Nonlinear Mixed-effects Modeling Research Articles

Pooled Population Pharmacokinetic Analysis and Dose Recommendations for Ciprofloxacin in Intensive Care Unit Patients with Obesity.

Recent studies have explored the influence of obesity and critical illness on ciprofloxacin pharmacokinetics. However, variation across the subpopulation of individuals with obesity admitted to the intensive care unit (ICU) with varying renal function remains unexamined. This study aims to characterize ciprofloxacin pharmacokinetics in ICU patients with obesity and provide dose recommendations for this special population. Individual patient data of 34 ICU patients with obesity (BMI >30 kg/m2) from four studies evaluating ciprofloxacin pharmacokinetics in ICU patients were pooled and combined with data from a study involving 10 individuals with obesity undergoing bariatric surgery. All samples were collected after intravenous administration. Non-linear mixed effects modeling and simulation were used to develop a population pharmacokinetic model and describe ciprofloxacin exposure in plasma. Model-based dose evaluations were performed using a pharmacokinetic/pharmacodynamic target of AUC/MIC >125. The data from patients with BMI ranging from 30.2 to 58.1 were best described by a two-compartment model with first-order elimination and a proportional error model. The inclusion of Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) as a covariate on clearance reduced inter-individual variability from 57.3% to 38.5% (P <.001). Neither body weight nor ICU admission significantly influenced clearance or volume of distribution. Renal function is a viable predictor for ciprofloxacin clearance in ICU patients with obesity, while critical illness and body weight do not significantly alter clearance. As such, body weight and critical illness do not need to be accounted for when dosing ciprofloxacin in ICU patients with obesity. Individuals with CKD-EPI >60 mL/min/1.73 m2 may require higher dosages for the treatment of pathogens with minimal inhibitory concentration ≥0.25 mg/L.

Assessment of body mass-related covariates for rifampicin pharmacokinetics in healthy Caucasian volunteers.

Currently, body weight-based dosing of rifampicin is recommended. But lately, fat-free mass (FFM) was reported to be superior to body weight (BW). The present evaluation aimed to assess the influence of body mass-related covariates on rifampicin's pharmacokinetics (PK) parameters in more detail using non-linear mixed effects modeling (NLMEM). Twenty-four healthy Caucasian volunteers were enrolled in a bioequivalence study, each receiving a test and a reference tablet of 600mg of rifampicin separated by a wash-out period of at least 9days. Monolix version 2023R1 was used for NLMEM. Monte Carlo simulations (MCS) were performed to visualize the relationship of body size descriptors to the exposure to rifampicin. A one-compartment model with nonlinear (Michaelis-Menten) elimination and zero-order absorption kinetics with a lag time best described the data. The covariate model including fat-free mass (FFM) on volume of distribution (V/F) and on maximum elimination rate (Vmax/F) lowered the objective function value (OFV) by 56.4. The second-best covariate model of sex on V/F and Vmax/F and BW on V/F reduced the OFV by 51.2. The decrease in unexplained inter-individual variability on Vmax/F in both covariate models was similar. For a given dose, MCS showed lower exposure to rifampicin with higher FFM and accordingly in males compared to females with the same BW and body height. Our results indicate that beyond BW, body composition as reflected by FFM could also be relevant for optimized dosing of rifampicin. This assumption needs to be studied further in patients treated with rifampicin.

Population pharmacokinetic modelling and simulation of tranexamic acid in adult trauma patients.

