Nonlinear Mixed-effects Approach Research Articles

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.

Pharmacokinetic Evaluation of Oral Viscous Budesonide in Paediatric Patients with Eosinophilic Oesophagitis in Repaired Oesophageal Atresia

Eosinophilic oesophagitis is a long-term complication of oesophageal atresia (EA), an uncommon condition that affects approximately 1 in 3500 infants. An exploratory, open-label phase 2 clinical trial was conducted in paediatric eosinophilic oesophagitis after oesophageal atresia (EoE-EA) to assess the safety, pharmacokinetics, and efficacy of oral viscous budesonide (OVB). In total, eight patients were enrolled in the study and assigned to a twice-daily dosing regimen of either 0.8 or 1 mg OVB, depending on age and height, administered for 12 weeks. OVB was safe and effective in the treatment of EoE-EA. The current investigation focuses on the pharmacokinetics of budesonide and the impact of an oral viscous formulation on its absorption and bioavailability. Using a non-linear mixed effects approach, two distinct absorption profiles were identified, despite marked interindividual variability in drug concentrations. Budesonide exposure was higher than previously reported in children following oral inhalation. Even though no significant effect has been observed on serum cortisol levels, future studies should consider exploring different doses, schedules, and/or treatment durations, as there may be an opportunity to reduce the risk of cortisol suppression.

Pharmacokinetics of N-acetyl-l-cysteine in chickens.

N-acetyl-l-cysteine (NAC) has been suggested as an antioxidant that can alleviate the negative effects of stress conditions in broilers. However, knowledge of its pharmacokinetics (PK) in this avian species is very limited. Therefore, the study aimed to shed more light on the PK properties of NAC in chickens. Broilers were subjected to single intravenous (i.v.) or oral (p.o.) treatment or multiple NAC administrations via the feed. Drug concentrations were determined by LC-MS/MS, and the data were subjected to non-compartmental analysis and modeled by non-linear mixed effect approach. NAC was eliminated in a short time after i.v. treatment, with a t1/2el of 0.93 (0.59-2.09) h. It showed limited distribution with population mean of volumes of distribution in the central and peripheral compartments V1 of 0.148 L/kg and V2 of 0.199 L/kg, respectively, and Vdarea of 0.39 (0.258-0.635) L/kg. The value of MRT was 1.76 h (range of 0.96-2.69, p < .05) after single p.o. treatment, indicating a twofold increase if compared to i.v. administration (0.87 h, 0.55-1.78). Both methods of Pk analysis revealed very limited bioavailability, <10%. Feeding behavior led to a later achievement of lower maximum plasma concentrations (5.74, range of 3.44-9.32 μg/mL, p < .05), which were maintained during the 5 days of treatment.

Factors Influencing Quetiapine Pharmacokinetic Variability: A Review of Population Pharmacokinetics

Abstract: Atypical antipsychotic quetiapine (QTP) exhibits high pharmacokinetic variability and population pharmacokinetic (PopPK) analysis is one of the approaches used to characterize factors influencing QTP pharmacokinetic variability. Though QTP is not regarded as a narrow therapeutic index drug, knowledge of this area is of importance. Thus, this review was conducted to summarize significant predictors for QTP pharmacokinetic variability identified using a PopPK analysis and to explore any knowledge gaps to be investigated. PubMed, Scopus, and CINAHL Complete databases were searched for eligible studies, and 75 articles were identified. Of these, only five studies were included as they were conducted using a nonlinear mixed-effects approach. This review found that only limited predictors for QTP pharmacokinetics were identified, with body weight being a predictor for the volume of distribution and age and γ-glutamyl transpeptidase being predictors for QTP clearance. None of the studies included elderly patients aged &gt;65 years, and thus factors associated with aging were not investigated. Also, most of the participants in the PopPK analyses were from clinical trials which might not reflect real-world patients e.g., the impacts of polypharmacy may not be available. Moreover, while a population pharmacokinetic-pharmacodynamic model explaining QTP exposure and clinical response using the scores of the Brief Psychiatric Rating Scale is available, knowledge relevant to the relationship between exposure and QTP side effects has not been explored. Based on this limited information, future PopPK research encompassing a wide range of patient characteristics is required.

