scholarly journals Model-informed precision dosing of levetiracetam in pediatrics population

2021 ◽  
Author(s):  
Julia Macente ◽  
Frederico Martins ◽  
Rodolfo Bonan ◽  
Edilainy Caleffi-Marchesini ◽  
Leonardo Pereira ◽  
...  
Keyword(s):  
Body Weight ◽  
Pbpk Model ◽  
Dose Range ◽  
Linear Regression Analysis ◽  
Simulated Data ◽  
Therapeutic Regimen ◽  
Pbpk Modeling ◽  
Multivariate Linear Regression Analysis ◽  
Modeling Methods ◽  
Titration Phase

Aims: Assessing the suitability and safety of doses of levetiracetam in pediatrics using physiologic-based pharmacokinetic (PBPK) modeling. Methods: A PBPK model of levetiracetam was developed and validated for healthy adults and scaled for children (0.5 to 12 years old). Prediction of levetiracetam exposure at steady- state, were carried out for different therapeutic regimens to achieve the target of Cmax values within the therapeutic range of 5 to 46 µg ml-1. Then, a multivariate linear regression analysis (MLR) was applied to correlate the simulated data with covariates: dose, therapeutic regimen, sex, age and body weight (BW), to describe the best model prediction for the initial dosing in pediatrics. Results: The results indicated the suitability of the PBPK model for adults and pediatrics. For children aged 0.5 to 6 y.o. the dose range capable of reaching the pharmacokinetic target is between 10 and 100 mg kg-1 day-1, for 7 to 9 y.o. doses between 20 and 90 mg kg-1 day-1, and for 10 to 12 y.o. doses between 20 to 80 mg kg-1 day-1. Further, the MLR related Cmax to dose, therapeutic regimen, and BW. Conclusions: For 3 daily administrations, it is suggested that maximum daily doses of 80 mg kg-1 could be used for ages between 0.5 and 6 y.o. and 100 mg kg-1 for ages above 7 years old, since they weigh below 50 kg. The PBPK model lumped to MLR could be very supportive for clinical decisions to safety and effectiveness of prescription of levetiracetam along the titration phase.

Effect of Patient Characteristics on Vessel Enhancement in Pediatric Chest Computed Tomography Angiography

2019 ◽  
Vol 70 (2) ◽  
pp. 181-185
Author(s):  
Takanori Masuda ◽  
Takeshi Nakaura ◽  
Yoshinori Funama ◽  
Tomoyasu Sato ◽  
Tetsuya Nitta ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Body Weight ◽  
Regression Analysis ◽  
Linear Regression ◽  
Linear Regression Analysis ◽  
Patient Characteristics ◽  
Multivariate Linear Regression Analysis ◽  
Chest Computed Tomography ◽  
Pediatric Chest ◽  
Vessel Enhancement

Introduction To evaluate the effect of sex, age, height, cardiac output (CO), total body weight (TBW), body surface area (BSA), and lean body weight (LBW) on vessel enhancement of the ascending aorta in pediatric chest computed tomography angiography (c-CTA). Materials and Methods This retrospective study received institutional review board approval; parental prior informed consent for inclusion was obtained for all patients. All 50 patients were examined using our routine protocol; iodine (600 mg/kg) was the contrast medium (CM). Unenhanced and contrast-enhanced scans were obtained. We calculated the CM volume per vessel enhancement and performed univariate and multivariate linear regression analysis of the relationship between CM volume per vessel enhancement and each of the body parameters. Results All patient characteristics were significantly related to CM volume per vessel enhancement ( P < .05). Multivariate linear regression analysis revealed a significant correlation between CM volume per vessel enhancement and TBW, BSA, and LBW, but not the patient sex, age, CO, and height. The LBW model for CM volume per vessel enhancement yielded the highest determination coefficient (R2 = .913) and the lowest Akaike Information Criterion (400.324). Conclusions Our findings support the delivery of an iodine dose adjusted to the LBW at c-CTA.

scholarly journals In Vitro and In Vivo Bioequivalence Study of 3D-Printed Instant-Dissolving Levetiracetam Tablets and Subsequent Personalized Dosing for Chinese Children Based on Physiological Pharmacokinetic Modeling