The aim of this study is to describe the disposition of tranexamic acid (TXA) in adult trauma patients and derive a dosing regimen that optimizes exposure based on a predefined exposure target. We performed a population pharmacokinetic (popPK) analysis of participants enrolled in the Tranexamic Acid Mechanisms and Pharmacokinetics in Traumatic Injury (TAMPITI) trial (≥18 years with traumatic injury, given ≥1 blood product and/or requiring immediate transfer to the operating room) who were randomized to a single dose of either 2 or 4g of TXA ≤2h from time of injury. PopPK analysis was conducted using nonlinear mixed-effects modelling (NONMEM). Simulations were then performed using the final model to generate estimated plasma TXA concentrations in 1000 simulated participants. Dosing schemes were evaluated to determine maintenance of TXA plasma concentrations >10mg/L for ≥8h after administration of the initial dose. TXA PK was best described by a two-compartment model with proportional residual error and allometric scaling on all parameters. Platelet count, skeletal muscle oxygen saturation measured by near-infrared spectroscopy and interleukin-8 concentration were significant covariates on TXA clearance. Based on simulations, a 2g IV bolus dose, repeated 3h later, best achieved the target exposure. According to simulations from a popPK model of TXA, a 2g IV bolus with a repeated dose 3h later would be most likely to maintain concentrations >10mg/L for 8h in >95% of adult trauma patients and should be considered for patients with ongoing haemorrhage.

Population pharmacokinetics of intravenous daptomycin in critically ill patients: implications for selection of dosage regimens

Daptomycin is gaining prominence for the treatment of methicillin-resistant Staphylococcus aureus infections. However, the dosage selection for daptomycin in critically ill patients remains uncertain, especially in Chinese patients. This study aimed to establish the population pharmacokinetics of daptomycin in critically ill patients, optimize clinical administration plans, and recommend appropriate dosage for critically ill patients in China. The study included 64 critically ill patients. Blood samples were collected at the designated times. The blood daptomycin concentration was determined using validated liquid chromatography-tandem mass spectrometry. A nonlinear mixed-effects model was applied for the population pharmacokinetic analysis and Monte Carlo simulations of daptomycin. The results showed a two-compartment population pharmacokinetic model of daptomycin in critically ill adult Han Chinese patients. Monte Carlo simulations revealed that a daily dose of 400 mg of daptomycin was insufficient for the majority of critically ill adult patients to achieve the anti-infective target. For critically ill adult patients with normal renal function (creatinine clearance rate &amp;gt;90 mL/min), the probability of achieving the target only reached 90% when the daily dose was increased to 700 mg. For patients undergoing continuous renal replacement therapy (CRRT), 24 h administration of 500 mg met the pharmacodynamic goals and did not exceed the safety threshold in most patients. Therefore, considering its efficacy and safety, intravenous daptomycin doses are best scaled according to creatinine clearance, and an increased dose is recommended for critically ill patients with hyperrenalism. For patients receiving CRRT, medication is recommended at 24 h intervals.

Recommendation of mavacamten posology by model-based analyses in adults with obstructive hypertrophic cardiomyopathy.

Mavacamten is the first cardiac myosin inhibitor approved by the US Food and Drug Administration for the treatment of adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM). The phase III EXPLORER-HCM (NCT03470545) study used a dose-titration scheme based on mavacamten exposure and echocardiographic assessment of Valsalva left ventricular outflow tract gradient (VLVOTg) and left ventricular ejection fraction (LVEF). Using population pharmacokinetic/exposure-response modeling and simulations of virtual patients, this in silico study evaluated alternative dose-titration regimens for mavacamten, including regimens that were guided by echocardiographic measures only. Mavacamten exposure-response models for VLVOTg (efficacy) and LVEF (safety) were developed using patient data from five clinical studies and characterized using nonlinear mixed-effects models. Simulations of five echocardiography-guided regimens were performed in virtual cohorts constructed based on either expected or equal population distributions of cytochrome P450 2C19 (CYP2C19) metabolizer phenotypes. Each regimen aimed to maximize the proportions of patients who achieved a VLVOTg below 30 mm Hg while maintaining LVEF above 50% over 40 weeks and 104 weeks, respectively. The exposure-response models successfully characterized mavacamten efficacy and safety parameters. Overall, the simulated regimen with the optimal benefit-risk profile across CYP2C19 phenotypes had steps for down-titration at weeks 4 and 8 (for VLVOTg <20 mm Hg), and up-titration at week 12 (for VLVOTg ≥30 mm Hg and LVEF ≥55%), and every 12 weeks thereafter. This simulation-optimized regimen is recommended in the mavacamten US prescribing information.

Penciclovir pharmacokinetics after oral and rectal administration of famciclovir in African elephants (Loxodonta africana) shows that effective concentrations can be achieved from rectal administration, despite lower absorption.

