Time Course Of Concentration Research Articles

Population pharmacokinetic modeling of zavegepant, a calcitonin gene-related peptide receptor antagonist, in healthy adults and patients with migraine.

Zavegepant (ZAVZPRET™) is a high-affinity, selective, small-molecule calcitonin gene-related peptide receptor antagonist available for acute treatment of migraine in adults. A population pharmacokinetic analysis was performed to describe zavegepant plasma concentration-time course, characterize bioavailability, and identify covariates affecting zavegepant exposure. The model was developed and validated using data from 10 phase I clinical studies, wherein zavegepant was administered intravenously, intranasally, or orally to healthy adults and patients with migraine. Plasma concentration-time data were analyzed using nonlinear mixed-effects modeling. A three-compartment model with first-order elimination from the central compartment, and sequential zero- and first-order absorption best described the observed plasma concentration-time course of zavegepant. Bioavailability was 5.1% and 0.65% for intranasal and oral treatment, respectively; absorption rate constants were 5.8 and 0.8 h-1, respectively. Body weight-based empirical allometric scaling was applied using standard exponents (0.75 for clearance and 1 for volume of distribution). Age (range 18-71 years), race, ethnicity, sex, renal function, and co-administration of oral contraceptives or sumatriptan did not significantly change zavegepant pharmacokinetics. Moderate hepatic impairment (Child-Pugh score 7-9) or co-administration of rifampin decreased elimination clearance of oral zavegepant by ~40%. The zavegepant population pharmacokinetic model adequately characterized zavegepant concentration-time profiles, the bioavailability of intranasal and oral zavegepant, as well as the effect of intrinsic and extrinsic factors on zavegepant pharmacokinetics.

Methyl jasmonate effects on Lactuca serriola L.: Antioxidant defense and bioactive compound changes.

The effect of methyl jasmonate (MeJA) foliar spray on the activity of antioxidant enzymes-Superoxide dismutase (SOD), Catalase (CAT), Ascorbate peroxidase (APX), and Guaiacol peroxidase (GPX)-along with assessments of total phenolic and flavonoid contents and antioxidant activity (IC50), was examined in Prickly lettuce (Lactuca serriola L.). The study involved treating plants with three MeJA solutions (0, 200, and 400 µM) and harvesting samples at four distinct time intervals. Varied MeJA concentrations and time intervals resulted in a substantial increase in the activity of all the antioxidant enzymes investigated in this study. Both concentration levels and time courses exhibited progressive outcomes. Moreover, MeJA treatment led to elevated levels of total phenolic and flavonoid contents, reaching peaks of 17.02 (mg GAL/g DW) and 8.3 (mg QUE/g DW), respectively, particularly in response to the 400 µM concentration. However, the total flavonoid content did not show any significant variation between the two concentrations. Based on the half-maximal inhibitory concentration (IC50) values, the antioxidant activity in MeJA-treated plants was found to be lower compared to the controls. However, our findings suggest that, under specific conditions discussed in this study, MeJA has the potential to enhance the nutritional value of L. serriola.

Safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121: An overview of phase I randomized trials in healthy volunteers.

Cognitive impairment associated with schizophrenia predicts poor functional outcomes, but currently no efficacious pharmacotherapies are available. Four phase I trials examined the safety, tolerability and pharmacokinetics of the phosphodiesterase 2 inhibitor BI 474121, along with potential drug-drug interactions. Trial 1 evaluated single rising doses (SRDs) of BI 474121 versus placebo in healthy males. The influence of drug formulation and food on drug bioavailability was also examined. Trial 2 evaluated SRD of BI 474121 versus placebo in healthy Japanese males. Trial 3 evaluated multiple rising doses of BI 474121 in healthy young (with/without midazolam) and elderly (without midazolam) participants versus placebo. Trial 4 investigated interactions between itraconazole and single-dose BI 474121 in healthy males. No deaths, serious adverse events (AEs), severe AEs or protocol-specified AEs of special interest were observed. BI 474121 absorbed rapidly during fasting, achieved maximum concentration of analyte in plasma and dose proportionality via tablet formulation, and decreased in a multiphasic manner. BI 474121 steady state occurred within 11 days of multiple oral administration. Multiple doses increased BI 474121 plasma concentrations, but did not alter the time course of plasma concentrations. Urinary excretion of unchanged BI 474121 was negligible. No clinically relevant inhibition or induction of CYP3A4 by BI 474121 was observed. Itraconazole co-administration produced higher exposures of BI 474121 versus BI 474121 alone. BI 474121 demonstrated favourable safety and pharmacokinetic profiles in healthy Caucasian and Japanese individuals, supporting further clinical development.