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 20
Author(s):  
Xianfu Li ◽  
En Liang ◽  
Xiaoxuan Hong ◽  
Xiaolu Han ◽  
Conghui Li ◽  
...  
Keyword(s):  
3D Printing ◽  
Pbpk Model ◽  
Dose Range ◽  
Chinese Children ◽  
Pbpk Modeling ◽  
Printing Technology ◽  
3D Printing Technology ◽  
Pbpk Models ◽  
3D Printed

Recently, the development of Binder Jet 3D printing technology has promoted the research and application of personalized formulations, which are especially useful for children’s medications. Additionally, physiological pharmacokinetic (PBPK) modeling can be used to guide drug development and drug dose selection. Multiple technologies can be used in combination to increase the safety and effectiveness of drug administration. In this study, we performed in vivo pharmacokinetic experiments in dogs with preprepared 3D-printed levetiracetam instant-dissolving tablets (LEV-IDTs). Bioequivalence analysis showed that the tablets were bioequivalent to commercially available preparations (Spritam®) for dogs. Additionally, we evaluated the bioequivalence of 3D-printed LEV-IDTs with Spritam® by a population-based simulation based on the established PBPK model of levetiracetam for Chinese adults. Finally, we established a PBPK model of oral levetiracetam in Chinese children by combining the physiological parameters of children, and we simulated the PK (pharmacokinetics) curves of Chinese children aged 4 and 6 years that were administered the drug to provide precise guidance on adjusting the dose according to the effective dose range of the drug. Briefly, utilizing both Binder jet 3D printing technology and PBPK models is a promising route for personalized drug delivery with various age groups.

scholarly journals Evaluation of Hypertension, Proteinuria, and Abnormalities of Body Weight in Italian Adolescents Participating in the World Kidney Days

2020 ◽  
Vol 45 (2) ◽  
pp. 286-296 ◽  
Author(s):  
Yuri Battaglia ◽  
Pasquale Esposito ◽  
Salvatore Corrao ◽  
Luigi Russo ◽  
Alessandro Balducci ◽  
...  
Keyword(s):  
Body Weight ◽  
Kidney Diseases ◽  
Linear Regression Analysis ◽  
Normal Weight ◽  
Overweight And Obesity ◽  
Class I ◽  
Multivariate Linear Regression Analysis ◽  
School Project ◽  
Diastolic Hypertension ◽  
Italian Adolescents

Introduction: World Kidney Day (WKD) was promoted by the Italian Kidney Foundation and the Italian Society of Nephrology for raising awareness, detection, prevention, and treatment of kidney diseases. The Italian WKD focused on the “School Project” by screening students attending the fifth year of high school. The main goal of the “School Project” was to assess in healthy adolescents the presence of hypertension (HTN) and proteinuria; as well as to evaluate potential interrelations between overweight, obesity (both measured with different anthropometric methods), blood pressure (BP) levels, and proteinuria. The ancillary goal was to have an estimate of awareness on some nephrology topics. Methods: The study population consisted of 17- to 19-year-old students. HTN was defined as systolic BP (SBP) ≥140 mm Hg and/or diastolic BP (DBP) ≥90 mm Hg. Isolated systolic hypertension (ISH) was defined as SBP ≥140 mm Hg and DBP <90 mm Hg; isolated diastolic hypertension as SBP <140 mm Hg and DBP ≥90 mm Hg; systolic and diastolic hypertension as SBP ≥140 mm Hg and DBP ≥90 mm Hg; pre-hypertension as SBP >120 mm Hg but <140 mm Hg or DBP >80 mm Hg but <90 mm Hg; and optimal BP as SBP ≤120 mm Hg and DBP ≤80 mm Hg. Urine tests were performed with a dipstick; the subjects were regarded as proteinuric when the urine dipstick was positive (proteinuria ≥30 mg/dL). Body weight, height, and waist circumference (WC) were measured; body mass index (BMI), waist-to-height ratio (WHtR), and conicity index (Ci) were calculated. According to the BMI, the following classifications were adopted: underweight (<18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25–29.9 kg/m2), class-I obesity (30–34.9 kg/m2), class-II obesity (35–39.9 kg/m2), class-III obesity (≥40 kg/m2). Results: Data from 12,125 students (45.6% males) were evaluated. HTN was found in 1,349 participants (11.1%; 61.1% male), and ISH was present in 7.4%. Overweight (24.1%) and class-I (6%), -II (3.6%), and -III (1%) obesity were present in hypertensive participants. Compared to participants with normal BP, hypertensive participants had a higher BMI (p < 0.001), WC (p < 0.001), and WHtR (p < 0.001); whereas the Ci was not different (p = 0.527). Multivariate linear regression analysis showed that both WC and BMI were predictors of abnormal SBP and DBP (p < 0.001) both in males and females. Proteinuria was present in 14.8, 13.8, 14.7, and 14.7% of all normal weight, overweight, obese, and all subjects, respectively. In addition, no association was found between body weight, proteinuria, and BP. Conclusion: This study shows that overweight and obesity were significantly associated to HTN in Italian adolescents. BMI and WC were predictors of SBP and DBP. The occurrence of proteinuria was quite similar to that of HTN, but it was not associated with anthropometric indicators or HTN.