To evaluate the pharmacokinetics of famciclovir and its metabolite penciclovir following a single dose administered orally and rectally in African elephants (Loxodonta africana). 15 African elephants (6 males and 9 females) of various ages. Famciclovir (15 mg/kg) was administered orally or per rectum once, with at least a three-week washout period between administrations. Blood was collected at 13 different timepoints per administration for 6 elephants, occurring between February and March 2020. An additional 9 elephants were sampled at variable timepoints per administration utilizing a sparse sampling design between July 2020 and January 2021. Plasma famciclovir and penciclovir levels were measured via HPLC and fluorescence detection. Pharmacokinetic analysis was completed in the summer of 2021 using noncompartmental analysis and nonlinear mixed-effects modeling. Famciclovir was not detected in any sample, suggesting complete metabolism. Key pharmacokinetic parameters for penciclovir following oral administration were time to maximum concentration (tmax; 2.12 hours), area under the concentration-versus-time curve (AUC; 33.93 μg·h/mL), maximum observed concentration (Cmax; 3.73 μg/mL), and absorption half-life (t1/2; 0.65 hours). Following rectal administration, the values were: tmax, 0.65 hours; AUC, 15.62 μg·h/mL; Cmax, 2.52 μg/mL; and absorption t1/2, 0.13 hours. Famciclovir was rapidly metabolized to penciclovir. Oral administration resulted in slower absorption but higher maximum plasma concentration and higher AUC compared to rectal administration. African elephants administered famciclovir via oral and rectal routes resulted in measurable serum penciclovir, and these findings may be utilized by clinicians treating viral infections in this species.

Characterization and Determinants of Long-Term Immune Recovery Under Suppressive Antiretroviral Therapy.

We developed a robust characterization of immune recovery trajectories in people living with HIV on antiretroviral treatment (ART) and relate our findings to epidemiological risk factors and bacterial pneumonia. Using data from the Swiss HIV Cohort Study and the Zurich Primary HIV Infection Cohort Study (n = 5907), we analyzed the long-term trajectories of CD4 cell and CD8 cell counts and their ratio in people living with HIV on ART for at least 8 years by fitting nonlinear mixed-effects models. The determinants of long-term immune recovery were investigated using generalized additive models. In addition, prediction accuracy of the modeled trajectories and their impact on the fit of a model for bacterial pneumonia was assessed. Overall, our population showed good immune recovery (median plateau [interquartile range]-CD4: 718 [555-900] cells/μL, CD8: 709 [547-893] cells/μL, CD4/CD8: 1.01 [0.76-1.37]). The following factors were predictive of recovery: age, sex, nadir/zenith value, pre-ART HIV-1 viral load, hepatitis C, ethnicity, acquisition risk, and timing of ART initiation. The fitted models proved to be an accurate and efficient way of predicting future CD4 and CD8 cell recovery dynamics: Compared with carrying forward the last observation, mean squared errors of the fitted values were lower by 1.3%-18.3% across outcomes. When modeling future episodes of bacterial pneumonia, using predictors derived from the recovery dynamics improved most model fits. We described and validated a method to characterize individual immune recovery trajectories of people living with HIV on suppressive ART. These trajectories accurately predict long-term immune recovery and the occurrence of bacterial pneumonia.

Prediction of Individual Disease Progression Including Parameter Uncertainty in Rare Neurodegenerative Diseases: The Example of Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS)