A Population Pharmacokinetic Study to Compare a Novel Empagliflozin L-Proline Formulation with Its Conventional Formulation in Healthy Subjects.

Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is commonly used for the treatment of type 2 diabetes mellitus (T2DM). CKD-370 was newly developed as a cocrystal formulation of empagliflozin with co-former L-proline, which has been confirmed to be bioequivalent in South Korea. This study aimed to quantify the differences in the absorption phase and pharmacokinetic (PK) parameters of two empagliflozin formulations in healthy subjects by using population PK analysis. The plasma concentration data of empagliflozin were obtained from two randomized, open-label, crossover, phase 1 clinical studies in healthy Korean subjects after a single-dose administration. A population PK model was constructed by using a nonlinear mixed-effects (NLME) approach (Monolix Suite 2021R1). Interindividual variability (IIV) and interoccasion variability (IOV) were investigated. The final model was evaluated by goodness-of-fit (GOF) diagnostic plots, visual predictive checks (VPCs), prediction errors, and bootstrapping. The PK of empagliflozin was adequately described with a two-compartment combined transit compartment model with first-order absorption and elimination. Log-transformed body weight significantly influenced systemic clearance (CL) and the volume of distribution in the peripheral compartment (V2) of empagliflozin. GOF plots, VPCs, prediction errors, and the bootstrapping of the final model suggested that the proposed model was adequate and robust, with good precision at different dose strengths. The cocrystal form did not affect the absorption phase of the drug, and the PK parameters were not affected by the different treatments.

Effect of Individual Patient Characteristics and Treatment Choices on Reliever Medication Use in Moderate-Severe Asthma: A Poisson Analysis of Randomised Clinical Trials.

Even though increased use of reliever medication, including short-acting beta agonists (SABA), provides an indirect measure of symptom worsening, there have been limited efforts to assess how different patterns of reliever use correlate with symptom control and future risk of exacerbations. Here, we evaluate the effect of individual baseline characteristics on reliever use in patients with moderate-severe asthma on regular maintenance therapy with fluticasone propionate (FP) or combination therapy with fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR). A drug-disease model describing the number of 24-h puffs and overnight occasions was developed with data from five clinical studies (N = 6212). The model was implemented using a nonlinear mixed effects approach and a Poisson function, considering clinical and demographic baseline characteristics. Goodness of fit and model predictive performance were assessed. Heatmaps were created to summarise the effect of concurrent baseline factors on reliever utilisation. The final model accurately described individual patterns of reliever use, which is significantly increased with time since diagnosis, smoking, higher Asthma Control Questionnaire (ACQ-5) score and higher body mass index (BMI) at baseline. Whilst the number of puffs decreases slowly after an initial drop relative to the start of treatment, exacerbating patients utilise significantly more reliever than those who do not exacerbate. The mean effect of FP/SAL (median dose: 250/50μg BID) on reliever use was slightly higher than that of BUD/FOR (median dose: 160/4.5μg BID), i.e. a 75.3% vs 69.3% reduction in reliever use, respectively. The availability of individual-level patient data in conjunction with a parametric approach enabled the characterisation of interindividual differences in the patterns of reliever use in patients with moderate-severe asthma. Taken together, individual demographic and clinical characteristics, as well as exacerbation history, can be considered an indicator of the degree of asthma control. High SABA reliever use suggests suboptimal clinical management of patients on maintenance therapy.

Tofacitinib pharmacokinetics in children and adolescents with juvenile idiopathic arthritis.