Nedosiran population pharmacokinetic and pharmacodynamic modelling and simulation to guide clinical development and dose selection in patients with primary hyperoxaluria type 1.

To characterize pharmacokinetic and pharmacodynamic profiles of nedosiran in patients with primary hyperoxaluria type 1 (PH1), identify influential covariates and confirm therapeutic doses. A population pharmacokinetic (PK)/pharmacodynamic (PD) (POP-PKPD) model was developed to characterize the concentration-time course of nedosiran and the corresponding effect on 24-h urinary oxalate (Uox). Simulations of dosing to achieve clinically meaningful reduction in Uox in children, adolescents and adults with PH1 were performed. Analyses included PK data from 143 healthy participants and PH1/PH2 patients, and PD data from 46 PH1 patients. Nedosiran PK was described by a two-compartment model with dual n-transit absorption and parallel linear and nonlinear elimination. The relationship between nedosiran exposure and Uox was described by an indirect response model. Body weight, estimated glomerular filtration rate (eGFR) and disease status were identified as influential covariates for the POP-PK model. The simulation results supported a weight-banded dosing regimen of nedosiran sodium in adolescents and adults (≥12 years) with PH1 of 170 mg (weight ≥50 kg) and 136 mg (weight <50 kg), in children (6-11 years) with PH1 of 3.5mg/kg, and no dose adjustments for PH1 patients with relatively preserved kidney function (eGFR ≥ 30 mL/min/1.73m2). Following the proposed dosing regimens, the simulated median fold-changes in PK AUC0-τ,ss were acceptable (≤1.51 fold-change) and ~71% of PH1 patients across all age groups achieved near-normal Uox (<0.6mmol) by week 52. The final POP-PKPD model characterizes observed nedosiran PK and Uox data. Simulations support nedosiran dosing regimens in PH1 patients aged ≥6years with relatively preserved kidney function.

NfL concentration in CSF is a quantitative marker of the rate of neurodegeneration in aging and Huntington's disease: a semi-mechanistic model-based analysis.

The concentrations of neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and plasma have become key biomarkers of many neurodegenerative diseases, including Huntington's Disease (HD). However, the relationship between the dynamics of NfL concentrations in CSF and the time-course of neurodegeneration (whole brain atrophy) has not yet been described in a quantitative and mechanistic manner. Here, we present a novel semi-mechanistic model, which postulates that the amount of NfL entering the CSF corresponds to the amount of NfL released from damaged neurons, whose degeneration results in a decrease in brain volume. In mathematical terms, the model expresses the NfL concentration in CSF in terms of the NfL concentration in brain tissue, the rate of change of whole brain volume and the CSF flow rate. To test our model, we used a non-linear mixed effects approach to analyze NfL and brain volume data from the HD-CSF study, a 24-month prospective study of individuals with premanifest HD, manifest HD and healthy controls. The time-course of whole brain volume, obtained from MRI, was represented empirically by a 2nd order polynomial, from which its rate of change was computed. CSF flow rates in healthy and HD populations were taken from recent literature data. By estimating the NfL concentration in brain tissue, the model successfully described the time-course of the NfL concentration in CSF in both HD subjects and healthy controls. Furthermore, the model-derived estimate of NfL concentration in brain agreed well with recent direct experimental measurements. The consistency of our model with the NfL and brain volume data suggests that the NfL concentration in CSF reflects the rate, rather than the extent, of neurodegeneration and that the increase in NfL concentration over time is a measure of the accelerating rate of neurodegeneration associated with aging and HD. For HD subjects, the degree of acceleration was found to increase markedly with the number of CAG repeats on their HTT gene. The application of our semi-mechanistic NfL model to other neurodegenerative diseases is discussed.