The aim of this study was to develop a model to predict individual subject disease trajectories including parameter uncertainty and accounting for missing data in rare neurological diseases, showcased by the ultra-rare disease Autosomal-Recessive Spastic Ataxia Charlevoix Saguenay (ARSACS). We modelled the change in SARA (Scale for Assessment and Rating of Ataxia) score versus Time Since Onset of symptoms using non-linear mixed effect models for a population of 173 patients with ARSACS included in the prospective real-world multicenter Autosomal Recessive Cerebellar Ataxia (ARCA) registry. We used the Multivariate Imputation Chained Equation (MICE) algorithm to impute missing covariates, and a covariate selection procedure with a pooled p-value to account for the multiply imputed data sets. We then investigated the impact of covariates and population parameter uncertainty on the prediction of the individual trajectories up to 5 years after their last visit. A four-parameter logistic function was selected. Men were estimated to have a 25% lower SARA score at disease onset and a moderately higher maximum SARA score, and time to progression (T50) was estimated to be 35% lower in patients with age of onset over 15 years. The population disease progression rate started slowly at 0.1 points per year peaking to a maximum of 0.8 points per year (at 36.8 years since onset of symptoms). The prediction intervals for SARA scores 5 years after the last visit were large (median 7.4 points, Q1-Q3: 6.4–8.5); their size was mostly driven by individual parameter uncertainty and individual disease progression rate at that time.Graphical

Why the racing industry and equestrian disciplines need to implement population pharmacokinetics: To learn, explain, summarize, harmonize, and individualize.

Population pharmacokinetics (POP PK) is a powerful pharmacokinetic tool, which measures quantitatively, and explains the variability in drug exposure and drug effect between individuals. POP PK uses an observational (nonexperimental) approach; it is conducted in the target population living in its normal environment (e.g., farm and race-track). The strength of the POP PK approach lies in its greater relevance for the population studied in its different natural environments than experimental studies carried out in more or less biased laboratory conditions. In clinical settings, it is commonly necessary to restrict the number of samples per subject collected for analysis and the derived data cannot be analyzed using traditional individual data analytical methods; rather data are merged and analyzed with an appropriate statistical tool: the nonlinear mixed effect model (NLMEM). POP PK modeling is frequently used with the objective of adjusting drug dosage, and hence drug exposure, not only for the whole population but also for subgroups of animals (e.g., for a given breed, sex, and age). It can also have application at the individual subject level, in the context of precision medicine. For horses, the use of the POP PK/PD model will allow prescribers to estimate an individual Withdrawal Time for a given horse whose treatment they are supervising. Another potential field of application will be meta-analysis of existing data to generate new knowledge on a drug or to collate and synthesize, in an objective and transparent manner, existing data; this will facilitate harmonization of screening limits at an international level.

Pharmacokinetic Models for Inhaled Fluticasone Propionate and Salmeterol Xinafoate to Quantify Batch-to-Batch Variability.

Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1, R2, T1, T2) of Advair Diskus (100μg FP/50μg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R1 and R2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUCinf) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1µm, < 2µm) had a higher AUCinf. This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study.

Uncertainty Computation at Finite Distance in Nonlinear Mixed Effects Models-a New Method Based on Metropolis-Hastings Algorithm.

The standard errors (SE) of the maximum likelihood estimates (MLE) of the population parameter vector in nonlinear mixed effect models (NLMEM) are usually estimated using the inverse of the Fisher information matrix (FIM). However, at a finite distance, i.e. far from the asymptotic, the FIM can underestimate the SE of NLMEM parameters. Alternatively, the standard deviation of the posterior distribution, obtained in Stan via the Hamiltonian Monte Carlo algorithm, has been shown to be a proxy for the SE, since, under some regularity conditions on the prior, the limiting distributions of the MLE and of the maximum a posterior estimator in a Bayesian framework are equivalent. In this work, we develop a similar method using the Metropolis-Hastings (MH) algorithm in parallel to the stochastic approximation expectation maximisation (SAEM) algorithm, implemented in the saemix R package. We assess this method on different simulation scenarios and data from a real case study, comparing it to other SE computation methods. The simulation study shows that our method improves the results obtained with frequentist methods at finite distance. However, it performed poorly in a scenario with the high variability and correlations observed in the real case study, stressing the need for calibration.

Leishmania blood parasite dynamics during and after treatment of visceral leishmaniasis in Eastern Africa: A pharmacokinetic-pharmacodynamic model.