These analyses characterized tofacitinib pharmacokinetics (PKs) in children and adolescents with juvenile idiopathic arthritis (JIA). Data were pooled from phase I (NCT01513902), phase III (NCT02592434), and open-label, long-term extension (NCT01500551) studies of tofacitinib tablet/solution (weight-based doses administered twice daily [b.i.d.]) in patients with JIA aged 2 to less than 18 years. Population PK modeling used a nonlinear mixed-effects approach, with covariates identified using stepwise forward-inclusion backward-deletion procedures. Simulations were performed to derive dosing recommendations for children and adolescents with JIA. Two hundred forty-six pediatric patients were included in the population PK model. A one-compartment model with first-order elimination and absorption with body weight as a covariate for oral clearance and apparent volume of distribution sufficiently described the data. Oral solution was associated with comparable average concentration (Cavg) and slightly higher (113.9%) maximum concentration (Cmax) versus tablet, which was confirmed by a subsequent randomized, open-label, bioavailability study conducted in healthy adult participants (n = 12) by demonstrating adjusted geometric mean ratios (90% confidence interval) between oral solution and tablet of 1.04 (1.00-1.09) and 1.10 (1.00-1.21) for area under the curve extrapolated to infinity and Cmax, respectively (NCT04111614). A dosing regimen of 3.2 mg b.i.d. solution in patients 10 to less than 20 kg, 4 mg b.i.d. solution in patients 20 to less than 40 kg, and 5 mg b.i.d. tablet/solution in patients greater than or equal to 40 kg, irrespective of age, was proposed to achieve constant Cavg across weight groups. In summary, population PK characterization informed a simplified tofacitinib dosing regimen that has been implemented in pediatric patients with JIA.

The Minimum Target Diameter and the Harvest Age of Oak Natural Secondary Forests in Different Sites Conditions: Case Study in Hunan Province, China

Maintaining permanent forest canopy cover and eventually harvesting timber by predetermined target diameter are often considered as a prototype for future management of the oak natural forest. However, target diameters and harvest age based on average forest growth rates from wide geographical areas often hamper improved management of oak forests. In this study, based on the sampling of 129 target trees from 51 oak natural secondary forest plots in Hunan Province, China, an individual-tree DBH (diameter at breast height) growth model of oak target trees was developed, and the site type (41 levels) was related to the model as random effects by a nonlinear mixed-effects approach. Moreover, the 41 site types were clustered into four site type groups (STG1, STG2, STG3, and STG4) by the K-means clustering algorithm to improve the model performance and practicality. With the help of the model, the five target diameters (including 24, 30, 40, 50, and 60 cm) were simulated in each of the four STGs, and the minimum target diameter was determined for each STG based on the theory of quantitative maturity. In the four STGs, the harvest age of the 24 cm diameter target ranged from 30 to 51 years; the harvest age of the 60 cm target diameter ranged from 131 to 220 years, with the oaks failing to reach 60 cm in the lowest-quality STG4; the minimum target diameter ranged from 21 cm to 29 cm. Results showed that lower-quality sites exclude higher target diameters from optimal harvesting strategies, in contrast to the higher target diameter as a more reasonable strategy in higher quality sites, and that the minimum target diameter is significantly influenced by site conditions. Therefore, it is necessary to develop a diverse target-diameter-harvesting strategy adapted for the complex site conditions of oak forests in Hunan Province towards site-specific timber management to improve the sustainability of timber production in oak forests.

Comparing the impact of atezolizumab plus bevacizumab and lenvatinib on the liver function in hepatocellular carcinoma patients: A mixed-effects regression model approach.

This retrospective study compared the impact of atezolizumab plus bevacizumab (Atez/Bev) and lenvatinib (LEN) on the liver function in patients with hepatocellular carcinoma. We included 526 patients who received Atez/Bev and 731 who received LEN March 2018 and July 2022 in this study. We conducted a 1:1 propensity-score-matched analysis and identified 324 patients in each group for inclusion in the present analysis. Nonlinear mixed-effects regression models were employed, allowing for the evaluation and inclusion of cases where treatment was interrupted due to disease progression, adverse events, or loss to follow-up. These models were used to compare the ALBI score between the Atez/Bev and LEN groups. Following propensity score matching, the mean ALBI scores in the Atez/Bev and LEN groups were -2.41 ± 0.40 and -2.44 ± 0.42 at baseline, and -2.17 ± 0.56 and -2.19 ± 0.58 at 12 weeks, respectively. Although the ALBI score significantly worsened during treatment in both groups (p < 0.001), there was no significant difference in the rate of ALBI score deterioration between the groups (p = 0.06). Subgroup analyses showed that LEN-treated patients with BCLC advanced stage (p = 0.02) and those who initially received the full dose (p < 0.001) had a significantly greater worsening of ALBI score compared to Atez/Bev. Using a nonlinear mixed-effects regression approach, which allowed for the inclusion of cases with treatment interruption, we found no significant difference in the trend of liver function deterioration between the Atez/Bev and LEN groups. Caution should be exercised for LEN-treated patients with BCLC advanced stage or those receiving the full dose of LEN.