Structural and practical identifiability of contrast transport models for DCE-MRI.

Contrast transport models are widely used to quantify blood flow and transport in dynamic contrast-enhanced magnetic resonance imaging. These models analyze the time course of the contrast agent concentration, providing diagnostic and prognostic value for many biological systems. Thus, ensuring accuracy and repeatability of the model parameter estimation is a fundamental concern. In this work, we analyze the structural and practical identifiability of a class of nested compartment models pervasively used in analysis of MRI data. We combine artificial and real data to study the role of noise in model parameter estimation. We observe that although all the models are structurally identifiable, practical identifiability strongly depends on the data characteristics. We analyze the impact of increasing data noise on parameter identifiability and show how the latter can be recovered with increased data quality. To complete the analysis, we show that the results do not depend on specific tissue characteristics or the type of enhancement patterns of contrast agent signal.

No Sequestration of Commonly Used Anti-Infectives in the Extracorporeal Membrane Oxygenation (ECMO) Circuit-An Ex Vivo Study.

Patients undergoing extracorporeal membrane oxygenation (ECMO) often require therapy with anti-infective drugs. The pharmacokinetics of these drugs may be altered during ECMO treatment due to pathophysiological changes in the drug metabolism of the critically ill and/or the ECMO therapy itself. This study investigates the latter aspect for commonly used anti-infective drugs in an ex vivo setting. A fully functional ECMO device circulated an albumin-electrolyte solution through the ECMO tubes and oxygenator. The antibiotic agents cefazolin, cefuroxim, cefepime, cefiderocol, linezolid and daptomycin and the antifungal agent anidulafungin were added. Blood samples were taken over a period of four hours and drug concentrations were measured via high-pressure liquid chromatography (HPLC) with UV detection. Subsequently, the study analyzed the time course of anti-infective concentrations. The results showed no significant changes in the concentration of any tested anti-infectives throughout the study period. This ex vivo study demonstrates that the ECMO device itself has no impact on the concentration of commonly used anti-infectives. These findings suggest that ECMO therapy does not contribute to alterations in the concentrations of anti-infective medications in severely ill patients.

Acetaminophen overdose causes a breach of the blood-bile barrier in mice but not in rats.

Acetaminophen (APAP) is known to cause a breach of the blood-bile barrier in mice that, via a mechanism called futile bile acid (BA) cycling, increases BA concentrations in hepatocytes above cytotoxic thresholds. Here, we compared this mechanism in mice and rats, because both species differ massively in their susceptibility to APAP and compared the results to available human data. Dose and time-dependent APAP experiments were performed in male C57BL6/N mice and Wistar rats. The time course of BA concentrations in liver tissue and in blood was analyzed by MALDI-MSI and LC-MS/MS. APAP and its derivatives were measured in the blood by LC-MS. APAP-induced liver damage was analyzed by histopathology, immunohistochemistry, and by clinical chemistry. In mice, a transient increase of BA in blood and in peri-central hepatocytes preceded hepatocyte death. The BA increase coincided with oxidative stress in liver tissue and a compromised morphology of bile canaliculi and immunohistochemically visualized tight junction proteins. Rats showed a reduced metabolic activation of APAP compared to mice. However, even at very high doses that caused cell death of hepatocytes, no increase of BA concentrations was observed neither in liver tissue nor in the blood. Correspondingly, no oxidative stress was detectable, and the morphology of bile canaliculi and tight junction proteins remained unaltered. In conclusion, different mechanisms cause cell death in rats and mice, whereby oxidative stress and a breach of the blood-bile barrier are seen only in mice. Since transient cholestasis also occurs in human patients with APAP overdose, mice are a clinically relevant species to study APAP hepatotoxicity but not rats.

