Disposition Phase Research Articles

Pharmacokinetics of desflurane uptake and disposition in piglets.

Many respiratory but few arterial blood pharmacokinetics of desflurane uptake and disposition have been investigated. We explored the pharmacokinetic parameters in piglets by comparing inspiratory, end-tidal, arterial blood, and mixed venous blood concentrations of desflurane. Seven piglets were administered inspiratory 6% desflurane by inhalation over 2h, followed by a 2-h disposition phase. Inspiratory and end-tidal concentrations were detected using an infrared analyzer. Femoral arterial blood and pulmonary artery mixed venous blood were sampled to determine desflurane concentrations by gas chromatography at 1, 3, 5, 10, 20, 30, 40, 50, 60, 80, 100, and 120min during each uptake and disposition phase. Respiratory and hemodynamic parameters were measured simultaneously. Body uptake and disposition rates were calculated by multiplying the difference between the arterial and pulmonary artery blood concentrations by the cardiac output. The rates of desflurane body uptake increased considerably in the initial 5min (79.8ml.min-1) and then declined slowly until 120min (27.0ml.min-1). Similar characteristics of washout were noted during the subsequent disposition phase. Concentration-time curves of end-tidal, arterial, and pulmonary artery blood concentrations fitted well to zero-order input and first-order disposition kinetics. Arterial and pulmonary artery blood concentrations were best fitted using a two-compartment model. After 2h, only 21.9% of the desflurane administered had been eliminated from the body. Under a fixed inspiratory concentration, desflurane body uptake in piglets corresponded to constant zero-order infusion, and the 2-h disposition pattern followed first-order kinetics and best fitted to a two-compartment model.

Invariant and suboptimal trajectories of self-regulated learning during secondary school: implications focused on quality in higher education.

It has been shown that self-regulation of learning is a key variable for an adequate transition and adjustment from secondary school to tertiary education, and it is also associated with successful academic results; therefore, it is relevant to analyze its levels of development in the pre-university stage. The aim of this research was to evaluate the trajectories of self-regulation of learning in secondary school students. The method considered a longitudinal design and included a sample of 403 students from 9th to 12th grade in Chile. An instrument with adequate psychometric properties was used to measure the learning self-regulation process (disposition, performance and self-evaluation phases). The results showed that self-regulation is at suboptimal levels in its different phases (M = 4.25 to M = 4.71). Linear mixed models showed: a significant effect of sex on the disposition variable in favor of females; and that the phases of disposition, performance and self-evaluation do not change over time. It is concluded that, if self-regulation of learning is not specifically trained, it does not increase during secondary school. The findings are discussed considering the possible practical implications for educational policies, research, timely intervention and impact on the quality of school and university education.

Clinical Drug-Drug Interaction Between Vatiquinone, a 15-Lipoxygenase Inhibitor, and Rosuvastatin, a Breast Cancer Resistance Protein Substrate.

Vatiquinone is a small-molecule inhibitor of 15-lipoxygenase in phase 3 development for patients with mitochondrial disease and Friedreich ataxia. The objective of this analysis was to determine the effect of vatiquinone on the pharmacokinetic profile of rosuvastatin, a breast cancer resistance protein substrate. In vitro investigations demonstrated potential inhibition of BCRP by vatiquinone (half maximal inhibitory concentration, 3.8 µM). An open-label, fixed-sequence drug-drug interaction study in healthy volunteers was conducted to determine the clinical relevance of this finding. Subjects received a single dose of 20-mg rosuvastatin followed by a 7-day washout. On days 8 through 14, subjects received 400mg of vatiquinone 3 times daily. On day12, subjects concomitantly received a single dose of 20-mg rosuvastatin. The geometric mean ratio for maximum plasma concentration was 77.8%; however, the rosuvastatin disposition phase appeared unaffected. The geometric mean ratios for the area under the plasma concentration-time curve from time 0 to time t and from time 0 to infinity were 103.2% and 99.9%, respectively. Mean rosuvastatin apparent elimination half-life was similar between treatment groups. These results demonstrate that vatiquinone has no clinically relevant effect on the pharmacokinetics of rosuvastatin.