With the current treatment options for visceral leishmaniasis (VL), recrudescence of the parasite is seen in a proportion of patients. Understanding parasite dynamics is crucial to improving treatment efficacy and predicting patient relapse in cases of VL. This study aimed to characterize the kinetics of circulating Leishmania parasites in the blood, during and after different antileishmanial therapies, and to find predictors for clinical relapse of disease. Data from three clinical trials, in which Eastern African VL patients received various antileishmanial regimens, were combined in this study. Leishmania kinetoplast DNA was quantified in whole blood with real-time quantitative PCR (qPCR) before, during, and up to six months after treatment. An integrated population pharmacokinetic-pharmacodynamic model was developed using non-linear mixed effects modelling. Parasite proliferation was best described by an exponential growth model, with an in vivo parasite doubling time of 7.8 days (RSE 12%). Parasite killing by fexinidazole, liposomal amphotericin B, sodium stibogluconate, and miltefosine was best described by linear models directly relating drug concentrations to the parasite elimination rate. After treatment, parasite growth was assumed to be suppressed by the host immune system, described by an Emax model driven by the time after treatment. No predictors for the high variability in onset and magnitude of the immune response could be identified. Model-based individual predictions of blood parasite load on Day 28 and Day 56 after start of treatment were predictive for clinical relapse of disease. This semi-mechanistic pharmacokinetic-pharmacodynamic model adequately captured the blood parasite dynamics during and after treatment, and revealed that high blood parasite loads on Day 28 and Day 56 after start of treatment are an early indication for VL relapse, which could be a useful biomarker to assess treatment efficacy of a treatment regimen in a clinical trial setting.

Time-Varying Clearance in Milrinone Pharmacokinetics from Premature Neonates to Adolescents.

Milrinone is an inotrope and vasodilator used for prophylaxis or treatment of low cardiac output syndrome after weaning from cardiopulmonary bypass (CPB). It is renally eliminated and has an acceptable therapeutic range of 100-300μg/L, but weight-based dosing alone is associated with poor target attainment. We aimed to develop a population pharmacokinetic model for milrinone from premature neonates to adolescents, and to evaluate how age, renal function and recovery from CPB may impact dose selection. Fifty paediatric patients (aged 4 days to 16 years) were studied after undergoing cardiac surgery supported by CPB. Data from 29 premature neonates (23-28 weeks' postmenstrual age) treated for prophylaxis of low systemic blood flow were available for a pooled pharmacokinetic analysis. Population parameters were estimated using non-linear mixed effects modelling (NONMEM 7.5.1). There were 369 milrinone measurements available for analysis. A one-compartment model with zero-order input and first-order elimination was used to describe milrinone disposition. Population parameters were clearance 17.8L/70kg [95% CI 15.8-19.9] and volume 20.4L/h/70kg [95% CI 17.8-22.1]. Covariates included size, postmenstrual age and renal function for clearance, and size and postnatal age for volume. Milrinone clearance is reduced by 39.5% [95% CI 24.0-53.7] immediately after bypass, and recovers to baseline clearance with a half-time of 12.0h [95% CI 9.7-15.2]. Milrinone volume was 2.07 [95% CI 1.87-2.27] times greater at birth than the population standard and decreased over the first days of life with a half-time of 0.977days [95% CI 0.833-1.12]. Milrinone is predominately renally eliminated and so renal function is an important covariate describing variability in clearance. Increasing clearance over time likely reflects increasing cardiac output and renal perfusion due to milrinone and return to baseline following CPB.

Five multivariate Duchenne muscular dystrophy progression models bridging six-minute walk distance and MRI relaxometry of leg muscles.

The study aimed to provide quantitative information on the utilization of MRI transverse relaxation time constant (MRI-T2) of leg muscles in DMD clinical trials by developing multivariate disease progression models of Duchenne muscular dystrophy (DMD) using 6-min walk distance (6MWD) and MRI-T2. Clinical data were collected from the prospective and longitudinal ImagingNMD study. Disease progression models were developed by a nonlinear mixed-effect modeling approach. Univariate models of 6MWD and MRI-T2 of five muscles were developed separately. Age at assessment was the time metric. Multivariate models were developed by estimating the correlation of 6MWD and MRI-T2 modelvariables. Full model estimation approach for covariate analysis and five-fold cross validation were conducted. Simulations were performed to compare the models and predict the covariate effects on the trajectories of 6MWD and MRI-T2. Sigmoid Imax and Emax models best captured the profiles of 6MWD and MRI-T2 over age. Steroid use, baseline 6MWD, and baseline MRI-T2 were significant covariates. The median age at which 6MWD is half of its maximum decrease in the five models was similar, while the median age at which MRI-T2 is half of its maximum increase varied depending on the type of muscle. The models connecting 6MWD and MRI-T2 successfully quantified how individual characteristics alter disease trajectories. The models demonstrate a plausible correlation between 6MWD and MRI-T2, supporting the use of MRI-T2. The developed models will guide drug developers in using the MRI-T2 to most efficient use in DMD clinical trials.

