routes (linear and nonlinear), with significant relationships between renal function and the linear elimination route, and between body weight and volume of distribution. For a subject with normal renal function, the linear clearance was estimated to be 5.06 l hr−1. The nonlinear elimination was quantified with a Michaelis–Menten constant (K m) of 567 pg ml−1 and a maximum rate of metabolism (V max) of 1.6 μg h−1. For subcutaneous administration, 37% of the subcutaneous dose is absorbed via the zero‐order process, and the remaining 63% via the nonlinear pathway.ConclusionsThe present analysis provides a comprehensive population pharmacokinetic model for exenatide, expanding the elimination process to include both linear and nonlinear components, providing a suitable platform for a broad range of concentrations and patient conditions that can be leveraged in future modelling efforts of sustained‐release exenatide formulations.

Influence of electron beam irradiation on nonlinear optical properties of Al doped ZnO thin films for optoelectronic device applications in the cw laser regime

We present the studies on third-order nonlinear optical properties of Al doped ZnO thin films irradiated with electron beam at different dose rate. Al doped ZnO thin films were deposited on a glass substrate by spray pyrolysis deposition technique. The thin films were irradiated using the 8 MeV electron beam from microtron ranging from 1 kG y to 5 kG y. Nonlinear optical studies were carried out by employing the single beam Z-scan technique to determine the sign and magnitude of absorptive and refractive nonlinearities of the irradiated thin films. Continuous wave He–Ne laser operating at 633 nm was used as source of excitation. The open aperture Z-scan measurements indicated the sample displays reverse saturable absorption (RSA) process. The negative sign of the nonlinear refractive index n2 was noted from the closed aperture Z-scan measurements indicates, the films exhibit self-defocusing property due to thermal nonlinearity. The third-order nonlinear optical susceptibility χ(3) varies from 8.17 × 10−5 esu to 1.39 × 10−3 esu with increase in electron beam irradiation. The present study reveals that the irradiation of electron beam leads to significant changes in the third-order optical nonlinearity. Al doped ZnO displays good optical power handling capability with optical clamping of about ∼5 mW. The irradiation study endorses that the Al doped ZnO under investigation is a promising candidate photonic device applications such as all-optical power limiting.

Enhanced third-order optical nonlinearity in Ce3+ ion-doped zinc sulfide–polyvinyl alcohol freestanding nanocomposite films

Undoped, 0, 2, and 5 mol% Ce-doped ZnS–PVA nanocomposite films have been prepared using in situ chemical method. X-ray diffraction patterns confirm that the prepared nanocomposite films are in cubic structure of ZnS. UV–Vis optical absorption spectra of Ce3+-doped ZnS–PVA films exhibit the red-shifted phenomenon with the increasing Ce dopant concentration in ZnS. Scanning electron microscope images reveal the morphology changes in the films with Ce doping. The high values of real and imaginary parts of dielectric constant at low frequencies are attributed to the space charge polarization, whereas the loss tangent of Ce-doped ZnS–PVA nanocomposite films at low frequency with the increasing Ce dopant concentration indicates the enhancement of optical quality of the films. The Z-scan technique exhibits a reverse saturable absorption process in nonlinear absorption studies and self-focusing optical nonlinearity in nonlinear refractive studies under the experimental conditions. The highest nonlinear optical parameters such as nonlinear absorption coefficient, nonlinear refractive index, and third-order nonlinear optical susceptibility are found to be about 9336.6 cm/GW, 1.782 × 10−4 cm2/GW, and 2.103 × 10−5 esu, respectively, for 5 mol% Ce3+-doped films. The estimated third-order nonlinear optical susceptibility is eight orders of magnitude larger than that of bulk ZnS, and four–five orders of magnitude higher than those of the some representative materials reported. Hence, the Ce3+-doped ZnS–PVA nanocomposite films investigated here emerge as promising candidates for the development of nonlinear optical devices.