Pharmacokinetics and Safety of Vedolizumab Following Administration of a Single Intravenous Dose in Healthy Chinese Subjects.

Vedolizumab is a humanized monoclonal antibody, indicated for the treatment of moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), that specifically binds to the α4β7 integrin. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of vedolizumab following a single intravenous (IV) infusion in healthy adult Chinese subjects. Sixteen participants received a single IV infusion of vedolizumab (300mg). Blood samples were collected to measure vedolizumab serum concentrations. The safety of all subjects was monitored. The pharmacokinetic analysis showed that vedolizumab reached the maximum observed serum concentration (Cmax) at approximately 1.32hours. The mean Cmax and area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUC0-t) and to infinity (AUC0-∞) were 137.25µg/mL, 2360days·µg/mL, and 2395days·µg/mL, respectively. The elimination of vedolizumab was relatively slow, with a mean terminal disposition phase half-life elimination (t1/2) of 20.23days. Six subjects were positive for anti-vedolizumab antibodies (AVAs) on day 106 and day 127. Finally, 4 out of 16 subjects (25.0%) had treatment-emergent adverse events (TEAEs), all of which were upper respiratory tract infections. Vedolizumab was well tolerated in healthy Chinese subjects when administered as a single-dose IV 300mg infusion. In this study, the rate of AVA positivity was 37.5%, which occurred near the end of the study; no significant differences in pharmacokinetic profiles were observed between the AVA-positive and AVA-negative groups. http://www.chinadrugtrials.org.cn : CTR20171528.

When and How to Use Extant Literature in Classic Grounded Theory

Glaser and Strauss (1967) sprinkled suggestions about the use of the literature throughout their seminal work as did Glaser in subsequent years. They, however, did not lay out a clear and structured overview of how to use the literature. The aim of this paper is to weave together the recommendations from classic grounded theory originators and to describe how, why, and when to review the literature and which literature to review. The paper includes a section debunking the no literature myth followed by descriptions of the three phases of the classic grounded theory literature review—the introduction phase, the integration phase, and the disposition phase. The three phases work together to substantiate, confirm, and enhance an emerging grounded theory and situate it within the existing body of knowledge.

Population pharmacokinetic analysis of RO5459072, a low water-soluble drug exhibiting complex food-drug interactions.

AimsRO5459072, a cathepsin‐S inhibitor, Biopharmaceutics Classification System class 2 and P‐glycoprotein substrate, exhibited complex, nonlinear pharmacokinetics (PK) while fasted that seemed to impact both the absorption and the disposition phases. When given with food, all nonlinearities disappeared. Physiologically based PK (PBPK) modelling attributed those nonlinearities to dose‐dependent solubilisation and colonic absorption. The objective of this population PK analysis was to complement the PBPK analysis.MethodsPK profiles in 39 healthy volunteers after first oral dosing (1–600 mg) while fasted or fed in single and multiple ascending dose studies were analysed using population compartmental modelling.ResultsThe PK of RO5459072 while fed was characterized by a 1‐compartmental PK model with linear absorption and elimination. The nonlinearities while fasted were captured using dose dependent bioavailability and 2 sequential first‐order absorption phases: one following drug administration and one occurring 11 hours later and only for doses >10 mg. The bioavailability in the first absorption phase increased between 1 and 10 mg and then decreased with dose, in agreement with in vitro dissolution and solubility studies. The remaining fraction of doses to be absorbed by the second absorption phase was found to have a bioavailability similar to that in the first absorption phase.ConclusionThe population PK model supported that dissolution‐ and solubility‐limited absorption from the proximal and distal intestine alone explains the nonlinear PK of RO5459072 in fasted state and the linear PK in fed state. This work, together with the PBPK analysis, raised our confidence in the understanding of this complex PK.