Saliva monitoring of prednisolone in children with first onset steroid-sensitive nephrotic syndrome: Is it possible?

Prednisolone is the cornerstone of treatment for idiopathic nephrotic syndrome in children, but is associated with marked side-effects. Therapeutic drug monitoring using saliva would be a patient-friendly option to monitor prednisolone treatment. To assess the feasibility of saliva monitoring, we described the pharmacokinetics (PK) of unbound prednisolone in plasma and saliva of children with first onset steroid-sensitive nephrotic syndrome (SSNS). Children (age 2-16 years) with SSNS participating in a randomized, placebo-controlled trial with levamisole were treated with an 18-week tapering schedule of prednisolone. Five serial samples were collected at 4 (saliva) and 8weeks (saliva and plasma) after first onset. A nonlinear mixed-effects model was used to estimate the PK parameters of unbound prednisolone and the saliva-to-plasma ratio. Monte Carlo simulations were performed to assess the predictive performance of saliva monitoring. From 39 children, 109 plasma and 275 saliva samples were available. Estimates (relative squared error) of unbound plasma clearance and volume of distribution were 93 (5%) L h-1 70 kg-1 and 158 (7%) L 70 kg-1, respectively. Typical saliva-to-plasma ratio was 1.30 (8%). Monte Carlo simulations demonstrated that on basis of 4 saliva samples and a single plasma sample unbound plasma area-under-the-concentration-time curve can be predicted within 20% imprecision in 79% of the patients compared to 87% based on 4 plasma samples. Saliva proved to be a reliable and patient-friendly option to determine prednisolone plasma exposure in children with SSNS. This opens opportunities for further PK and pharmacodynamics studies of prednisolone in a variety of paediatric conditions.

Correction to: Bayesian high-dimensional covariate selection in non-linear mixed-effects models using the SAEM algorithm

Correction to: Bayesian high-dimensional covariate selection in non-linear mixed-effects models using the SAEM algorithm

Population pharmacokinetics and dosing optimization of perampanel in children with epilepsy: A real-world study.

The purposes of this study were to explore the pharmacokinetics of perampanel (PER) in children with epilepsy, identify factors that contribute to pharmacokinetic variations among subjects, evaluate the connection between PER exposure and clinical outcome, and establish an evidence-based approach for tailoring individualized antiepileptic treatment in this specific population. In this prospective study, PER plasma concentrations and genetic information on metabolic enzymes were obtained from 194 patients younger than 18 years. The disposition kinetics of PER in pediatric patients following oral dosing were characterized using nonlinear mixed effect models. The effective range for the plasma concentration of PER was determined by assessing the efficacy and safety of PER treatment and analyzing the relationship between drug exposure and clinical response. Monte Carlo simulations were then performed to evaluate and optimize the current dosing regimens. The pharmacokinetic profile of PER was adequately described by a one-compartment model with first-order absorption and elimination. Body weight, total bilirubin level, and concomitant oxcarbazepine were found to have significant influences on PER pharmacokinetics. Model estimates of apparent clearance and volume of distribution were .016 ± .009 L/h/kg and 1.47 ± .78 L/kg, respectively. The effective range predicted from plasma concentration data in responders was 215-862 μg/L. Dosing scenarios stratified according to essential covariates were proposed through simulation analysis. In this study, we captured the pharmacokinetic/pharmacodynamic characteristics of PER in pediatric epilepsy patients through analysis of real-world data and adopted a pharmacometric approach to support an individualized dosing strategy for PER in this specific population.