A reaction–diffusion coupled kinetic model for hydrothermal acid pretreatment of wheat straw

Hydrothermal acid pretreatment is a promising method to overcome the recalcitrance of lignocellulosic biomass for subsequent efficient enzymatic hydrolysis and biofuel production. However, little is known about heterogeneous catalysis reactions involving the proton diffusion in the pore of lignocellulosic biomass coupled with the hydrolysis of hemicellulose and cellulose catalyzed by proton. In this study, a reaction–diffusion coupled kinetic model for hydrothermal acid pretreatment of wheat straw was developed based on the visualization of particle geometry and pore features. The increase rate of average proton concentration in the pores is higher at a higher temperature or a smaller particle size. A mathematical model was successfully developed to describe the time courses of average proton concentration dictated by initial acid concentration and an unsteady diffusion fitting parameter. The kinetic parameters of each reaction step for hydrothermal acid pretreatment of wheat straw were obtained by fitting experimental data. The activation energies for the hydrolysis of slow-hydrolyzing cellulose, fast-hydrolyzing cellulose, and hemicellulose were determined of 937.8 kJ·mol−1, 90.7 kJ·mol−1, and 39.8 kJ·mol−1, respectively, indicating the temperature dependence of slow-hydrolyzing cellulose with a high crystalline index is strongest. The prediction accuracy of this model can be further improved at higher stirring speeds and initial acid concentrations. Additionally, the model demonstrates high prediction accuracy across three different particle sizes. Generally, this model can gratifyingly correlate data of formation and degradation of monosaccharides and furfural in the hydrothermal acid pretreatment of wheat straw with fair accuracy.

Individualized physiology-based digital twin model for sports performance prediction: a reinterpretation of the Margaria–Morton model

Performance in many racing sports depends on the ability of the athletes to produce and maintain the highest possible work i.e., the highest power for the duration of the race. To model this energy production in an individualized way, an adaptation and a reinterpretation (including a physiological meaning of parameters) of the three-component Margaria–Morton model were performed. The model is applied to the muscles involved in a given task. The introduction of physiological meanings was possible thanks to the measurement of physiological characteristics for a given athlete. A method for creating a digital twin was therefore proposed and applied for national-level cyclists. The twins thus created were validated by comparison with field performance, experimental observations, and literature data. Simulations of record times and 3-minute all-out tests were consistent with experimental data. Considering the literature, the model provided good estimates of the time course of muscle metabolite concentrations (e.g., lactate and phosphocreatine). It also simulated the behavior of oxygen kinetics at exercise onset and during recovery. This methodology has a wide range of applications, including prediction and optimization of the performance of individually modeled athletes.

Pharmacokinetic and Pharmacodynamic Modeling Analysis of Delpazolid (LCB01-0371) in Adult Patients with Pulmonary Tuberculosis.

Delpazolid (LCB01-0371) is a novel oxazolidinone derivative with a good safety profile for treating gram-positive pathogenic infections such as Mycobacterium abscessus, a highly pathogenic drug-resistant Mycobacterium. In this study, we evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of delpazolid after 14 days of multiple oral administration, using data from adult patients with pulmonary tuberculosis. 800 mg once a day, 400 mg twice a day, 800 mg twice a day, and 1200 mg once a day delpazolid for 14 days were tested in 63 patients with pulmonary tuberculosis. For PK blood collection, inpatient and outpatient scheduling were separately implemented. Plasma concentrations of delpazolid were measured at visits 2, 4, 6, and 8 in outpatients, and four sparse blood samples were measured in inpatients. PD models were sequentially fitted using individual PK parameter estimates obtained from PK compartmental models. For PK modeling, 180 plasma concentrations of delpazolid from 56 patients were included. A two-compartment mixed first- and zero-order absorption model best described the time course of plasma concentration. For the PD model, 448 bacterial titer data from 60 patients were used. The time course of bacterial titers (log10 CFU/mL) was described by a model that consists of the growth and killing rate of bacteria with the sigmoid Emax model. The PK-PD simulation suggested that the bacterial titers are the lowest on the 800 mg bid regimen among the four, consistent with observed data, as all regimens substantially decrease. In the dose-response relationship, the effectiveness of delpazolid was suggested.