Model-based analysis on systemic availability of co-administered cannabinoids after controlled vaporised administration.

The most important two medicinal cannabinoids are Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD). Vaporised administration is superior due to its higher systemic availability, lower individual variability and faster drug delivery. Although it is common THC is co-administered with CBD, the influence of CBD on the pharmacokinetics, especially the systemic availability of THC after vaporised administration, is unknown. To investigate the influence of different doses of co-administered CBD on the systemic availability of THC, and to compare the availability of THC and CBD in a sample of frequent and infrequent cannabis users. The study used a randomised, double-blind, crossover placebo-controlled design. THC and/or CBD in ethanol was vaporised and inhaled. Plasma concentrations of THC and CBD were analysed. The THC data created in this study were pooled together with published THC pharmacokinetic data in order to cover all the phases of THC disposition. Population pharmacokinetic model of THC was developed based on the pooled data. The model of CBD was developed based on the data created in this study. Population pharmacokinetic models of THC and CBD were developed. With concomitant inhalation of high-dose CBD, the systemic availability of THC decreased significantly. Frequent cannabis users appeared to have higher systemic availability of THC and CBD when high-dose CBD was administered. The results observed in this study are useful for guiding future pharmacokinetic studies of medicinal cannabinoids, and for development of dosing guidelines for medical use of cannabis in the 'real-world' setting.

Multicarrier PWM Strategies for Hybrid Symmetrical Multilevel Inverter with Reduced Switch Count

Multilevel inverters are widely used for high power and high voltage applications. The performance of multilevel inverters are superior to conventional two level inverters in terms of reduced total harmonic distortion, higher dc link voltages, lower electromagnetic interference and increased quality in the output voltage waveform. This paper presents a single phase hybrid eleven level multilevel inverter topology with reduced switch count to compensate the above mentioned disadvantages. This paper also presents various high switching frequency based multi carrier pulse width modulation strategies such as Phase Disposition PWM Strategy (PDPWM), Phase Opposition and Disposition PWM Strategy (PODPWM), Alternate Phase opposition Disposition PWM (APODPWM), Carrier Overlapping PWM (COPWM), Variable frequency carrier PWM (VFPWM), Third Harmonic Injection PWM (TFIPWM) applied to the proposed eleven level multilevel inverter and is analyzed for RL load. FFT analysis is carried out and total harmonic distortion, fundamental output voltage are calculated. Simulation is carried out in MATLAB/SMULINK.

Determination of piperaquine concentration in human plasma and the correlation of capillary versus venous plasma concentrations.

A considerable challenge in quantification of the antimalarial piperaquine in plasma is carryover of analyte signal between assays. Current intensive pharmacokinetic studies often rely on the merging of venous and capillary sampling. Drug levels in capillary plasma may be different from those in venous plasma, Thus, correlation between capillary and venous drug levels needs to be established. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) was used to develop the method. Piperaquine was measured in 205 pairs of capillary and venous plasma samples collected simultaneously at ≥24hr post dose in children, pregnant women and non-pregnant women receiving dihydroartemisinin-piperaquine as malaria chemoprevention. Standard three-dose regimen over three days applied to all participants with three 40mg dihydroartemisinin/320mg PQ tablets per dose for adults and weight-based dose for children. Correlation analysis was performed using the program Stata® SE12.1. Linear regression models were built using concentrations or logarithm transformed concentrations and the final models were selected based on maximal coefficient of determination (R2) and visual check. An LC-MS/MS method was developed and validated, utilizing methanol as a protein precipitation agent, a Gemini C18 column (50x2.0mm, 5μm) eluted with basic mobile phase solvents (ammonium hydroxide as the additive), and ESI+ as the ion source. This method had a calibration range of 10-1000 ng/mL and carryover was negligible. Correlation analysis revealed a linear relationship: Ccap = 1.04×Cven+4.20 (R2 = 0.832) without transformation of data, and lnCcap = 1.01×lnCven+0.0125, (R2 = 0.945) with natural logarithm transformation. The mean ratio (±SD) of Ccap/Cven was 1.13±0.42, and median (IQR) was 1.08 (0.917, 1.33). Capillary and venous plasma PQ measures are nearly identical overall, but not readily exchangeable due to large variation. Further correlation study accounting for disposition phases may be necessary.

