Variability In Clearance Research Articles

Performance Analysis of Inter-Stage Leakage Flows at Rotating Conditions in an Axial Compressor

For the compressor with shrouded stator blades, the stator well is a rotor-stator space between the rotating drum and the stationary shroud. Due to the pressure difference, a reverse leakage flow would travel through the stator well and inject into the main flow path. Although, the labyrinth seal is commonly placed under the shroud, the rotation effect and seal clearance variation in actual operation process have great impact on the characteristics of this inter-stage leakage, as well as the compressor performance. In this paper, experiments were conducted at a compressor inter-stage seal test rig. The leakage flow rates, total temperatures and swirl ratios were obtained at different speeds and working clearances. The proportions of rotation effect and the clearance reduction effect were analyzed by data processing. Comparisons indicate that the working clearance and leakage flow reduce about 43% and 50% respectively, when the rotational speed ω=8100 r/min. The proportion of reduction caused by the rotation effect is around 15%, while the influence of working clearance variation is much greater, accounting for about 35%. The windage heating coefficient and swirl ratio in the outlet cavity are almost in exponential relationship with the rotor speed. The increases in total temperature and swirl ratio generated by the rotation effect are found to be about 80%. In addition, the swirl and radial velocity profiles in the cavities were discussed by validated numerical simulations to reveal the typical flow characteristics. The data presented can provide guidance for better leakage conditions prediction as well as the inter-stage seal design enhancement.

Numerical study of the effect of aspect ratio on the flow characteristics of the Ground Transportation System

The effect of varying the aspect ratio of a 1:8 scaled Ground Transportation System (GTS) was numerically investigated using the steady formulation of the RANS k−ω SST model. Cases of different aspect ratios (defined as the ratio of the varying width to the baseline width (Eq. (1)), with and without a boat-tail, were considered. For the GTS without boat-tail, a quasi-linear decline in the drag coefficient was found with increasing aspect ratio, resulting from a variation in the strength of the side shear layers, and the consequent change in the vertical symmetry of the near-wake. The average length of the wake was found to increase with increasing aspect ratios, resulting from an increase in the size of high Reynolds shear stress regions in the wake. For the GTS with boat-tail, variation of aspect ratio was found to have no effect on the critical boat-tail angle, albeit the magnitude of reduction in the drag coefficient differed between low and high aspect ratio configurations. Variation of the ground clearance (G∗) of the GTS (without boat-tail) concluded a G∗ value corresponding to minimum drag coefficient (G∗=0.083), while retaining of vertical quasi-symmetry was observed for G∗≥0.29.

Research on the Influence of Clearance Variation on the Stiffness Fluctuation of Ball Bearing Under Different Operating Conditions

Abstract The vibration induced by the varying compliance (VC) or the stiffness fluctuation of ball bearing plays a key role in the dynamic performance of the rotor system. The aim of this article is to study the stiffness fluctuation behaviors of ball bearing under different operating conditions. This article presents an improved mathematic model for ball bearing with wider applicability based on the new initial/reference position assumption and the ball-raceway contact/separation determination. The proposed model not only gets rid of the limitations of the raceway control hypothesis but also considers the space constraints of the cage on the balls. The advantages of the proposed model are presented through the typical working condition analysis, and the influences of the internal clearance on the stiffness and stiffness fluctuation of ball bearing under different operating conditions are given and discussed. The results show that bearing stiffness and stiffness fluctuation are determined by the external loads, rotating speeds, and internal clearances together, and properly increasing the axial load can effectively reduce the amplitudes and frequency components of the stiffness fluctuation. As an exploratory research work on the excitation source for the VC vibration of the bearing-rotor system, this article not only explains the complexity and diversity of the rotor VC vibration behavior from another side but also provides new ideas and important supplements for the rotor nonlinear analysis.

Population Pharmacokinetics of Brigatinib in Healthy Volunteers and Patients With Cancer.