Population pharmacokinetics of the dual endothelin receptor antagonist aprocitentan in subjects with or without essential or resistant hypertension.

Aprocitentan is a novel, potent, dual endothelin receptor antagonist that recently demonstrated efficacy in the treatment of difficult-to-treat (resistant) hypertension. The aim of this study was to develop a population pharmacokinetic (PK) model describing aprocitentan plasma concentration over time, to investigate relationships between subject-specific factors (covariates) and model parameters, and to quantify the influence of the identified covariates on the exposure to aprocitentan via model-based simulations, enabling judgment about the clinical relevance of the covariates.PK data from 902 subjects in ten Phase 1, one Phase 2, and one Phase 3 study were pooled to develop a joint population PK model. The concentration-time course of aprocitentan was described by a two-compartment model with absorption lag time, first-order absorption and elimination, and reduced relative bioavailability following very high doses of 300 and 600mg.The population PK model described the observed data well. Volume and clearance parameters were associated with body weight. Renal function as reflected by estimated glomerular filtration rate (eGFR), hepatic impairment, and sex were identified as relevant covariates on clearance.The subject-specific characteristics of body weight, eGFR, hepatic impairment, and sex were shown to influence exposure parameters area under the concentration-time curve and maximum concentration in steady state to a limited extent, i.e., not more than 25% different from a reference subject, and therefore do not warrant dose adjustments.

Population Pharmacokinetics and CD20 Binding Dynamics for Mosunetuzumab in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma (R/R NHL)