Characterization of anti-drug antibody dynamics using a bivariate mixed hidden-markov model by nonlinear-mixed effects approach

Biological therapies may act as immunogenic triggers leading to the formation of anti-drug antibodies (ADAs). Population pharmacokinetic (PK) models can be used to characterize the relationship between ADA and drug disposition but often rely on the ADA bioassay results, which may not be sufficiently sensitive to inform on this characterization.In this work, a methodology that could help to further elucidate the underlying ADA production and impact on the drug disposition was explored. A mixed hidden-Markov model (MHMM) was developed to characterize the underlying (hidden) formation of ADA against the biologic, using certolizumab pegol (CZP), as a test drug. CZP is a PEGylated Fc free TNF-inhibitor used in the treatment of rheumatoid arthritis and other chronic inflammatory diseases.The bivariate MHMM used information from plasma drug concentrations and ADA measurements, from six clinical studies (n = 845), that were correlated through a bivariate Gaussian function to infer about two hidden states; production and no-production of ADA influencing PK. Estimation of inter-individual variability was not supported in this case. Parameters associated with the observed part of the model were reasonably well estimated while parameters associated with the hidden part were less precise. Individual state sequences obtained using a Viterbi algorithm suggested that the model was able to determine the start of ADA production for each individual, being a more assay-independent methodology than traditional population PK. The model serves as a basis for identification of covariates influencing the ADA formation, and thus has the potential to identify aspects that minimize its impact on PK and/or efficacy.

FRI478 Pharmacometrics-based Computer Model Utilizing Heart Rate To Monitor Thyroid Function In Children With Graves' Disease

Abstract Disclosure: B. Steffens: None. G. Koch: None. F. Claude: None. F. Bachmann: None. J. Schropp: None. M. Janner: None. D. l'Allemand: None. D. Konrad: None. M. Pfister: None. G. Szinnai: None. Graves’ disease (GD) with onset in childhood or adolescence is a pediatric rare disease (ORPHA:525731) with a ten times lower incidence than in adults. Leading clinical signs of hyperthyroidism are sinus tachycardia, weight loss, tremor, and goiter. First-line treatment are anti-thyroid drugs in order to normalize thyroid function. However, dose finding in pediatric GD is complex due to a broad spectrum of disease severity at diagnosis, and highly variable disease activity during follow-up, especially during puberty. As thyroid hormones have a strong positive chronotropic effect, heart rate (HR) turns out to be a useful clinical marker to monitor thyroid activity under treatment. Our overall aim was to provide a practical pharmacometrics-based (PMX-based) computer model characterizing both, individual FT4 dynamics and the relation between FT4 and tachycardia in children with various disease severity of GD during the first 120 days of treatment. Development of the PMX computer model was based on the non-linear mixed effects approach (i) linking FT4 kinetics with HR dynamics, (ii) accounting for inter-individual variability, and (iii) incorporating individual patient characteristics. Retrospectively collected clinical (resting heart rate during consultation) and laboratory data (FT4) from 41 children and adolescents with GD at four pediatric hospitals in Switzerland (75% female, median age 11.2 [IQR 8.5, 13.5] years) with 187 FT4 measurements and 132 HR measurements, and 124 paired measurements, were available and used for model development. Pediatric patients showed median FT4 of 59.6 [IQR 44.5, 73.0] pmol/l and median HR of 112 [IQR 100, 128] bpm at diagnosis. GD severity groups were defined based on FT4 measurement at diagnosis, resulting in equal numbers of mild (13), moderate (14) and severe (14) GD. We observed a significant difference in HR at diagnosis (p &amp;lt; 0.01) between the three GD severity groups based on FT4 at diagnosis. The final PMX computer model accounted for inter-individual variability and clinically relevant covariate effects such as age, gender, and GD severity, and was able to accurately predict FT4 and HR dynamics for each individual patient during the first 120 days of treatment. A PMX-based computer model that leverages individual HR dynamics can be applied to facilitate personalized pharmacotherapy in pediatric GD and mitigate the risk for under- or overdosing of anti-thyroid drugs in these patients. Prospective randomized validation trials are warranted to further validate and fine-tune such computer-supported personalized dosing in children with Graves’ disease. Presentation: Friday, June 16, 2023