Background and objectivesBrigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib.MethodsPlasma concentration–time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-effects modeling (NONMEM software version 7.3).ResultsBrigatinib plasma concentrations were best described by a three-compartment model with a transit compartment input (number of transit compartments = 2.35; mean transit time = 0.9 h). The final model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total bilirubin, aspartate aminotransferase, and alanine aminotransferase, were found to meaningfully explain variability in apparent clearance, suggesting that no dose adjustment is required based on these covariates.ConclusionsResults from these population pharmacokinetic analyses informed the prescribing guidance for patients with mild or moderate renal impairment in the US Prescribing Information and the European Summary of Product Characteristics for brigatinib.Electronic supplementary materialThe online version of this article (10.1007/s40262-020-00929-4) contains supplementary material, which is available to authorized users.

Estimation of piperacillin clearance with different glomerular filtration rate formulas in critically ill children.

Glomerular filtration rate (GFR) is difficult to assess in critically ill children using gold standard method and alternatives are needed. This study aimed to determine the most accurate GFR estimation formula for assessing piperacillin clearance in critically ill children, using a published piperacillin pharmacokinetics (PK) population model. All children hospitalized in the paediatric intensive care unit of a single institution who were receiving piperacillin were included. PK were described using the nonlinear mixed effect modelling software MONOLIX. In the initial PK model, GFR was estimated according to the Schwartz 1976 formula. We evaluated a set of 12 additional validated formulas, developed using plasma creatinine and/or cystatin C concentrations, in the building model to assess the lowest between-subject variability for piperacillin clearance. We included 20 children with a median (range) postnatal age of 1.9 (0.1-19) years, body weight of 12.5 (3.5-69) kg. Estimated GFR according to the Schwartz 1976 formula was 160.5 (38-315) mL min-1 1.73 m-2 . Piperacillin clearance was best predicted by the Bouvet combined formula. The combined Bouvet formula was the most accurate GFR estimation formula for assessing piperacillin clearance in critically ill children.

Investigation on tip clearance control for the high-pressure rotor of an uncooled vaneless counter-rotating turbine

In order to develop a tip clearance control system for an uncooled vaneless counter-rotating turbine, tip clearance variation of its high pressure rotor blade at off-design conditions is analyzed. Aero-thermal interaction simulation is performed to predict the temperature and deformation of the solid blade. At operating conditions with rotating speeds greater than 60% design value and expansion ratios greater than 85% design value, the blade tip clearance height at leading edge remains unchanged when the expansion ratio decreases, meanwhile that at trailing edge decreased obviously. However, the tip clearance height variations at the leading edge and trailing edge are almost the same in a conventional subsonic turbine at such conditions. The cause is that the flow in the high-pressure rotor is choked at these conditions. The choked flow results in that the fluid and solid blade temperatures upstream of the throat are not affected by the back pressure and only those downstream of the throat increases with the back pressure. Consequently, the blade height at leading edge keeps constant, and that at trailing edge varies because of thermal expansion. To avoid the rubbing of the blade and case, the blade height at trailing edge is diminished by 30%. As a result, the blade tip clearance height at low speed operating conditions increases in axial direction. Such a design leads to a stronger tip leakage flow. More flow losses might be generated. Therefore, a casing cooling method is proposed to control the blade tip clearance height at leading edge and trailing edge respectively. The deformations of the casing with different mass flow rate of cooling air at design and off-design conditions are calculated. It shows that the blade tip clearance heights at leading edge and at trailing edge of the rotor can be well controlled with appropriate amount of cooling air.

Population Pharmacokinetic Models of Tacrolimus in Adult Transplant Recipients: A Systematic Review

Numerous population pharmacokinetic (PK) models of tacrolimus in adult transplant recipients have been published to characterize tacrolimus PK and facilitate dose individualization. This study aimed to (1) investigate clinical determinants influencing tacrolimus PK, and (2) identify areas requiring additional research to facilitate the use of population PK models to guide tacrolimus dosing decisions. The MEDLINE and EMBASE databases, as well as the reference lists of all articles, were searched to identify population PK models of tacrolimus developed from adult transplant recipients published from the inception of the databases to 29 February 2020. Of the 69 studies identified, 55% were developed from kidney transplant recipients and 30% from liver transplant recipients. Most studies (91%) investigated the oral immediate-release formulation of tacrolimus. Few studies (17%) explained the effect of drug-drug interactions on tacrolimus PK. Only 35% of the studies performed an external evaluation to assess the generalizability of the models. Studies related variability in tacrolimus whole blood clearance among transplant recipients to either cytochrome P450 (CYP)3A5 genotype (41%), days post-transplant (30%), or hematocrit (29%). Variability in the central volume of distribution was mainly explained by body weight (20% of studies). The effect of clinically significant drug-drug interactions and different formulations and brands of tacrolimus should be considered for any future tacrolimus population PK model development. Further work is required to assess the generalizability of existing models and identify key factors that influence both initial and maintenance doses of tacrolimus, particularly in heart and lung transplant recipients.