Introduction: Mosunetuzumab (Mosun) is a CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate malignant B cells. Clinical data from GO29781 (NCT02500407), a Phase I/II, open-label, multicenter dose-escalation and expansion study of Mosun in pts with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL), was used to develop a population pharmacokinetic (popPK) model describing Mosun concentration-time data. Prior to initiation of Mosun, many patients had circulating levels of other anti-CD20 drugs (e.g. rituximab (R) or obinutuzumab (G)) from prior treatment. In order to elucidate exposure-response (ER) relationships in the presence of these competitors, CD20 binding and R/G pharmacokinetics were incorporated into the popPK model to calculate the Mosun CD20 receptor occupancy percentage (RO%) over time. Methods: Mosun PK data were available in 439 pts with indolent or aggressive R/R NHL who received either Mosun fixed dosing (n= 32; 0.05-2.8mg every 3 weeks (q3w)) or Cycle 1 step-up dosing (n=407, 0.4/1.0/2.8 - 1/2/60/30mg). The popPK model was developed using NONMEM® software (v7.4.3), with a clinical cut-off date of December 4, 2020. Clinically relevant covariates were investigated for their potential to explain Mosun PK variability. The Mosun CD20 RO% time course for each pt was derived by integrating the Mosun, R, and G model predicted concentration-time courses and their respective CD20 affinities (Kds) into the popPK model. R and G concentration-time courses were predicted by the model using their baseline values and published half-lives, and binding kinetics were assumed to be at equilibrium. PopPK model simulations (n=1000) were done with the final model to establish Mosun concentration ranges for the approved 1/2/60/30 mg dose regimen, given that this regimen was designed to mitigate cytokine release syndrome (CRS) through its step-up Cycle 1 design. Additional popPK model simulations, incorporating Mosun dose delays, were conducted and compared to the 1/2/60/30 mg nominal dose regimen to inform treatment resumption protocols necessary to mitigate CRS. Results : A two-compartment PK model with time-dependent clearance (CL) best described Mosun PK. Mosun CL decreased from an initial value of 1.08 L/day transitioning to a steady state clearance of 0.584 L/day by Cycle 4 (Figure 1A). Mosun terminal phase half-life at steady state was 16.1 days. Concentrations of R/G were present in 50% of patients prior to Mosun therapy (Figure 1A), and the median predose R/G concentration for these patients was 10.0 µg/mL. Statistically relevant covariates on PK parameters included body weight, albumin, sex, tumor burden, and baseline concentrations of R/G; however, no covariate was deemed to have a clinically relevant impact on PK at the recommended dose of 1/2/60/30mg. Mosun CD20 RO% was more variable than Mosun PK (Figure 1B), attributed to the large variability in baseline R/G concentrations. The 60mg loading doses increased Mosun CD20 RO% to steady-state ranges by Cycle 1 (Figure 1B), thereby providing Mosun efficacious exposure in the presence of competing residual, transient R/G concentrations from prior treatment therapies (Figure 1A). From the popPK model simulations, patients with dose delays greater than or equal to 6 weeks had Mosun concentrations that fell below levels after the Day 1 (1mg) and Day 8 (2mg) doses; as such, these pts are instructed to repeat these doses prior to treatment continuation. For Mosun dose delays less than 6 weeks, popPK simulations supported pts either to repeat the last Mosun dose administered, or to continue along with the planned regimen [Lunsumio ® USPI]. Conclusions: Mosun PK was characterized using a two-compartment model with time dependent CL. R/G PK and CD20 binding kinetics were incorporated into the Mosun popPK model to calculate Mosun CD20 RO% over time. The use of two 60mg loading doses enables early achievement of Mosun steady-state target CD20 RO% range, especially benefitting those pts with high levels of precirculating R or G. Simulations with the popPK model supported labeling recommendations for restarting Mosun treatment after dose delays. Acknowledgments: This study was sponsored by F. Hoffmann-La Roche Ltd / Genentech, Inc

A network-based transcriptomic landscape of HepG2 cells uncovering causal gene-cytotoxicity interactions underlying drug-induced liver injury.

Drug-induced liver injury (DILI) remains the main reason for drug development attritions largely due to poor mechanistic understanding. Toxicogenomic to interrogate the mechanism of DILI has been broadly performed. Gene coregulation network-based transcriptome analysis is a bioinformatics approach that potentially contributes to improve mechanistic interpretation of toxicogenomic data. Here we performed an extensive concentration time course response-toxicogenomic study in the HepG2 cell line exposed to 20 DILI compounds, 7 reference compounds for stress response pathways, and 10 agonists for cytokines and growth factor receptors. We performed whole transcriptome targeted RNA sequencing to more than 500 conditions and applied weighted gene coregulated network analysis to the transcriptomics data followed by the identification of gene coregulated networks (modules) that were strongly modulated upon the exposure of DILI compounds. Preservation analysis on the module responses of HepG2 and PHH demonstrated highly preserved adaptive stress response gene coregulated networks. We correlated gene coregulated networks with cell death onset and causal relationships of 67 critical target genes of these modules with the onset of cell death was evaluated using RNA interference screening. We identified GTPBP2, HSPA1B, IRF1, SIRT1, and TSC22D3 as essential modulators of DILI compound-induced cell death. These genes were also induced by DILI compounds in PHH. Altogether, we demonstrate the application of large transcriptome datasets combined with network-based analysis and biological validation to uncover the candidate determinants of DILI.