Comments on D.A. Noe's papers on noncompartmental pharmacokinetic analysis: Performance characteristics of the adjusted r2 algorithm for determining the start of the terminal disposition phase and comparison with a simple r2 algorithm and a visual inspection method https://onlinelibrary.wiley.com/doi/10.1002/pst.1979and Criteria for reporting noncompartmental estimates of half‐life and area under the curve extrapolated to infinity https://onlinelibrary.wiley.com/doi/10.1002/pst.1978

Comments on D.A. Noe's papers on noncompartmental pharmacokinetic analysis: Performance characteristics of the adjusted r² algorithm for determining the start of the terminal disposition phase and comparison with a simple r² algorithm and a visual inspection method https://onlinelibrary.wiley.com/doi/10.1002/pst.1979<i>and</i> Criteria for reporting noncompartmental estimates of half‐life and area under the curve extrapolated to infinity https://onlinelibrary.wiley.com/doi/10.1002/pst.1978

Diffusion modelling of percutaneous absorption kinetics. Predicting urinary excretion from in vitro skin permeation tests (IVPT) for an infinite dose

In this work, we developed a number of generalised skin diffusion based pharmacokinetic models to relate published in vivo urinary excretion data to matching experimentally generated in vitro human skin permeation test (IVPT) data for a series of topically applied salicylate esters. A simplified linear in vivo model was found to inadequately describe the time course of urinary excretion over the entire sampling period. We represented the skin barrier as both a one layer (stratum corneum) and a two-layer (stratum corneum with viable epidermis) diffusion model and convoluted their Laplace solutions with that for a single exponential disposition phase to describe the urinary excretion profiles in the Laplace domain. We also derived asymptotic approximations for the model and estimated the conditions under which they could be used. We then sought to develop in vitro - in vivo relationships (IVIVR) for topically applied methyl, ethyl and glycol salicylates using our experimental IVPT data and the literature urinary excretion data. Good linear IVIVRs for ethyl and glycol salicylates were obtained, but the IVIVR for methyl salicylate was poor, perhaps because of topical stimulation of local skin blood flow by methyl salicylate. The ratio of the hydrated to dehydrated skin permeation for all salicylate esters was the same in both the IVPT and in vivo studies. A diffusion based one compartment pharmacokinetic model was also developed to describe the urinary excretion of solutes after removal of topical products and to compare the methyl salicylate skin permeation for five different body sites. The work presented here is consistent with the development of skin IVIVRs, but suggests that different skin conditions, application sites and local skin effects may affect model predictions.

Rejoinder to comments from D. Weiner and N.S. Teuscher on: Performance characteristics of the adjusted r2 algorithm for determining the start of the terminal disposition phase and comparison with a simple r2 algorithm and a visual inspection method https://onlinelibrary.wiley.com/doi/10.1002/pst.1979 and Criteria for reporting noncompartmental estimates of half-life and area under the curve extrapolated to infinity https://onlinelibrary.wiley.com/doi/10.1002/pst.1978.

Rejoinder to comments from D. Weiner and N.S. Teuscher on: Performance characteristics of the adjusted r2 algorithm for determining the start of the terminal disposition phase and comparison with a simple r2 algorithm and a visual inspection method https://onlinelibrary.wiley.com/doi/10.1002/pst.1979 and Criteria for reporting noncompartmental estimates of half-life and area under the curve extrapolated to infinity https://onlinelibrary.wiley.com/doi/10.1002/pst.1978.