Axial Turbine Performance Estimation During Dynamic Operations

During service, a turbine engine undergoes frequently dynamic operations. Because of the changes in mass flow, temperature, pressure, as well as the different reaction of the components of turbine to these changes, the turbine performances may vary significantly. It is critical to understand and quantify these variations to design and integrate the turbine to the engine. This paper presents a study of the performances and the variation of the performances for an axial gas turbine across its operating envelope. Numerical simulations are used to describe the flow across the turbine and to estimate the turbine maps. Using theoretical charts for typical turbine thermal expansion, the variation of tip clearance across the working line is approximated. Because of the changes of the tip clearance, using a single geometry may not supply relevant information during real dynamic operations. In order to eliminate these additional errors in the numerical study, a number of turbines maps are recalculated for different tip clearances, respectively to engine regimes. With the resulting data, the working line is recalculated across multiple maps. The comparison between the two working lines is presented as well as the study of performance variation of the turbine across the operation envelope and the influence of tip clearance at different regimes.

Experimental Studies of Different thick Steel sheets and variable clearance in MIG Brazing

Current automotive industry trend is developing the new materials and technologies for automobile BIW to enhance the latest stringent requirements like safety, weight and safer body. Main aim is to reduce the weight of body without compromising the targeted quality and safety norms. One of the solutions is different grades of steel sheets and different thickness combination are used combinedly to weld depend on the function of the designed structural component. Reduction of weight is searched most in the recent high strength steels. Target is to reduce dead load and reduce the cost. In this scenario roof outer and inner panel which is having closed ring type assembly. For ring panel assembly different thickness materials and variable clearance joinery is welded by MIG brazing tags. As per benchmark study the strongest joint 930.8 Mpa is achieved when the joint clearance is .038mm. When the clearance is narrower than it’s harder for the filler metal to distribute itself adequately throughout the joint and joint strength is weakened. Conversely, if the gap is wider than necessary, the strength of the joint will be reduced almost to that of the filler metal itself. But in ordinary day-to-day brazing, need not this much precise to get a sufficiently strong joint. In this study analyzing the tensile shearing strength of the joinery with respect to the thickness and variable clearance. Also, parameters contributing to the strength variation. MIG brazing welding processes is using CMT machine and CuSi3 of brazing wire.

Pharmacokinetics of Testosterone Enanthate After Intramuscular Injection for Transgender Men

Aim: To clarify the pharmacokinetics (PKs) of testosterone enanthate intramuscular injection in transgender men. Materials and Methods: This is a single-center nonblind single-drug administration study. After screening, 10 Japanese transgender men were administered 250 mg of testosterone enanthate intramuscularly. If the subjects had already received testosterone treatment, a screening test was carried out after washout for at least 4 weeks. The total testosterone (TT) and free testosterone (FT) and estradiol (E2) levels were examined for 4 weeks. At days 0 and 28, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels were examined. Results: Mean age was 31.1 ± 7.2 years, and four subjects received first-time testosterone administration. Mean TT level at baseline was under the cutoff value in hypogonadal men. Mean time to reach its maximum level was 1.7 days, and in all cases within 3 days. Then, the level decreased and reached <3.0 ng/mL at day 21. Mean time to maximum level of FT was 3.4 days, but in three cases it was at day 7. The coefficient of variation in apparent total clearance and distribution volume for TT was large. The PK parameters of E2 could not be calculated in four cases. In the remaining six, E2 gradually decreased and reached the nadir at day 21. LH and FSH were not different before and after injection. No specific adverse event associated with testosterone administration was observed. Conclusions: PK profiles in transgender men after testosterone enanthate 250 mg single injection were clarified.

MTXPK.org: A Clinical Decision Support Tool Evaluating High-Dose Methotrexate Pharmacokinetics to Inform Post-Infusion Care and Use of Glucarpidase.