A physiologically based pharmacokinetic model for V937 oncolytic virus in mice.

Introduction: Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a direct and/or immune-induced tumor lysis. However, the mechanisms governing OV pharmacokinetics are still poorly understood. This work aims to develop a physiologically based pharmacokinetic model of the novel OV, V937, in non-tumor-bearing mice to get a quantitative understanding of its elimination and tissue uptake processes. Materials and methods: Model development was performed using data obtained from 60 mice. Viral levels were quantified from eight tissues after a single intravenous V937 dose. An external dataset was used for model validation. This test set included multiple-dose experiments with different routes of administration. V937 distribution in each organ was described using a physiological structure based on mouse-specific organ blood flows and volumes. Analyses were performed using the non-linear mixed-effects approach with NONMEM 7.4. Results: Viral levels showed a drop from 108 to 105 copies/µg RNA at day 1 in blood, reflected in a high estimate of total clearance (18.2mL/h). A well-stirred model provided an adequate description for all organs except the muscle and heart, where a saturable uptake process improved data description. The highest numbers of viral copies were observed in the brain, lymph node, kidney, liver, lung, and spleen on the first day after injection. On the other hand, the maximum amount of viral copies in the heart, muscle, and pancreas occurred 3days after administration. Conclusion: To the best of our knowledge, this is the first physiologically based pharmacokinetic model developed to characterize OV biodistribution, representing a relevant source of quantitative knowledge regarding the in vivo behavior of OVs. This model can be further expanded by adding a tumor compartment, where OVs could replicate.

Pharmacokinetics, safety, and efficacy of GM1 ganglioside in healthy subjects and patients with multiple myeloma: Two dose-escalation studies

PurposeThis study aimed to assess the pharmacokinetics, safety, and efficacy of GM1 in healthy Chinese subjects and patients with multiple myeloma. MethodsThe data used in this study was derived from two dose-escalation trials: GM1-101, involving 70 healthy subjects, and GM1-201, which included 160 multiple myeloma patients. Population pharmacokinetics (PopPK) analysis was conducted on a subset of 90 participants using a nonlinear mixed-effects approach, and potential covariates were explored quantitatively. Observations of any abnormalities in vital signs, physical examinations, laboratory tests, and electrocardiograms during the study period, along with any spontaneously reported and directly observed adverse events, were documented for safety evaluation. Furthermore, neurotoxicity scales were used to assess the efficacy of GM1 as a prophylaxis for chemotherapy-induced peripheral neuropathy and to perform exposure-response analyses in conjunction with pharmacokinetic parameters. ResultsA one-compartment model with first-order elimination best characterized the pharmacokinetics of GM1. The clearance and volume of distribution, as estimated by the final model, were 0.0942 L/h and 3.27 L for GM1-A, and 0.0714 L/h and 2.82 L for GM1-B, respectively. Covariates such as sex, body weight, and albumin significantly influenced pharmacokinetic parameters, yet the variation in steady-state exposure between subjects and reference subjects was less than 45% within their 90% confidence interval. Adverse reactions related to GM1 occurred in 20 (28.6%) and 57 (35.6%) subjects in the GM1-101 and GM1-201 cohorts, respectively. The changes in TNSc and FACT-Ntx scores from baseline at the end of periods 4 and 6 were lower in each GM1 dose group compared to the blank control group. The 400 mg dose group of GM1 displayed greater effectiveness than other dose groups. However, exposure-response analysis revealed no significant modification in efficacy with increasing GM1 exposure. ConclusionsThis study provides the first population pharmacokinetic analysis of GM1. GM1 exhibits a favorable safety profile among healthy subjects and patients with multiple myeloma. GM1 proved effective in mitigating chemotherapy-induced peripheral neuropathy, but this study observed no significant correlation between its efficacy and exposure. Trial registration numbersChiCTR2000041283 and ChiCTR2000041283