Nonlinear optical measurements of conducting copolymers of aniline under CW laser excitation

Synthesis and measurements of third-order optical nonlinearity and optical limiting of conducting copolymers of aniline are presented. Single beam z-scan technique was employed for the nonlinear optical studies. Continuous wave He–Ne laser operating at 633nm was used as the source of excitation. Copolymer samples exhibited reverse saturable absorption (RSA) process. The nonlinear refraction studies depict that the copolymers exhibit self-defocusing property. The estimated values of βeff, n2 and χ(3) were found to be of the order of 10−2cm/W, 10−5esu and 10−7esu respectively. Self-diffraction rings were observed due to refractive index change when exposed to the laser beam. A good optical limiting and clamping of power of ∼0.9mW and ∼0.05mW was observed. Therefore, copolymers of aniline emerge as a potential candidate for photonic device applications.

Largely enhanced saturable absorption of a complex of plasmonic and molecular-like au nanocrystals.

A saturable absorber is a nonlinear functional material widely used in laser and photonic nanodevices. Metallic nanostructures have prominent saturable absorption (SA) at the plasmon resonance frequency owing to largely enhanced ground state absorption. However, the SA of plasmonic metal nanostructures is hampered by excited-state absorption processes at very high excitation power, which usually leads to a changeover from SA to reversed SA (SA→RSA). Here, we demonstrate tunable nonlinear absorption behaviours of a nanocomplex of plasmonic and molecular-like Au nanocrystals. The SA→RSA process is efficiently suppressed, and the stepwise SA→SA process is fulfilled owing to energy transfer in the nanocomplex. Our observations offer a strategy for preparation of the saturable absorber complex and have prospective applications in liquid lasers as well as one-photon nonlinear nanodevices.

Third-order nonlinear optical response of indigo carmine under 633 nm excitation for nonlinear optical applications

Abstract We report thermally induced third-order nonlinearity and optical limiting behaviour of Indigo Carmine dye. z-Scan technique was used to determine the sign and magnitude of absorptive and refractive nonlinearities. Continuous wave (CW) He–Ne laser operating at 633 nm was used as source of excitation. In open aperture z-scan experiments, samples exhibited reverse saturable absorption (RSA) process. For closed aperture z-scan experiments, samples revealed self-defocusing property. The presence of donor and acceptor groups in the structure increases the conjugation length and in turn increases the optical nonlinearity. Induced self-diffraction rings pattern was recorded for the samples and it is attributed to refractive index change and thermal lensing. Also, optical limiting and clamping studies were carried out for various input power. Optical clamping of about ~1 mW was observed. This endorses that the dye under investigation is a positive candidate for opto-electronic and photonic applications.

Pharmacology and toxicology of mycophenolate in organ transplant recipients: an update.

This review aims to provide an update of the literature on the pharmacology and toxicology of mycophenolate in solid organ transplant recipients. Mycophenolate is now the antimetabolite of choice in immunosuppressant regimens in transplant recipients. The active drug moiety mycophenolic acid (MPA) is available as an ester pro-drug and an enteric-coated sodium salt. MPA is a competitive, selective and reversible inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), an important rate-limiting enzyme in purine synthesis. MPA suppresses T and B lymphocyte proliferation; it also decreases expression of glycoproteins and adhesion molecules responsible for recruiting monocytes and lymphocytes to sites of inflammation and graft rejection; and may destroy activated lymphocytes by induction of a necrotic signal. Improved long-term allograft survival has been demonstrated for MPA and may be due to inhibition of monocyte chemoattractant protein 1 or fibroblast proliferation. Recent research also suggested a differential effect of mycophenolate on the regulatory T cell/helper T cell balance which could potentially encourage immune tolerance. Lower exposure to calcineurin inhibitors (renal sparing) appears to be possible with concomitant use of MPA in renal transplant recipients without undue risk of rejection. MPA displays large between- and within-subject pharmacokinetic variability. At least three studies have now reported that MPA exhibits nonlinear pharmacokinetics, with bioavailability decreasing significantly with increasing doses, perhaps due to saturable absorption processes or saturable enterohepatic recirculation. The role of therapeutic drug monitoring (TDM) is still controversial and the ability of routine MPA TDM to improve long-term graft survival and patient outcomes is largely unknown. MPA monitoring may be more important in high-immunological recipients, those on calcineurin-inhibitor-sparing regimens and in whom unexpected rejection or infections have occurred. The majority of pharmacodynamic data on MPA has been obtained in patients receiving MMF therapy in the first year after kidney transplantation. Low MPA area under the concentration time from 0 to 12 h post-dose (AUC0-12) is associated with increased incidence of biopsy-proven acute rejection although AUC0-12 optimal cut-off values vary across study populations. IMPDH monitoring to identify individuals at increased risk of rejection shows some promise but is still in the experimental stage. A relationship between MPA exposure and adverse events was identified in some but not all studies. Genetic variants within genes involved in MPA metabolism (UGT1A9, UGT1A8, UGT2B7), cellular transportation (SLCOB1, SLCO1B3, ABCC2) and targets (IMPDH) have been reported to effect MPA pharmacokinetics and/or response in some studies; however, larger studies across different ethnic groups that take into account genetic linkage and drug interactions that can alter a patient's phenotype are needed before any clinical recommendations based on patient genotype can be formulated. There is little data on the pharmacology and toxicology of MPA in older and paediatric transplant recipients.