Methotrexate (MTX), an antifolate, is administered at high doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high‐dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life‐threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 SDs above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of laboratory results that do not directly correspond to the algorithm prove to be a limitation of its use. The goal of our study was to develop a clinical decision support tool to optimize the administration of glucarpidase for patients receiving HD MTX. Here, we describe the development of a novel 3‐compartment MTX population pharmacokinetic (PK) model using 31,672 MTX plasma concentrations from 772 pediatric patients receiving HD MTX for the treatment of acute lymphoblastic leukemia and its integration into the online clinical decision support tool, MTXPK.org. This web‐based tool has the functionality to utilize individualized demographics, serum creatinine, and real‐time drug concentrations to predict the elimination profile and facilitate model‐informed administration of glucarpidase.

Vibration Characteristics of Rolling Element Bearings with Different Radial Clearances for Condition Monitoring of Wind Turbine

Rolling element bearing is a vital component in rotating machinery, such as a wind turbine (WT) system. By accurately monitoring its health condition, the faults can be detected at an early stage, providing sufficient lead time to perform maintenance and hence reducing accidents and economic losses. Bearing usually suffers from various wears and tears, which result in a gradual increase in clearance through its lifetime. Insufficient understanding of vibration characteristics under different clearances brings difficulties for bearing condition monitoring. Thus, this paper presents a nonlinear bearing vibration model with six degrees of freedom (DOF) to investigate the vibration characteristics under different radial clearances and load conditions. Then, a dedicated bearing test is established to verify the reasonability and effectiveness of the vibration model. Furthermore, a comprehensive simulation analysis is conducted to study the vibration characteristics over an extended range of the internal radial clearance and external load. Results show that the dynamic force on each ball presents an impulse whose magnitudes increases whereas the pulse width reduces with clearance increases. Ball pass frequency of outer race (BPFO) is the dominant modulation component and the frequency is in accordance with the number of dynamic force impulses. Two indicators, i.e., root mean square (RMS) value and spectral centroid, are proposed to indicate clearance changes. In general, they show an uptrend with the increase in clearance, which is in line with the dynamic force increasing with clearance, especially the spectral centroid of the low frequency band. However, it should be noted that the RMS value and spectral centroid exhibit a fluctuating behavior due to nonlinear vibration responses. For the first time, this study shows the details of vibration characteristics with clearance variations and provides a foundation for monitoring the bearing conditions before any obvious local defects on raceways.

Differences in Theophylline Clearance Between Patients With Chronic Hepatitis and Those With Liver Cirrhosis.

Theophylline, a xanthine derivative drug, is used for the treatment of respiratory diseases, such as asthma, and is primarily eliminated by hepatic metabolism. There is marked interindividual variability in theophylline clearance. Therefore, the aim of this study was to evaluate the influence of chronic hepatitis (CH), liver cirrhosis (LC), and other covariates on theophylline clearance by population pharmacokinetic (PPK) analysis. The authors retrospectively obtained 496 trough concentrations of theophylline at steady state from 226 adult patients with bronchial asthma. The liver functions of the patients were classified into 3 categories: normal hepatic function, CH, and LC. The PPK analysis was performed using the NONMEM program. CH, LC, age, smoking status, coadministration of clarithromycin (CAM), and sex were considered as covariates that affected theophylline clearance. Theophylline clearance (CL/F per kg) was significantly influenced by CH, LC, smoking, and CAM. The final model of theophylline clearance was as follows: CL/F (L/h·kg) = 0.0484 × 1.40 × 0.861 × 0.889 × 0.557. Smoking is a well-known factor that markedly enhances CL/F through the induction of CYP1A enzymes, whereas CAM has been reported to inhibit CYP3A4. The final model for hepatic function showed that CL/F in CH and LC patients was 0.043 and 0.027 L/h/kg, respectively, and it was lower than that in patients with normal hepatic function. As theophylline clearance depends on intrinsic hepatic clearance, lower CL/F in patients with LC than in those with CH may be due to a decrease in the metabolic enzymatic capability of LC patients. Differences exist in theophylline clearance between CH and LC patients as per the PPK analysis.

Factors increasing the risk of inappropriate vancomycin therapy in ICU patients: A prospective observational study.