Population Pharmacokinetics of Difloxacin in Crucian Carp (Carassius auratus) after a Single Oral Administration.

This study aimed to investigate the population pharmacokinetics of difloxacin in crucian carp (Carassius auratus) orally provided a single dose of 20 mg/kg body weight (BW). To achieve this, fish were sampled at various intervals using a sparse sampling strategy, and plasma samples were analyzed using the high-performance liquid chromatography (HPLC) method. Subsequently, naïve average data were analyzed using a non-compartmental method, and a population model was developed based on the nonlinear mixed effects approach. The covariate of BW and the relationship between covariances were sequentially incorporated into the population model. However, it was found that only covariance and not BW affected the population parameters. Therefore, the covariance model was taken as the final population model, which revealed that the typical values of the absorption rate constant (tvKa), apparent volume of distribution per bioavailability (tvV), and clearance rate per bioavailability (tvCl) were 1.18 1/h, 14.18 L/kg, and 0.20 L/h/kg, respectively. Based on the calculated free AUC/MIC values, the current oral dose of difloxacin (20 mg/kg BW) cannot generate adequate plasma concentrations to inhibit pathogens with MIC values above 0.83 μg/mL. Further study should be carried out to collect the pathogens from crucian carp and determine the MIC data of difloxacin against them. Pharmacodynamic experiments must also be further carried out to determine the optimal therapeutic dose for the treatment of Aeromonas hydrophila infection.

Model-based assessment of combination therapies – ranking of radiosensitizing agents in oncology

BackgroundTo increase the chances of finding efficacious anticancer drugs, improve development times and reduce costs, it is of interest to rank test compounds based on their potential for human use as early as possible in the drug development process. In this paper, we present a method for ranking radiosensitizers using preclinical data.MethodsWe used data from three xenograft mice studies to calibrate a model that accounts for radiation treatment combined with radiosensitizers. A nonlinear mixed effects approach was utilized where between-subject variability and inter-study variability were considered. Using the calibrated model, we ranked three different Ataxia telangiectasia-mutated inhibitors in terms of anticancer activity. The ranking was based on the Tumor Static Exposure (TSE) concept and primarily illustrated through TSE-curves.ResultsThe model described data well and the predicted number of eradicated tumors was in good agreement with experimental data. The efficacy of the radiosensitizers was evaluated for the median individual and the 95% population percentile. Simulations predicted that a total dose of 220 Gy (5 radiation sessions a week for 6 weeks) was required for 95% of tumors to be eradicated when radiation was given alone. When radiation was combined with doses that achieved at least 8 mu mathrm{g}/mathrm{mL} of each radiosensitizer in mouse blood, it was predicted that the radiation dose could be decreased to 50, 65, and 100 Gy, respectively, while maintaining 95% eradication.ConclusionsA simulation-based method for calculating TSE-curves was developed, which provides more accurate predictions of tumor eradication than earlier, analytically derived, TSE-curves. The tool we present can potentially be used for radiosensitizer selection before proceeding to subsequent phases of the drug discovery and development process.

Clinically practical pharmacometrics computer model to evaluate and personalize pharmacotherapy in pediatric rare diseases: application to Graves' disease.