Antibiofilm Property and Biocompatibility of Siloxane-Based Polymer Coatings Applied to Biomaterials

Biofilm infections sometimes occur on biomaterials inserted into the body because biomaterials can block the attack of immune cells such as macrophages, promoting biofilm formation by invading bacteria. Owing to their use in antifouling applications, including biofilm formation, siloxane-based polymer coatings are considered a promising method to prevent biofilm formation on the surface of biomaterials. In this study, we explored the antibiofilm property and biocompatibility of siloxane-based polymer coatings. Biofilm formation and cytotoxicity tests were performed using Escherichia coli and Staphylococcus epidermidis to quantify the biofilms while U937 cells were used to measure the time course of viable cell concentration and viability, respectively. In both the biofilm formation and cytotoxicity tests, stainless steel SUS316L plates and titanium plates coated with the siloxane-based polymer and sterilized in an autoclave were used as the biomaterials. The amount of biofilm formed on the polymer-coated titanium plate was substantially higher than that on a noncoated titanium plate in the case of S. epidermidis. The viable cell concentration and viability of U937 cultured on the polymer-coated titanium plate were lower than those of U937 cultured on the noncoated titanium plate. The same trend was observed between polymer-coated and noncoated SUS316L plates. These results indicate that the siloxane-based polymer coatings need additional treatment to achieve a satisfactory antibiofilm property and that they are sensitive to autoclave treatment, resulting in cytotoxicity.

The mechanism of MinD stability modulation by MinE in Min protein dynamics.

The patterns formed both in vivo and in vitro by the Min protein system have attracted much interest because of the complexity of their dynamic interactions given the apparent simplicity of the component parts. Despite both the experimental and theoretical attention paid to this system, the details of the biochemical interactions of MinD and MinE, the proteins responsible for the patterning, are still unclear. For example, no model consistent with the known biochemistry has yet accounted for the observed dual role of MinE in the membrane stability of MinD. Until now, a statistical comparison of models to the time course of Min protein concentrations on the membrane has not been carried out. Such an approach is a powerful way to test existing and novel models that are difficult to test using a purely experimental approach. Here, we extract time series from previously published fluorescence microscopy time lapse images of in vitro experiments and fit two previously described and one novel mathematical model to the data. We find that the novel model, which we call the Asymmetric Activation with Bridged Stability Model, fits the time-course data best. It is also consistent with known biochemistry and explains the dual MinE role via MinE-dependent membrane stability that transitions under the influence of rising MinE to membrane instability with positive feedback. Our results reveal a more complex network of interactions between MinD and MinE underlying Min-system dynamics than previously considered.

A convolution-based in vitro-in vivo correlation model for methylphenidate hydrochloride delayed-release and extended-release capsule.

Delayed-release and extended-release methylphenidate hydrochloride (JORNAY PM®) is a novel capsule formulation of methylphenidate hydrochloride, used to treat attention deficit hyperactivity disorder in patients 6 years and older. In this paper, we develop a Level A invitro-in vivo correlation (IVIVC) model for extended-release methylphenidate hydrochloride to support post-approval manufacturing changes by evaluating a point-to-point correlation between the fraction of drug dissolved invitro and the fraction of drug absorbed invivo. Dissolution data from an invitro study of three different release formulations: fast, medium, and slow, and pharmacokinetic data from two invivo studies were used to develop an IVIVC model using a convolution-based approach. The time-course of the drug concentration resulting from an arbitrary dose was considered as a function of the invivo drug absorption and the disposition and elimination processes defined by the unit impulse response function using the convolution integral. An IVIVC was incorporated in the model due to the temporal difference seen in the scatterplots of the estimated fraction of drug absorbed invivo and the fraction of drug dissolved invitro and Levy plots. Finally, the IVIVC model was subjected to evaluation of internal predictability. This IVIVC model can be used to predict invivo profiles for different invitro profiles of extended-release methylphenidate hydrochloride.