Vancomycin trough levels are frequently subtherapeutic in intensive care unit (ICU) patients. The aim of this study was to identify patients at risk of therapeutic failure defined as vancomycin area-under-the-curve0-24 /minimum inhibitory concentration (AUC0-24 /MIC) <400, and to examine possible effects of different MICs, the variability in renal clearance and continuous renal replacement therapy (CRRT), and the relevance of vancomycin therapy. A prospective observational study of ICU patients 18years at initiation of vancomycin therapy was conducted from May 2013 to October 2015. The patients were divided into four groups according to renal function and CRRT-mode as follows: normal- or augmented renal clearance and continuous venovenous hemodialysis or -hemofiltration. Vancomycin peak and trough levels were measured at 24, 48, and 72hours after therapy initiation. Relevance of vancomycin therapy was retrospectively evaluated based on microbiological results. Eighty-three patients were included, median age 54.5years, 74.5% male, SAPS II score 46, and 90day mortality 28%. Vancomycin therapy was initiated on ICU-day 8 (IQR, 5-12), with a median treatment time of 7.5 (IQR, 5-12) days. AUC0-24 /MIC>400 was reached in 81% and 8% with MIC=1 and 2mg/L respectively. The CRRT groups had higher AUC0-24 /MIC-ratios than the non-CRRT groups (P<.001). Augmented renal clearance increased the risk of AUC0-24 /MIC<400, independent of MIC-value. Initiation of vancomycin therapy was retrospectively considered relevant in 28 patients (34%). A MIC-value >1mg/L and augmented renal clearance, were factors increasing the risk of therapeutic failure. Vancomycin treatments could have been omitted or shortened in most of these patients.

Biological mechanisms underlying inter-individual variation in factor VIII clearance in haemophilia.

Previous studies have highlighted marked inter‐individual variations in factor VIII (FVIII) clearance between patients with haemophilia (PWH). The half‐life of infused FVIII has been reported to vary from as little as 5.3 hours in some adult PWH, up to as long as 28.8 hours in other individuals. These differences in clearance kinetics have been consistently observed using a number of different plasma‐derived and recombinant FVIII products. Furthermore, recent studies have demonstrated that half‐life for extended half‐life (EHL‐) FVIII products also demonstrates significant inter‐patient variation. Since time spent with FVIII trough levels <1% has been shown to be associated with increased bleeding risk in PWH on prophylaxis therapy, this variability in FVIII clearance clearly has major clinical significance. Recent studies have provided significant novel insights into the cellular basis underlying FVIII clearance pathways. In addition, accumulating data have shown that endogenous plasma VWF levels, ABO blood group and age, all play important roles in regulating FVIII half‐life in PWH. Indeed, multiple regression analysis suggests that together these factors account for approximately 34% of the total inter‐individual variation in FVIII clearance observed between subjects with severe haemophilia A. In this review, we consider these and other putative modulators of FVIII half‐life, and discuss the biological mechanisms through which these factors impact upon FVIII clearance in vivo.

Population Pharmacokinetic/Pharmacodynamic Modeling of Glenzocimab (ACT017) a Glycoprotein VI Inhibitor of Collagen-Induced Platelet Aggregation.

Glenzocimab (ACT017) is a humanized monoclonal antigen‐binding fragment (Fab) directed against the human platelet glycoprotein VI, a key receptor for collagen and fibrin that plays a major role in thrombus growth and stability. Glenzocimab is being developed as an antiplatelet agent to treat the acute phase of ischemic stroke. During a phase I study in healthy volunteers, the population pharmacokinetics (PK) and pharmacodynamics (PD) of glenzocimab were modeled using Monolix software. The PK/PD model thus described glenzocimab plasma concentrations and its effects on ex vivo collagen‐induced platelet aggregation. Glenzocimab was found to have dose‐proportional, 2‐compartmental PK with a central distribution volume of 4.1 L, and first and second half‐lives of 0.84 and 9.6 hours. Interindividual variability in clearance in healthy volunteers was mainly explained by its dependence on body weight. The glenzocimab effect was described using an immediate effect model with a dose‐dependent half maximal inhibitory concentration: Larger doses resulted in a stronger effect at the same glenzocimab plasma concentration. The mechanism of the overproportional concentration effect at higher doses remained unexplained. PK/PD simulations predicted that 1000‐mg glenzocimab given as a 6‐hour infusion reduced platelet aggregation to 20% in 100% of subjects at 6 hours and in 60% of subjects at 12 hours after dosing. Simulations revealed a limited impact of creatinine clearance on exposure, suggesting that no dose adjustments were required with respect to renal function. Future studies in patients with ischemic stroke are now needed to establish the relationship between ex vivo platelet aggregation and the clinical effect.