Third-order nonlinear optical studies of anthraquinone dyes using a CW He–Ne laser

We present investigations on the third-order optical nonlinearity and optical power limiting of anthraquinone dyes. Z-scan measurements were performed using a continuous wave He–Ne laser at 633 nm wavelength as an excitation source. The nonlinear refraction studies exhibited self-defocusing behavior of the dyes. The nonlinear absorption in the dyes was dominated by a reverse saturable absorption process. Self-diffraction ring patterns were observed due to the change in refractive index and thermal lensing. Increase of the electron donating ability of the substituents resulted in enhanced values of the nonlinear optical parameters, establishing the structure–property relationship. The optical limiting study revealed that the dyes possess a lower limiting threshold and clamping level which is very important for eye and sensor protection. Hence, the dyes investigated here emerge as promising candidates for future opto-electronic and photonic device applications such as optical power limiters.

Studies on third-order optical nonlinearity and power limiting of conducting polymers using the z-scan technique for nonlinear optical applications

We present the synthesis and characterization of third-order optical nonlinearity and optical limiting of the conducting polymers poly (aniline-co-o-anisidine) and poly (aniline-co-pyrrole). Nonlinear optical studies were carried out by employing the z-scan technique using a He–Ne laser operating in continuous wave mode at 633 nm. The copolymers exhibited a reverse saturable absorption process and self-defocusing properties under the experimental conditions. The estimated values of βeff, n2 and χ(3) were found to be of the order of 10−2 cm W−1, 10-5 esu and 10−7 esu respectively. Self-diffraction rings were observed due to refractive index change when exposed to the laser beam. The copolymers possess a lower limiting threshold and clamping level, which is essential to a great extent for power limiting devices. Therefore, copolymers of aniline emerge as a potential candidate for nonlinear optical device applications.

Studies on Lead Sulfide (PbS) Semiconducting Thin Films Deposited from Nanoparticles and Its NLO Application

Nanoparticle Lead sulfide was synthesized via simple chemical method and deposited on glass substrates at different substrate temperatures by thermal evaporation technique. The synthesized nanoparticle PbS was analyzed and confirmed by X-ray diffraction (XRD), Scanning electron microscopy SEM with EDX and thermogravimetry. The structural, optical, morphological and electrical properties of the deposited films were studied using XRD, UV-Vis, Raman, SEM with EDX, atomicforce microscopy AFM and Hall Effect measurements. The thickness of the deposited samples was measured using thickness profilometer. The Raman shift in the peak occurs toward lower energy with increasing substrate temperature deposited lead sulfide. The Z-scan study with open aperture was carried out at 532 nm using 5 ns laser pulse on the deposited films which shows that nonlinear absorption arises from saturable absorption process. The deposited PbS film exhibits p-type conductivity in Hall measurement.

Wavelength Dependence of the Complex Third-Order Nonlinear Optical Susceptibility of Poly(3-hexylthiophene) Studied by Femtosecond Z-Scan in Solution and Thin Film

Comprehensive studies of the third-order susceptibility of regioregular poly(3-hexylthiophene) in the wavelength range from 530 to 1600 nm for both thin film (with stacked chains interactions) and dilute solution (no chains interactions) were performed with the Z-scan technique. Negative nonlinear refraction was observed in the whole wavelength range of the measurements. The nonlinear absorption exhibits regions of two-photon and three-photon absorption, and on approaching the linear absorption region, a saturable absorption process is seen. It was found that for thin film the effective multiphoton absorption cross-sections σ2 and σ3 are 1.5 and 3 times bigger than for solution, respectively. Influence of the elongated conjugation length in the stacked polythiophene chains in thin film on the red shift of the multiphoton absorption cross-section spectra in comparison with those for polythiophene in solution is discussed.