Target Reserve and Turnover Parameters Determine Rightward Shift of Enalaprilat Potency From its Binding Affinity to the Angiotensin Converting Enzyme

Drug effects are often assumed to be directly proportional to the fraction of occupied targets. However, for a number of antagonists that exhibit target-mediated drug disposition (TMDD), such as angiotensin-converting enzyme (ACE) inhibitors, drug binding to the target at low concentrations may be significant enough to influence pharmacokinetics but insufficient to elicit a drug response (i.e., differences in drug-target binding affinity and potency). In this study, a pharmacokinetic/pharmacodynamic model for enalaprilat was developed in humans to provide a theoretical framework for assessing the relationship between ex vivo drug potency (IC50) and in vivo target-binding affinity (KD). The model includes competitive binding of angiotensin I and enalaprilat to ACE and accounts for the circulating target pool. Data were obtained from the literature, and model fitting and parameter estimation were conducted using maximum likelihood in ADAPT5. The model adequately characterized time-courses of enalaprilat concentrations and four biomarkers in the renin-angiotensin system and provided estimates for in vivo KD (0.646 nM) and system-specific parameters, such as total target density (32.0 nM) and fraction of circulating target (19.8%), which were in agreement with previous reports. Model simulations were used to predict the concentration-effect curve of enalaprilat, revealing a 6.3-fold increase in IC50 from KD. Additional simulations demonstrated that target reserve and degradation parameters are key factors determining the extent of shift of enalaprilat ex vivo potency from its in vivo binding affinity. This may be a common phenomenon for drugs exhibiting TMDD and has implications for translating binding affinity to potency in drug development.

Model-informed precision dosing in vancomycin treatment.

Introduction: While vancomycin remains a widely prescribed antibiotic, it can cause ototoxicity and nephrotoxicity, both of which are concentration-associated. Overtreatment can occur when the treatment lasts for an unnecessarily long time. Using a model-informed precision dosing scheme, this study aims to develop a population pharmacokinetic (PK) and pharmacodynamic (PD) model for vancomycin to determine the optimal dosage regimen and treatment duration in order to avoid drug-induced toxicity. Methods: The data were obtained from electronic medical records of 542 patients, including 40 children, and were analyzed using NONMEM software. For PK, vancomycin concentrations were described with a two-compartment model incorporating allometry scaling. Results and discussion: This revealed that systemic clearance decreased with creatinine and blood urea nitrogen levels, history of diabetes and renal diseases, and further decreased in women. On the other hand, the central volume of distribution increased with age. For PD, C-reactive protein (CRP) plasma concentrations were described by transit compartments and were found to decrease with the presence of pneumonia. Simulations demonstrated that, given the model informed optimal doses, peak and trough concentrations as well as the area under the concentration-time curve remained within the therapeutic range, even at doses smaller than routine doses, for most patients. Additionally, CRP levels decreased more rapidly with the higher dose starting from 10days after treatment initiation. The developed R Shiny application efficiently visualized the time courses of vancomycin and CRP concentrations, indicating its applicability in designing optimal treatment schemes simply based on visual inspection.

Orally administered low-molecular weight agaro-oligosaccharides are absorbed into the plasma of healthy humans.

Agaro-oligosaccharides (AOSs) are known to have biological activities, such as anti-inflammatory, anti-tumor, and anti-obesity effects. Although existing evidence suggests the presence of AOSs in peripheral tissues after oral administration, whether AOSs permeate into the blood circulation remains unknown. Thus, we hypothesized that AOSs with low-molecular weight can permeate the human gastrointestinal tract. To test this hypothesis, the time course of absorption was examined by analyzing plasma samples before and 1, 2, and 4 h after ingestion. Analysis was performed using liquid chromatography/mass spectrometry after labeling with p-aminobenzoic ethyl ester. Our results showed that the plasma concentration of agarobiose (Abi) was higher than that of agarotetraose (Ate); however, agarohexaose was not detected. Additionally, plasma levels of Abi and Ate were proportional to the dose. These results suggest that permeation efficiency is dependent on the molecular weight and that the systemic absorption of Abi via the gastrointestinal tract is better than that of Ate. These findings will contribute to a better understanding of the bioactivity of orally administered AOSs in peripheral tissues.