Abstract C008: Pharmacokinetic analysis of vincristine and its m1 metabolite in Kenyan pediatric cancer patients through co-modeling

Abstract Objectives: The aim of this study was to develop a pharmacokinetic (PK) model that can determine the PK of vincristine (VCR) and its M1 metabolite using concentration data from Kenyan pediatric cancer patients. VCR is one of the most widely used anticancer agents in treating a variety of malignancies in pediatric oncology. Regardless of its extensive pediatric use, dosing strategies for VCR are largely empirical as there is little information about its disposition and optimal therapeutic dosing. Our collaborator, Dr. Jamie Renbarger and her group have reported that CYP3A5 enzyme generates the major VCR metabolite, M1, more efficiently than CYP3A4 enzyme. This finding maybe clinically significant because CYP3A5 expression varies with up to 90%, 70% and 10-20% of expressions in Kenyans, African Americans and Caucasians, respectively. Therefore, it is crucial to monitor M1 and characterize its disposition in humans to provide an insight of inter-ethnic variability in VCR metabolism and clearance. Methods: Kenyan pediatric cancer patients (8 males:8 females, age range: 1-13 years, weight range: 7.0 - 36.6 kg, body surface area: 0.36 - 1.24 m2) were intravenously administered with VCR (delivered dose, 0.4 - 2.5 mg). Blood samples were collected using human dried blood spot (DBS) collection paper via finger prick at various time points depending on the feasibility and duration of patient stay for care in the hospital. Using a developed LC-MS-MS assay, the concentrations of VCR and M1 were measured from patient DBS samples. A PK compartmental model was developed through co-modeling of VCR and M1 using Phoenix (version 8.0). The model was selected based on comparison of quality of fit plots and on the likelihood ratio test on the difference of criteria (-2LL). Results: The best fit structural model for VCR and its M1 metabolite was established. The model consists of a one-way metabolite formation transfer from VCR to M1 compartments. Good correlations were observed between observed and predicted values of VCR and M1 in the subjects used. The best-fit PK parameter estimates were derived from the PK compartmental model. In one subject, values estimated for PK parameters that only our study could derive include: conversion rate constant from VCR to M1 of 0.04 1/hr, M1 metabolite volume of distribution of 51.49 L, and M1 metabolite elimination rate constant of 0.44 1/hr. Conclusion: For the first time, a compartmental PK model that could determine the PK parameters of VCR and its M1 metabolite from DBS samples through co-modeling was developed. The model resulted in a good fit for the subjects used. The model will be validated after further adjustments and could potentially be used to rationally modify future VCR dosing regimen for Kenyan pediatric patients. Further, this modification could be possibly extrapolated for African American pediatric patients. Additionally, using our validated model, we will characterize and predict the population PK of VCR and its M1 metabolite among different ethnic groups. Citation Format: Lorita Agu, Jamie Renbarger, Diana S-L. Chow. Pharmacokinetic analysis of vincristine and its m1 metabolite in Kenyan pediatric cancer patients through co-modeling [abstract]. In: Proceedings of the Twelfth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2019 Sep 20-23; San Francisco, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(6 Suppl_2):Abstract nr C008.