Graves' disease (GD) with onset in childhood or adolescence is a rare disease (ORPHA:525731). Current pharmacotherapeutic approaches use antithyroid drugs, such as carbimazole, as monotherapy or in combination with thyroxine hormone substitutes, such as levothyroxine, as block-and-replace therapy to normalize thyroid function and improve patients' quality of life. However, in the context of fluctuating disease activity, especially during puberty, a considerable proportion of pediatric patients with GD is suffering from thyroid hormone concentrations outside the therapeutic reference ranges. Our main goal was to develop a clinically practical pharmacometrics computer model that characterizes and predicts individual disease activity in children with various severity of GD under pharmacotherapy. Retrospectively collected clinical data from children and adolescents with GD under up to two years of treatment at four different pediatric hospitals in Switzerland were analyzed. Development of the pharmacometrics computer model is based on the non-linear mixed effects approach accounting for inter-individual variability and incorporating individual patient characteristics. Disease severity groups were defined based on free thyroxine (FT4) measurements at diagnosis. Data from 44 children with GD (75% female, median age 11 years, 62% receiving monotherapy) were analyzed. FT4 measurements were collected in 13, 15, and 16 pediatric patients with mild, moderate, or severe GD, with a median FT4 at diagnosis of 59.9 pmol/l (IQR 48.4, 76.8), and a total of 494 FT4 measurements during a median follow-up of 1.89 years (IQR 1.69, 1.97). We observed no notable difference between severity groups in terms of patient characteristics, daily carbimazole starting doses, and patient years. The final pharmacometrics computer model was developed based on FT4 measurements and on carbimazole or on carbimazole and levothyroxine doses involving two clinically relevant covariate effects: age at diagnosis and disease severity. We present a tailored pharmacometrics computer model that is able to describe individual FT4 dynamics under both, carbimazole monotherapy and carbimazole/levothyroxine block-and-replace therapy accounting for inter-individual disease progression and treatment response in children and adolescents with GD. Such clinically practical and predictive computer model has the potential to facilitate and enhance personalized pharmacotherapy in pediatric GD, reducing over- and underdosing and avoiding negative short- and long-term consequences. Prospective randomized validation trials are warranted to further validate and fine-tune computer-supported personalized dosing in pediatric GD and other rare pediatric diseases.

Development of a Predictive Dosing Nomogram to Achieve PK/PD Targets of Amikacin Initial Dose in Critically Ill Patients: A Non-Parametric Approach.

French guidelines recommend reaching an amikacin concentration of ≥8 × MIC 1 h after beginning infusion (C1h), with MIC = 8 mg/L for probabilistic therapy. We aimed to elaborate a nomogram guiding clinicians in choosing the right first amikacin dose for ICU patients in septic shock. A total of 138 patients with 407 observations were prospectively recruited. A population pharmacokinetic model was built using a non-parametric, non-linear mixed-effects approach. The total body weight (TBW) influenced the central compartment volume, and the glomerular filtration rate (according to the CKD-EPI formula) influenced its clearance. A dosing nomogram was produced using Monte Carlo simulations of the amikacin amount needed to achieve a C1h ≥ 8 × MIC. The dosing nomogram recommended amikacin doses from 1700 mg to 4200 mg and from 28 mg/kg to 49 mg/kg depending on the patient's TBW and renal clearance. However, a Cthrough ≤ 2.5 mg/L 24 h and 48 h after an optimal dose of amikacin was obtained with probabilities of 0.20 and 0.81, respectively. Doses ≥ 30 mg/kg are required to achieve a C1h ≥ 8 × MIC with MIC = 8 mg/L. Targeting a MIC = 8 mg/L should depend on local ecology.

Total and Unbound Pharmacokinetics of Cefiderocol in Critically Ill Patients.