Using "compartment model" dynamics to understand the transmission regularity of coronavirus disease 2019 (COVID-19) during the outbreak period

Since the outbreak of coronavirus disease 2019 (COVID-19) on a large scale in late January 2020, the relevant reports of COVID-19 dynamics modeling found that it was very important to establish an appropriate data collection system and scientifically deal with massive information for epidemic control. No matter in theory or in practice, the and treatment of virus infected persons with the kind of nonlinear epidemic diseases are affected by various factors, multiple levels, and different prevention and control measures. After confirming the route of human-to-human transmission, the data change rules of confirmed cases and new cases of infectious population in China and in the early stage of the outbreak I - 40 d after the closure of Wuhan were analyzed. China has quickly adopted measures to control the spread of the virus, such as city closure, isolation, and wearing masks, and has achieved phased success. In order to scientifically determine the degree of harm of infectious diseases, a simplified two-compartment model of transmission phase and disposition phase is proposed and analyzed based on domestic and international epidemic data. It is more practical to study the speed of virus and the dynamics analysis to control the outbreak. Acceding to data from the Global Epidemic l'invonian Consulting Center and WHO. the growth Me 041 and doubling time of the total number of confirmed caws and the number of confirmed cases from the two sources have little change. The study found that the global propagation doubling time is significantly shorter than 6.27 - 7.03 d in China. indicating that the global propagation rate is significantly higher than that in China. K. fir and atonality rate of the total number of confined eases in Italy. Spain. and Iran are obviously different from the global data. The special mortality:ate is significantly higher than the global level, with 9.576s. 6.59%. and 7. Sets respectively. which is alined twice that of the world. Therefore. the study believes that it is the key to deal with the pathway and could of the rate.

Evaluation of POD and APOD multicarrier SPWM techniques for three-phase seven-level diode clamped multilevel inverter fed induction motor drive using FPGA

Multilevel inverters have drawn tremendous interest in high power high voltage applications due to their merits such as reduced voltage stress on switches, lower EMI problems and reduction in THD. The MLI technology is also advantageous in improving output waveforms due to the higher number of levels in the waveform of output voltage along with a reduced input filter size which is useful for grid connected applications. This paper focuses on implementation of three-phase diode clamped multilevel inverter fed induction motor drive using various multicarrier-based sinusoidal pulse width modulation techniques. The performance analysis of the inverter is carried out using phase opposition disposition (POD) and alternate phase opposition disposition (APOD) techniques. In addition to this, the comparison of the modulation methods is also analysed. Simulation is performed using MATLAB/Simulink. The POD and APOD carrier-based sinusoidal pulse width modulation techniques for three-phase seven-level diode clamped multilevel inverter are implemented on VPE Spartan 3A DSP board using Xilinx field programmable gate array (FPGA) and the experimental results are presented to validate the effectiveness of the operation of the seven-level diode clamped multilevel inverter using PWM strategies.

Criteria for reporting noncompartmental estimates of half-life and area under the curve extrapolated to infinity.

Various criteria have been proposed for determining the reliability of noncompartmental pharmacokinetic estimates of the terminal disposition phase half-life (t1/2 ) and the extrapolated area under the curve (AUCextrap ). This simulation study assessed the performance of two frequently used reportability rules: the terminal disposition phase regression adjusted-r2 classification rule and the regression data point time span classification rule. Using simulated data, these rules were assessed in relation to the magnitude of the variability in the terminal disposition phase slope, the length of the terminal disposition phase captured in the concentration-time profile (data span), the number of data points present in the terminal disposition phase, and the type and level of variability in concentration measurement. The accuracy of estimating t1/2 was satisfactory for data spans of 1.5 and longer, given low measurement variability; and for spans of 2.5 and longer, given high measurement variability. Satisfactory accuracy in estimating AUCextrap was only achieved with low measurement variability and spans of 2.5 and longer. Neither of the classification rules improved the identification of accurate t1/2 and AUCextrap estimates. Based on the findings of this study, a strategy is proposed for determining the reportability of estimates of t1/2 and area under the curve extrapolated to infinity.