Population Pharmacokinetics of Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E‐Mutant Astrocytomas

Vemurafenib (Zelboraf) is an orally available BRAFV600E inhibitor approved for the treatment of unresectable or metastatic BRAFV600E -mutant melanoma. The primary objective of this work was to characterize the pharmacokinetics (PK) of vemurafenib in pediatric patients with recurrent/refractory astrocytomas harboring the BRAFV600E mutation. The study was also designed to evaluate the feasibility of replacing whole vemurafenib tablets with crushed tablets in young children unable to swallow tablets. Twenty-five pediatric patients (median age, 8.8 years; range, 3.3-19.2) with recurrent/refractory BRAFV600E -mutant astrocytomas received whole (n = 19) or crushed (n = 6) vemurafenib tablets twice daily. Plasma samples were collected on days 1, 15, and 22 in cycle 1 of vemurafenib treatment. Descriptive PK analyses demonstrated significant variability (approximately 6-fold) in drug exposure. A 1-compartment model with first-order absorption and elimination was developed by adjusting the vemurafenib PK model previously validated in adults with mutant BRAFV600E melanoma. After inclusion of allometric scaling on total body weight, the model adequately described the PK of vemurafenib in children between a wide age range of 3 to 19 years old. In the crushed-tablet cohort, relative bioavailability was approximately 96% (95% confidence interval, 49%-142%) compared to that seen in pediatric patients receiving whole tablets based on the preliminary comparison analysis results. Moderate intrapatient variability (48%) of vemurafenib clearance was observed. There was significant correlation (R2 = 0.83) between area under the plasma concentration-time curve and trough concentration at steady state. These results will help increase the number of pediatric patients for whom vemurafenib is accessible and facilitate improved dosing in pediatric patients with recurrent/refractory BRAFV600E astrocytomas.

Predictive engines based on pharmacokinetics modelling for tacrolimus personalized dosage in paediatric renal transplant patients

The development of predictive engines based on pharmacokinetic-physiological mathematical models for personalised dosage recommendations is an immature field. Nevertheless, these models are extensively applied during the design of new drugs. This study presents new advances in this subject, through a stable population of patients who underwent kidney transplantation and were prescribed tacrolimus. We developed 2 new population pharmacokinetic models based on a compartmental approach, with one following the physiologically based pharmacokinetic approach and both including circadian modulation of absorption and clearance variables. One of the major findings was an improved predictive capability for both models thanks to the consideration of circadian rhythms, both in estimating the population and in Bayesian individual customisation. This outcome confirms a plausible mechanism suggested by other authors to explain circadian patterns of tacrolimus concentrations. We also discovered significant intrapatient variability in tacrolimus levels a week after the conversion from a fast-release (Prograf) to a sustained-release formulation (Advagraf) using adaptive optimisation techniques, despite high adherence and controlled conditions. We calculated the intrapatient variability through parametric intrapatient variations, which provides a method for quantifying the mechanisms involved. We present a first application for the analysis of bioavailability changes in formulation conversion. The 2 pharmacokinetic models have demonstrated their capability as predictive engines for personalised dosage recommendations, although the physiologically based pharmacokinetic model showed better predictive behaviour.

Therapeutic drug monitoring of two co-administered drugs through development of two ecological chromatographic methods: Invivo application

Surgical site infections (SSI) and pain are the most common postoperative serious complications that increase hospitalization period, treatment cost, and rate of morbidity. Tinidazole (TNZ) and Ibuprofen (IBU) are among the most widely used postoperative and inpatient drugs. The former is used in prophylaxis and treatment of infections, whereas, the later provides long-lasting analgesia and reduces opioid consumption. Therapeutic drug monitoring (TDM) is required for TNZ to decrease the generation of antimicrobial resistance, maximize its efficacy and minimize its toxicity. Additionally, TDM of IBU may be required due to its substantial variability in disposition and clearance. No available method for the simultaneous determination of TNZ and IBU. Hence, the current work aimed to develop two green liquid chromatographic methods for TDM of the mentioned drugs. The first was a TLC-densitometric method using a mobile phase of ethylacetate: ethanol: 33% ammonia solution in the ratio of (7.5: 2.5: 0.05, by volume) using cyclizine as internal standard. The second method was an HPLC method, using methanol: 0.05 M K2HPO4 buffer pH 8 and sulphasalazine as an internal standard. The optimized methods demonstrated adequate sensitivity for the determination of the mentioned drugs as low as 0.98–8.4% of their reported Cmax. Thus, the methods were successfully applied for in-vivo TDM of the mentioned drugs. Bioanalytical validation parameters met the acceptance criteria of US FDA guidelines. NEMI, AMVI and eco scale metrics were applied for qualitative and quantitative assessment of the methods’ greenness. Being green, time and money-saving, the developed methods can be used for TDM of these inpatient drugs in clinical studies.