scholarly journals Quantitative Property-Property Relationship for Screening-Level Prediction of Intrinsic Clearance of Volatile Organic Chemicals in Rats and Its Integration within PBPK Models to Predict Inhalation Pharmacokinetics in Humans

2012 ◽  
Vol 2012 ◽  
pp. 1-22 ◽  
Author(s):  
Thomas Peyret ◽  
Kannan Krishnan
Keyword(s):  
Pbpk Model ◽  
Linear Regression Analysis ◽  
Intrinsic Clearance ◽  
Pbpk Modeling ◽  
Human Pharmacokinetics ◽  
Property Relationship ◽  
Pbpk Models ◽  
Quantitative Property ◽  
The Impact

The objectives of this study were (i) to develop a screening-level Quantitative property-property relationship (QPPR) for intrinsic clearance (CLint) obtained fromin vivoanimal studies and (ii) to incorporate it with human physiology in a PBPK model for predicting the inhalation pharmacokinetics of VOCs.CLint, calculated as the ratio of thein vivoVmax(μmol/h/kg bw rat) to theKm(μM), was obtained for 26 VOCs from the literature. The QPPR model resulting from stepwise linear regression analysis passed the validation step (R2=0.8; leave-one-out cross-validationQ2=0.75) forCLintnormalized to the phospholipid (PL) affinity of the VOCs. The QPPR facilitated the calculation ofCLint(L PL/h/kg bw rat) from the input data on logPow, log blood: water PC and ionization potential. The predictions of the QPPR as lower and upper bounds of the 95% mean confidence intervals (LMCI and UMCI, resp.) were then integrated within a human PBPK model. The ratio of the maximum (using LMCI forCLint) to minimum (using UMCI forCLint) AUC predicted by the QPPR-PBPK model was1.36±0.4and ranged from 1.06 (1,1-dichloroethylene) to 2.8 (isoprene). Overall, the integrated QPPR-PBPK modeling method developed in this study is a pragmatic way of characterizing the impact of the lack of knowledge ofCLintin predicting human pharmacokinetics of VOCs, as well as the impact of prediction uncertainty ofCLinton human pharmacokinetics of VOCs.

scholarly journals The relationship between the atherogenic index of plasma and arterial stiffness in essential hypertensive patients from China: a cross-sectional study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Juan Yin ◽  
Minghui Li ◽  
Lingling Yu ◽  
Feng Hu ◽  
Yu Yu ◽  
...  
Keyword(s):  
Essential Hypertension ◽  
Arterial Stiffness ◽  
Linear Regression Analysis ◽  
Cross Sectional Study ◽  
Atherogenic Index ◽  
Chinese Patients ◽  
Multivariate Linear Regression Analysis ◽  
Sectional Study ◽  
Cross Sectional ◽  
Atherogenic Index Of Plasma