A Vetting Protocol for the Analytical Procedures Platform for the AP-Phase of PCAOB Audits

Study Context AS5[2017], issued by the Public Company Accounting Oversight Board, requires the use of Analytical Procedures [AP] at the Planning and Substantive Phases of Assurance Audits of firms traded on active exchanges. Logically, an aspect of this requirement is satisfied by using a Panel of the Client’s data at the Planning Phase to forecast the Client’s YE-closing values and then at the Substantive Phase to dispose the directional difference between the: [Actual Client’s YE-value and the AP-Forecasted YE-value]—the Disposition Phase. Research Focus To date, neither the PCAOB nor the AICPA have suggested a pilot-test paradigm to vet the AP-forecasting Protocol under consideration. To address this lacuna, we detail an AP: Decision Support System [AP:DSS] that offers to the Audit InCharge a two-stage pre-analysis AP-vetting [Pilot-Test] platform that employs False Negative [FN] and False Positive [FP] Profilers. In inferential analyses, the FP-Risk is usually benchmarked using the FN-Risk. Deliverables A comprehensive AP-vetting model is offered and illustrated using: (i) a preliminary estimator of a reasonable sample size, (ii) two Standard Forecasting Models: The Excel versions of the OLS Linear Two-parameter and the Moving Average Models, and (iii) a Benchmarking protocol. Unique in this AP:DSS vetting protocol is that the FP-risk is contexted by the FN-risk from the independent benchmark domain. This duality enhances the inferential impact of the vetting protocol as it uses separate variable sets. The AP:DSS is available at no cost as an e-Download.

Identification of Modulators That Activate the Constitutive Androstane Receptor From the Tox21 10K Compound Library.

The constitutive androstane receptor (CAR; NR1I3) is a nuclear receptor involved in all phases of drug metabolism and disposition. However, recently it's been implicated in energy metabolism, tumor progression, and cancer therapy as well. It is, therefore, important to identify compounds that induce human CAR (hCAR) activation to predict drug-drug interactions and potential therapeutic usage. In this study, we screen the Tox21 10,000 compound collection to characterize hCAR activators. A potential novel structural cluster of compounds was identified, which included nitazoxanide and tenonitrozole, whereas known structural clusters, such as flavones and prazoles, were also detected. Four compounds, neticonazole, diphenamid, phenothrin, and rimcazole, have been identified as novel hCAR activators, one of which, rimcazole, shows potential selectivity toward hCAR over its sister receptor, the pregnane X receptor (PXR). All 4 compounds translocated hCAR from the cytoplasm into the nucleus demonstrating the first step to CAR activation. Profiling these compounds as hCAR activators would enable an estimation of drug-drug interactions, as well as identify prospective therapeutically beneficial drugs.

Population pharmacokinetic analysis of metformin administered as fixed-dose combination in Korean healthy adults.

Metformin, an oral antihyperglycemic agent, is widely used as the first-line pharmacotherapy for type 2 diabetes mellitus (T2DM). It has been in use for several decades as numerous different formulations. However, despite its use, population pharmacokinetic (PK) modeling of metformin is not well developed. The aim of the present study was to evaluate the effect of formulation on PK parameters by developing a population PK model of metformin in Koreans and using this model to assess bioequivalence. We used a comparative PK study of a single agent and a fixed-dose combination of metformin in 36 healthy volunteers. The population PK model of metformin was developed using NONMEM (version 7.3). Visual predictive checks and bootstrap methods were performed to determine the adequacy of the model. The plasma concentration-time profile was best described by a two-compartment, first-order elimination model with first-order absorption followed by zeroorder absorption with lag time. From the covariate analysis, formulation had significant effect (p < 0.01) on relative bioavailability (F = 0.94) and first-order absorption constant (Ka = 0.83), but the difference was within the range of bioequivalence criteria. No other covariate was shown to have significant effect on PK parameters. The PK profile of the disposition phase was consistent with the published literature. However, in the present study, the multiple peaks found during the absorption phase implied the possible diversity of absorption PK profile depending on formulation or population. Unlike traditional bioequivalence analysis, the population PK model reflects formulation differences on specific parameters and reflected simulation can be performed.