High-Dose Isoniazid Lacks EARLY Bactericidal Activity Against Isoniazid-resistant Tuberculosis Mediated by katG Mutations: A Randomized, Phase 2 Clinical Trial.

Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis (MDR-TB). However, its activity against Mycobacterium tuberculosis (M.tb) with katG mutations (which typically confer high-level resistance) is not established. To characterize early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG-mutated M.tb. A5312 was a Phase 2A randomized, open-label trial. Participants with tuberculosis caused by katG-mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive PK sampling was performed on day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA-mutated, and katG-mutated M.tb). EBA was determined using nonlinear mixed-effects modelling. Of 80 treated participants, 21 had katG-mutated M.tb. Isoniazid PK was best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived Cmax and AUC in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg∙h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal Emax relationship. Isoniazid potency against katG-mutated M.tb was approximately 10-fold lower than against inhA-mutated M.tb. The highest dose (20 mg/kg) did not demonstrate measurable EBA, except in a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG-mutated M.tb. Clinical trial registration available at www. gov, ID: NCT01936831.

Weather influenced nestling growth of an insectivorous but not a granivorous grassland passerine in Argentina

Nestling growth of birds can be affected by weather fluctuations. In general, it is expected that higher temperatures favor growth by improving food availability and nestling metabolism, while rain hinders it by reducing foraging efficiency. However, most of these patterns have been described in insectivorous cavity-nesting birds in temperate forests. We tested these predictions in two neotropical grassland ground-nesting birds with contrasting nestling diets and therefore potentially different responses to weather. We measured nestlings of the Hellmayr's Pipit (Anthus hellmayri, an insectivorous passerine) and the Grassland Yellow-Finch (Sicalis luteola, which feeds its nestlings exclusively with seeds) during three breeding seasons (2017–2020) in central-eastern Argentina. We took measurements of tarsus and body mass, modeled growth curves using nonlinear mixed-effects models, and evaluated the effects of minimum daily temperature and precipitation during the growth period and the 30 days prior to hatching. For pipits (60 nestlings from 21 nests), minimum temperatures during the growth period were positively associated with tarsus and body mass asymptotes. Also, there was a positive association between precipitation during the pre-hatching period and tarsus asymptote. Conversely, none of the weather variables analyzed had significant effects on nestling growth of finches (131 nestlings from 35 nests). Dietary contrast between species may explain the different results. Arthropod activity and abundance can be affected by weather variations within the span of a breeding season, whereas seeds may depend on conditions from previous years, making the effects harder to detect. Fledglings with reduced asymptotic size can have reduced chances of survival. Hence, pipit populations could be impacted if they experience cold and dry conditions during their breeding season, which is of major relevance in the current context of climate change.

Population pharmacokinetic study of imipramine in Taiwan people healthy volunteers

Imipramine is an antidepressant drug (ADs) that shows therapeutic efficacy in a maximum of 60–80% of patients who have experienced a major depressive episode (unipolar or bipolar). The purpose of the study was to investigate the pharmacokinetics of a multi-oral dose of Imipramine 25 mg tablet in a Taiwan healthy population. The study was a standard two-way, crossover, randomized, and single dose daily for 5 days study with a two-week washout period in 30 healthy volunteers who received 25 mg imipramine tablets (test and reference formulation). After drug administration, blood samples were taken according to the planned times over a period of 24 hours. The plasma concentrations of Imipramine were determined using the validated high-performance liquid chromatography method with ultraviolet detection. All the pharmacokinetic parameters for Imipramine in healthy volunteers were calculated using nonlinear mixed-effect modeling and standard non-compartmental methods. Values (relative standard error (RSE) %) for first-order absorption rate constant (Ka), oral clearance (Cl/F), and apparent volume of distribution (Vd/F) were 1.05 (7.11) 1/h, 6.99(0.27) L/h, and 71.7.9(4.80) L. The median for the time to peak plasma Imipramine concentration (Tmax) for the test and reference drug was 2(1.1-4) hours and 4(1.9-5) hours respectively. In conclusion, the imipramine pharmacokinetic model in the Taiwan healthy population was similar to other studied populations.