Abstract Background The atherogenic index of plasma (AIP) always remains in a potential association with arterial stiffness, however, this association has not been fully discovered and needs to be studied in depth in large hypertensive patient populations. The present analysis thus sought to further explore the association that exists between AIP and arterial stiffness in Chinese patients diagnosed with arterial hypertension. Methods This cross-sectional study analyzed 4744 Chinese individuals with essential hypertension. AIP was defined as the base 10 logarithm of the ratio of plasma of triglycerides to high-density lipoprotein cholesterol levels indicated in molar concentrations. Measurement of arterial stiffness was carried out via brachial-ankle pulse wave velocity (baPWV). Results Data were adjusted for potential confounding variables, and multivariate linear regression analysis revealed AIP to be positively correlated with baPWV (β = 1.34, 95% CI: 0.96 to 1.72, P < 0.001). When AIP was instead treated as a categorical variable divided into quartiles, the same relationship was observed (P for trend < 0.001). We additionally found AIP and baPWV had a stronger positive association in individuals with a body mass index (BMI) < 24 kg/m2 (P for interaction < 0.05). Conclusion AIP and arterial stiffness were positively correlated in essential hypertension patients in China, especially in those with a BMI < 24 kg/m2. Clinical trial registration ChiCTR1800017274.

scholarly journals Development of Physiologically Based Pharmacokinetic Model for Orally Administered Fexuprazan in Humans

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 813
Author(s):  
Yoo-Seong Jeong ◽  
Min-Soo Kim ◽  
Nora Lee ◽  
Areum Lee ◽  
Yoon-Jee Chae ◽  
...  
Keyword(s):  
Gastric Acid ◽  
Pbpk Model ◽  
Pbpk Modeling ◽  
Drug Candidate ◽  
Metabolite Formation ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Fexuprazan is a new drug candidate in the potassium-competitive acid blocker (P-CAB) family. As proton pump inhibitors (PPIs), P-CABs inhibit gastric acid secretion and can be used to treat gastric acid-related disorders such as gastroesophageal reflux disease (GERD). Physiologically based pharmacokinetic (PBPK) models predict drug interactions as pharmacokinetic profiles in biological matrices can be mechanistically simulated. Here, we propose an optimized and validated PBPK model for fexuprazan by integrating in vitro, in vivo, and in silico data. The extent of fexuprazan tissue distribution in humans was predicted using tissue-to-plasma partition coefficients in rats and the allometric relationships of fexuprazan distribution volumes (VSS) among preclinical species. Urinary fexuprazan excretion was minimal (0.29–2.02%), and this drug was eliminated primarily by the liver and metabolite formation. The fraction absorbed (Fa) of 0.761, estimated from the PBPK modeling, was consistent with the physicochemical properties of fexuprazan, including its in vitro solubility and permeability. The predicted oral bioavailability of fexuprazan (38.4–38.6%) was within the range of the preclinical datasets. The Cmax, AUClast, and time-concentration profiles predicted by the PBPK model established by the learning set were accurately predicted for the validation sets.

The Personal Sociability and Connections Scale (PeSCS): Development and initial assessment at a primary care facility

2021 ◽  
pp. 002076402199351
Author(s):  
Emmanouil K Symvoulakis ◽  
Manolis Linardakis ◽  
Apostolos Kamekis ◽  
Myfanwy Morgan ◽  
Spyridon Klinis
Keyword(s):  
Primary Care ◽  
Social Isolation ◽  
Convergent Validity ◽  
Interpersonal Relations ◽  
Linear Regression Analysis ◽  
Care Facility ◽  
Initial Assessment ◽  
Multivariate Linear Regression Analysis ◽  
Northern Greece ◽  
The Relationship