Population Pharmacokinetic Analysis of Ixazomib, an Oral Proteasome Inhibitor, Including Data from the Phase III TOURMALINE-MM1 Study to Inform Labelling.

Ixazomib is an oral proteasome inhibitor, approved in USA, Canada, Australia and Europe in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. We report a population pharmacokinetic model-based analysis for ixazomib that was pivotal in describing the clinical pharmacokinetics of ixazomib, to inform product labelling. Plasma concentration–time data were collected from 755 patients who received oral or intravenous ixazomib in once- or twice-weekly schedules in ten trials, including the global phase III TOURMALINE-MM1 study. Data were analysed using nonlinear mixed-effects modelling (NONMEM software version 7.2, ICON Development Solutions, Hanover, MD, USA). Ixazomib plasma concentrations from intravenous and oral studies were described by a three-compartment model with linear distribution and elimination kinetics, including first-order linear absorption with a lag time describing the oral dose data. Body surface area on the volume of the second peripheral compartment was the only covariate included in the final model. None of the additional covariates tested including body surface area (1.2–2.7 m2), sex, age (23–91 years), race, mild/moderate renal impairment and mild hepatic impairment were found to impact systemic clearance, suggesting that no dose adjustment is required based on these covariates. The geometric mean terminal disposition phase half-life was 9.5 days, steady-state volume of distribution was 543 L and systemic clearance was 1.86 L/h. The absolute bioavailability of an oral dose was estimated to be 58%.Electronic supplementary materialThe online version of this article (doi:10.1007/s40262-017-0526-4) contains supplementary material, which is available to authorized users.

Phase I Study of the Novel Investigational NEDD8-Activating Enzyme Inhibitor Pevonedistat (MLN4924) in Patients with Relapsed/Refractory Multiple Myeloma or Lymphoma

Evaluate the safety, pharmacokinetic profile, pharmacodynamic effects, and antitumor activity of the first-in-class investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in patients with relapsed/refractory lymphoma or multiple myeloma. Patients with relapsed/refractory myeloma (n = 17) or lymphoma (n = 27) received intravenous pevonedistat 25 to 147 mg/m(2) on days 1, 2, 8, 9 (schedule A; n = 27) or 100 to 261 mg/m(2) on days 1, 4, 8, 11 (schedule B; n = 17) of 21-day cycles. Maximum tolerated doses were 110 mg/m(2) (schedule A) and 196 mg/m(2) (schedule B). Dose-limiting toxicities included febrile neutropenia, transaminase elevations, muscle cramps (schedule A), and thrombocytopenia (schedule B). Common adverse events included fatigue and nausea. Common grade ≥3 events were anemia (19%; schedule A), and neutropenia and pneumonia (12%; schedule B). Clinically significant myelosuppression was uncommon. There were no treatment-related deaths. Pevonedistat pharmacokinetics exhibited a biphasic disposition phase and approximate dose-proportional increases in systemic exposure. Consistent with the short mean elimination half-life of approximately 8.5 hours, little-to-no drug accumulation in plasma was seen after multiple dosing. Pharmacodynamic evidence of NAE inhibition included increased skin levels of CDT-1 and NRF-2 (substrates of NAE-dependent ubiquitin ligases), and increased NRF-2-regulated gene transcript levels in whole blood. Pevonedistat-NEDD8 adduct was detected in bone marrow aspirates, indicating pevonedistat target engagement in the bone marrow compartment. Three lymphoma patients had partial responses; 30 patients achieved stable disease. Pevonedistat demonstrated anticipated pharmacodynamic effects in the clinical setting, a tolerable safety profile, and some preliminary evidence that may be suggestive of the potential for activity in relapsed/refractory lymphoma.