Cefiderocol is a siderophore cephalosporin antibiotic active against Gram-negative bacteria, including extended-spectrum beta-lactamase and carbapenemase-producing strains. The pharmacokinetics of cefiderocol has been studied in healthy subjects and particularly in phase II and III studies. This retrospective study investigated intravenous cefiderocol population pharmacokinetics in adult patients treated by cefiderocol. We studied 55 consecutive patients hospitalized in an intensive care unit. Cefiderocol plasma samples were obtained on different occasions during treatment. Plasma concentration was assayed using mass spectrometry. Data analysis was performed using a non-linear mixed-effect approach via Monolix 2020R1. A total of 205 plasma samples were obtained from 55 patients. Eighty percent of patients received cefiderocol for ventilator-associated pneumonia due to carbapenem-resistant Pseudomonas aeruginosa infection. Cefiderocol concentration time-courses were best fit to a two-compartment open model with first-order elimination. Elimination clearance was positively related to renal function (estimated by the CKD formula). Adding albumin plasma binding in the model significantly improved the model assuming a ~40% unbound drug fraction given a ~40 g/L albuminemia. The final model included CKD plus cefiderocol plasma binding effects. Fat-free mass was better than total body weight to influence, via the allometric rule, clearance and volume terms, but this effect was negligible. The final clearance based on free circulating drug (CLU) for a typical patient, CKD = 90, was 7.38 L/h [relative standard error, RSE, 22%] with a between-subject variability of 0.47 [RSE 10%] (exponential distribution). This study showed that albumin binding and CKD effects were significant predictors of unbound and total plasma cefiderocol concentrations. Our results indicate that individual adjustment of cefiderocol can be used to reach high minimum inhibitory concentrations based on an estimation of unbound drug concentration and optimize therapeutic efficacy.

Novel subcutaneous cytarabine infusion with the Omnipod system in dogs with meningoencephalomyelitis of unknown etiology.

To investigate the feasibility and pharmacokinetics of cytarabine delivery as a subcutaneous continuous-rate infusion with the Omnipod system. 6 client-owned dogs diagnosed with meningoencephalomyelitis of unknown etiology were enrolled through the North Carolina State University Veterinary Hospital. Cytarabine was delivered at a rate of 50 mg/m2/hour as an SC continuous-rate infusion over 8 hours using the Omnipod system. Plasma samples were collected at 0, 4, 6, 8, 10, 12, and 14 hours after initiation of the infusion. Plasma cytarabine concentrations were measured by high-pressure liquid chromatography. A nonlinear mixed-effects approach generated population pharmacokinetic parameter estimates. The mean peak plasma concentration (Cmax) was 7,510 ng/mL (range, 5,040 to 9,690 ng/mL; SD, 1,912.41 ng/mL), average time to Cmax was 7 hours (range, 4 to 8 hours; SD, 1.67 hours), terminal half-life was 1.13 hours (SD, 0.29 hour), and the mean area under the curve was 52,996.82 hours X μg/mL (range, 35,963.67 to 71,848.37 hours X μg/mL; SD, 12,960.90 hours X μg/mL). Cmax concentrations for all dogs were more than 1,000 ng/mL (1.0 μg/mL) at the 4-, 6-, 8-, and 10-hour time points. An SC continuous-rate infusion of cytarabine via the Omnipod system is feasible in dogs and was able to achieve a steady-state concentration of more than 1 μg/mL 4 to 10 hours postinitiation of cytarabine and a Cmax of 7,510 ng/mL (range, 5,040 to 9,690 ng/mL; SD, 1,912.41 ng/mL). These are comparable to values reported previously with IV continuous-rate infusion administration in healthy research Beagles and dogs with meningoencephalomyelitis of unknown etiology.

Modeling venous plasma samples in [18F] FDG PET studies: a nonlinear mixed-effects approach.

The gold-standard approach to quantifying dynamic PET images relies on using invasive measures of the arterial plasma tracer concentration. An attractive alternative is to employ an image-derived input function (IDIF), corrected for spillover effects and rescaled with venous plasma samples. However, venous samples are not always available for every participant. In this work, we used the nonlinear mixed-effects modeling approach to develop a model which infers venous tracer kinetics by using venous samples obtained from a population of healthy individuals and integrating subject-specific covariates. Population parameters (fixed effects), their between-subject variability (random effects), and the effects of covariates were estimated. The selected model will allow to reliably infer venous tracer kinetics in subjects with missing measurements. Clinical relevance - The derived model will be relevant for fully noninvasive dynamic FDG PET quantification using image-derived input functions in both healthy and patient populations when hemodynamics is not impaired.