Purpose: An individual’s lack of social connections and social isolation is often associated with feelings of loneliness which is regarded as having a negative effect on health. This paper describes the development and assessment of a 10 item ‘Personal Sociability and Connections Scale’ (PeSCS) to measure individual’s disposition and accompanying skills to seek out companionship and engage in interpersonal relations. Methods: The study was conducted at a rural primary care unit in Northern Greece. A total of 199 attenders were recruited over a 6-week period in 2020 and questionnaires completed. This informed the 10-items PeSCS that comprises Social, Behavioral, and Emotional components focusing on the expression of social comfort, willingness to share experiences, stories and concepts, and feelings of similarity at first contact. Reliability of the PeSC scale was assessed and the relationship with scale scores examined as an indicator of convergent validity. A multivariate linear regression analysis was performed to examine the relationship of PeSC scale score with the characteristics of participants. Results: Assessment of reliability of PeSC scale produced a Cronbach’s alpha of 0.809. The relationship between components and the total PeSCS scores identified significant correlations ( p < .001). At a multivariate level, male gender was the sample characteristic with a significant association with scale levels ( p < .05) and higher annual income with Social component ( p < .05). Otherwise the distribution of sociability dispositions was similar across population groups. Conclusion: The 10-item PeSC scale forms a simple and quick to complete measure whose overall reliability was rated as ‘meritorious’. The PeSC instrument may be a useful tool for assessing the causes and appropriate responses to the negative health effects of loneliness and social isolation.

A New Resuscitation Formula Based on Burn Index Provides More Reliable Prediction for Fluid Requirement in Adult Major Burn Patients

2021 ◽  
Author(s):  
Jianglin Tan ◽  
Junyi Zhou ◽  
Ning Li ◽  
Lili Yuan ◽  
Gaoxing Luo
Keyword(s):  
Fluid Resuscitation ◽  
Linear Regression Analysis ◽  
Fluid Volume ◽  
Multivariate Linear Regression Analysis ◽  
Burn Patients ◽  
Full Thickness ◽  
Burn Wound ◽  
Major Burn ◽  
Fluid Requirement ◽  
Actual Volume

Abstract The Third Military Medical University (TMMU) formula is widely used in fluid resuscitation in China. However, the actual volume needs usually exceed the prediction provided by the TMMU formula in major burn patients with a high proportion of full-thickness burn wounds. This retrospective study included 149 adult major burn patients (≥40% TBSA) who were admitted to the Burn Department, Southwest Hospital from 2014 to 2020 and received appropriate fluid resuscitation by the TMMU protocol. The actual volume infused in the first 48 hours postburn was compared to the estimation by the TMMU formula. A new fluid volume prediction formula was developed by multivariate linear regression analysis. The mean fluid requirements were 2.35 ml/kg/% TBSA and 1.75 ml/kg/% TBSA in the first and second 24 hours postburn, respectively. The TMMU formula underestimated the fluid requirement, and its prediction accuracy was 54.1% and 25.8% for the first and second 24 hours, respectively. The proportion of full-thickness burn wound was found to be associated with the fluid requirements postburn. A revised multifactorial formula consisting of the burn index, body weight, and inhalation injury was developed. Using the revised formula, the prediction reliability of resuscitation fluid volume improved to 65.3% and 61.1% in the first and second 24 hours, respectively. The TMMU formula showed low accuracy in predicting fluid requirements among major burn patients. A revised formula based on burn index was developed to provide better guidance for initiative fluid resuscitation for major burns by the TMMU protocol.

Analysis of the Relationships between Balance Ability and Walking in Terms of Muscle Activities and Lower Limb Kinematics and Kinetics

Biomechanics ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 190-201
Author(s):  
Pathmanathan Cinthuja ◽  
Graham Arnold ◽  
Rami J. Abboud ◽  
Weijie Wang
Keyword(s):  
Regression Analysis ◽  
Lower Limb ◽  
Linear Regression Analysis ◽  
Multivariate Linear Regression Analysis ◽  
Vastus Medialis ◽  
Balance Test ◽  
Balance Ability ◽  
Limb Kinematics ◽  
Lower Limb Kinematics ◽  
Kinematics And Kinetics