Exposure-Response Analysis For Pacritinib (SB1518), a Novel Oral JAK2/FLT3 Inhibitor, In Patients With Myelofibrosis

BackgroundPacritinib (SB1518) is a novel oral JAK2-FLT3 inhibitor. To date, once-daily (QD) dosing of pacritinib has been evaluated in two pharmacokinetic studies in healthy volunteers (n = 42) and in two phase 1/2 clinical trials in patients with advanced myeloid malignancies (n = 129). Due to less-than-proportional increase in systemic exposure with dose, administration of QD doses higher than 400 mg does not appreciably increase systemic exposure of pacritinib. Hence, the twice-daily (BID) regimen was conceived as an alternate dosing regimen to achieve higher systemic pacritinib exposure and potentially enhance clinical response of pacritinib. AimsCharacterize exposure-response relationship of pacritinib in early stage clinical development. MethodsTwo pharmacokinetic (PK) studies were conducted in healthy volunteers to assess the inter- and intra-individual PK variability and the effect of food on the PK of pacritinib. Two Phase 1/2 trials were also undertaken to characterize the population pharmacokinetics, safety, and efficacy of pacritinib in patients with advanced myeloid malignancies following oral administration of 100-600 mg QD. Safety (i.e., incidence and severity of key AEs including GI, thrombocytopenia and anemia) and efficacy (i.e., spleen size reduction) of pacritinib were assessed in patients. Based on the safety, tolerability and anti-tumor activity observed in the completed Phase 1/2 trials, the 400 mg QD regimen of pacritinib was selected for further clinical development in MF.A total of 65 patients received 400 mg QD regimen in Phase 2 trials for pacritinib. To construct the exposure-response relationship following QD dosing of pacritinib, patients with pharmacokinetic exposure data from completed Phase 1/2 trials (n = 129) were divided into quartiles [Q1-Q4] based on their model predicted area under the curve at steady-state (AUCss). For each exposure quartile, the mean reduction in spleen size was determined. In addition, exposure-response analysis on key safety parameters was similarly performed by comparing AE distributions across exposure quartiles. The key PK parameters were simulated for the 200 mg BID regimen and distribution of patients that fell into QD regimen-defined exposure quartiles was determined. ResultsPK simulation data indicated that administration of the 200 mg BID regimen is likely to result in a mean systemic exposure that is 41% higher relative to that of the 400 mg QD regimen. This is thought to be due to higher drug accumulation and reduced effect of saturable absorption processes on oral pacritinib bioavailability with the BID regimen. Evaluation of the efficacy time-course by exposure quartile revealed that patients in the highest quartile (Q4) exhibited the highest maximal response as well as the most durable clinical response over time relative to those that fell in the lower exposure quartiles (Figure 1). Whereas approximately 25% of patients from the completed Phase 1/2 trials fell in Q4 exposure zone with the 400 mg QD regimen, approximately 48% of patients on the 200 mg BID regimen are projected to fall in this exposure zone or higher. Moreover, assessment of key AEs including GI, anemia, and thrombocytopenia AEs by the exposure quartile, showed that these AEs were not worse with higher systemic exposure of pacritinib. [Display omitted] ConclusionsTogether, the exposure-safety and exposure-efficacy analyses support the potential utility of the 200 mg BID regimen of pacritinib in addition to the 400 mg QD regimen for the clinical development of pacritinib for myelofibrosis as well as other indications such as FLT3 mutated AML. The higher proportion of patients expected to achieve the Q4 exposure levels with the 200 mg BID regimen is predicted to correlate with higher splenic response rates relative to the 400 mg QD regimen. There was no significant exposure-response relationship on key AEs including GI, anemia and thrombocytopenia AEs. The lower local concentration of pacritinib in the GI tract with BID regimen may potentially decrease the incidence of GI adverse events such as diarrhea. Disclosures:Al-Fayoumi:Cell Therapeutics, Inc: Employment. Wang:Cell Therapeutics, Inc.: Employment. Li:Cell Therapeutics, Inc: Consultancy. Dean:Cell Therapeutics, Inc: Employment.