There is a lack of evidence about the ways in which balance ability influences the kinematic and kinetic parameters and muscle activities during gait among healthy individuals. The hypothesis is that balance ability would be associated with the lower limb kinematics, kinetics and muscle activities during gait. Twenty-nine healthy volunteers (Age 32.8 ± 9.1; 18 males and 11 females) performed a Star Excursion Balance test to measure their dynamic balance and walked for at least three trials in order to obtain a good quality of data. A Vicon® 3D motion capture system and AMTI® force plates were used for the collection of the movement data. The selected muscle activities were recorded using Delsys® Electromyography (EMG). The EMG activities were compared using the maximum values and root mean squared (RMS) values within the participants. The joint angle, moment, force and power were calculated using a Vicon Plug-in-Gait model. Descriptive analysis, correlation analysis and multivariate linear regression analysis were performed using SPSS version 23. In the muscle activities, positive linear correlations were found between the walking and balance test in all muscles, e.g., in the multifidus (RMS) (r = 0.800 p < 0.0001), vastus lateralis (RMS) (r = 0.639, p < 0.0001) and tibialis anterior (RMS) (r = 0.539, p < 0.0001). The regression analysis models showed that there was a strong association between balance ability (i.e., reaching distance) and the lower limb muscle activities (i.e., vastus medialis–RMS) (R = 0.885, p < 0.0001), and also between balance ability (i.e., reaching distance) and the lower limb kinematics and kinetics during gait (R = 0.906, p < 0.0001). In conclusion, the results showed that vastus medialis (RMS) muscle activity mainly contributes to balance ability, and that balance ability influences the lower limb kinetics and kinematics during gait.

scholarly journals 1315. No Dose Adjustment of Metformin with Fostemsavir Coadministration Based on Mechanistic Static and Physiologically Based Pharmacokinetic Models

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S669-S669
Author(s):  
Dung N Nguyen ◽  
Xiusheng Miao ◽  
Mindy Magee ◽  
Guoying Tai ◽  
Peter D Gorycki ◽  
...  
Keyword(s):  
Dose Adjustment ◽  
Pbpk Model ◽  
Systemic Exposure ◽  
Multidrug Resistant ◽  
Pbpk Modeling ◽  
Repeat Dose ◽  
Physiologically Based Pharmacokinetic ◽  
Physiologically Based

Abstract Background Fostemsavir (FTR) is an oral prodrug of the first-in-class attachment inhibitor temsavir (TMR) which is being evaluated in patients with multidrug resistant HIV-1 infection. In vitro studies indicated that TMR and its 2 major metabolites are inhibitors of organic cation transporters (OCT)1, OCT2, and multidrug and toxin extrusion transporters (MATEs). To assess the clinical relevance, of OCT and MATE inhibition, mechanistic static DDI prediction with calculated Imax,u/IC50 ratios was below the cut-off limits for a DDI flag based on FDA guidelines and above the cut-off limits for MATEs based on EMA guidelines. Methods Metformin is a commonly used probe substrate for OCT1, OCT2 and MATEs. To predict the potential for a drug interaction between TMR and metformin, a physiologically based pharmacokinetic (PBPK) model for TMR was developed based on its physicochemical properties, in vitro and in vivo data. The model was verified and validated through comparison with clinical data. The TMR PBPK model accurately described AUC and Cmax within 30% of the observed data for single and repeat dose studies with or without food. The SimCYP models for metformin and ritonavir were qualified using literature data before applications of DDI prediction for TMR Results TMR was simulated at steady state concentrations after repeated oral doses of FTR 600 mg twice daily which allowed assessment of the potential OCT1, OCT2, and MATEs inhibition by TMR and metabolites. No significant increase in metformin systemic exposure (AUC or Cmax) was predicted with FTR co-administration. In addition, a sensitivity analysis was conducted for either hepatic OCT1 Ki, or renal OCT2 and MATEs Ki values. The model output indicated that, a 10-fold more potent Ki value for TMR would be required to have a ~15% increase in metformin exposure Conclusion Based on mechanistic static models and PBPK modeling and simulation, the OCT1/2 and MATEs inhibition potential of TMR and its metabolites on metformin pharmacokinetics is not clinically significant. No dose adjustment of metformin is necessary when co-administered with FTR Disclosures Xiusheng Miao, PhD, GlaxoSmithKline (Employee) Mindy Magee, Doctor of Pharmacy, GlaxoSmithKline (Employee, Shareholder) Peter D. Gorycki, BEChe, MSc, PhD, GSK (Employee, Shareholder) Katy P. Moore, PharmD, RPh, ViiV Healthcare (Employee)

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