scholarly journals Population Pharmacokinetic-Pharmacodynamic Analysis of Anidulafungin in Adult Patients with Fungal Infections

2012 ◽  
Vol 57 (1) ◽  
pp. 466-474 ◽  
Author(s):  
Ping Liu
Keyword(s):  
Fungal Infections ◽  
Small Sample Size ◽  
Safety Data ◽  
Area Under The Curve ◽  
Positive Association ◽  
Disease Status ◽  
Small Sample ◽  
Adult Patients ◽  
Population Pharmacokinetic ◽  
Concentration Data

ABSTRACTTo evaluate the exposure-response relationships for efficacy and safety of intravenous anidulafungin in adult patients with fungal infections, a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from 262 patients in four phase 2/3 studies. The plasma concentration data were fitted with a previously developed population PK model. Anidulafungin exposures in patients with weight extremities (e.g., 40 kg and 150 kg) were simulated based on the final PK model. Since the patient population, disease status, and efficacy endpoints varied in these studies, the exposure-efficacy relationship was investigated separately for each study using logistic regression as appropriate. Safety data from three studies (n= 235) were pooled for analysis, and one study was excluded due to concomitant use of amphotericin B as a study treatment and different disease populations. The analysis showed that the same dosing regimen of anidulafungin can be administered to all patients regardless of body weight. Nonetheless, caution should be taken for patients with extremely high weight (e.g., >150 kg). There was a trend of positive association between anidulafungin exposure and efficacy in patients with esophageal candidiasis or invasive candidiasis, including candidemia (ICC); however, adequate characterization of the effect of anidulafungin exposure on response could not be established due to the relatively small sample size. No threshold value for exposure could be established, since patients with low exposure also achieved successful outcomes (e.g., area under the curve < 40 mg · h/liter in ICC patients). There was no association between anidulafungin exposure and the treatment-related adverse events or all-causality hepatic laboratory abnormalities.

scholarly journals Population Pharmacokinetic-Pharmacodynamic Analysis of Voriconazole and Anidulafungin in Adult Patients with Invasive Aspergillosis

2014 ◽  
Vol 58 (8) ◽  
pp. 4727-4736 ◽  
Author(s):  
Ping Liu ◽  
Diane R. Mould
Keyword(s):  
Combination Therapy ◽  
Invasive Aspergillosis ◽  
Treatment Duration ◽  
Area Under The Curve ◽  
Positive Association ◽  
Adult Patients ◽  
Population Pharmacokinetic ◽  
Efficacy And Safety ◽  
Binary Logistic Regression Model ◽  
Double Blind

ABSTRACTTo evaluate the exposure-response relationships for efficacy and safety of voriconazole and anidulafungin in adult patients with invasive aspergillosis (IA), a population pharmacokinetic-pharmacodynamic (PK-PD) analysis was performed with data from a phase 3, prospective, double-blind, comparative study evaluating voriconazole and anidulafungin combination therapy versus voriconazole (and placebo) monotherapy. Anidulafungin/placebo treatment duration was 2 to 4 weeks, and voriconazole treatment duration was 6 weeks. Efficacy (6-week all-causality mortality and 6-week global response [n= 176]) and safety (hepatic [n= 238], visual [n= 199], and psychiatric [n= 183] adverse events [AEs]) endpoints were analyzed separately using a binary logistic regression model. In IA patients receiving voriconazole monotherapy, no positive associations between voriconazole exposure and efficacy or safety were identified. In IA patients receiving combination therapy, no positive associations between voriconazole or anidulafungin exposures and efficacy were identified. The 6-week survival rate tended to increase as anidulafungin treatment duration increased; this finding should be considered with caution. Additionally, in IA patients receiving combination therapy, a positive association between voriconazole and anidulafungin exposures (area under the curve [AUC] and trough concentration [Cmin]) and hepatic AEs was established; a weak positive association between voriconazole exposure (AUC andCmin) and psychiatric AEs was also established, but no association between voriconazole exposure and visual AEs was identified. Besides the drug exposures, no other covariates (i.e., CYP2C19 genotype status, age, weight, body mass index, sex, race, or neutropenia status) were identified as significant predictors of the efficacy and safety endpoints in IA patients. This study was registered onClinicalTrials.gov(NCT00531479).

scholarly journals Population Pharmacokinetics of Amikacin in Adult Patients with Cystic Fibrosis

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Sílvia M. Illamola ◽  
Hoa Q. Huynh ◽  
Xiaoxi Liu ◽  
Zubin N. Bhakta ◽  
Catherine M. Sherwin ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Population Pharmacokinetics ◽  
Drug Disposition ◽  
Adult Patients ◽  
Therapeutic Drug ◽  
Population Pharmacokinetic ◽  
Concentration Data ◽  
First Order ◽  
Dosing Regimens ◽  
Pulmonary Exacerbations

ABSTRACTPractitioners commonly use amikacin in patients with cystic fibrosis. Establishment of the pharmacokinetics of amikacin in adults with cystic fibrosis may increase the efficacy and safety of therapy. This study was aimed to establish the population pharmacokinetics of amikacin in adults with cystic fibrosis. We used serum concentration data obtained during routine therapeutic drug monitoring and explored the influence of patient covariates on drug disposition. We performed a retrospective chart review to collect the amikacin dosing regimens, serum amikacin concentrations, blood sampling times, and patient characteristics for adults with cystic fibrosis admitted for treatment of acute pulmonary exacerbations. Amikacin concentrations were retrospectively collected for 49 adults with cystic fibrosis, and 192 serum concentrations were available for analysis. A population pharmacokinetic model was developed using nonlinear mixed-effects modeling with the first-order conditional estimation method. A two-compartment model with first-order elimination best described amikacin pharmacokinetics. Creatinine clearance and weight were identified as significant covariates for clearance and the volume of distribution, respectively, in the final model. Residual variability was modeled using a proportional error model. Typical estimates for clearance, central and peripheral volumes of distribution, and intercompartmental clearance were 3.06 liters/h, 14.4 liters, 17.1 liters, and 0.925 liters/h, respectively. The pharmacokinetics of amikacin in individuals with cystic fibrosis seems to differ from those in individuals without cystic fibrosis. However, further investigations are needed to confirm these results and, thus, the need for variations in amikacin dosing. Future pharmacodynamic studies will potentially establish the optimal amikacin dosing regimens for the treatment of acute pulmonary exacerbations in adult patients with CF.

scholarly journals Behavioral and cortisol responses to feeding frequency in pregnant sows under isocaloric intake

2020 ◽  
Vol 98 (8) ◽  
Author(s):  
Hayford Manu ◽  
Suhyup Lee ◽  
Mike C Keyes ◽  
Jim Cairns ◽  
Samuel K Baidoo
Keyword(s):  
Small Sample Size ◽  
Feeding Activity ◽  
Area Under The Curve ◽  
Total Activity ◽  
Small Sample ◽  
Experimental Unit ◽  
Feeding Frequency ◽  
Daily Feeding ◽  
Feeding Activities ◽  
Cortisol Responses

Abstract The study focused on behavioral and cortisol responses to feeding frequency in pregnant sows under isocaloric intake. Twenty-four sows [(Landrace × Yorkshire); BW 216.70 ± 3.98 kg; parity 3.04 ± 0.53] were balanced for parity and randomly assigned to 1 of 3 feeding frequency regimes. Sows were fed corn–soybean meal-based diet 1× [0730 (Control), T1], 2× [half ration at 0730 and 1530 hours, T2], or 3× [one-third portion at 0730, 1130, and 1530 hours, T3] from days 30 to 60 of gestation. Sows received 7055 kcal ME/d during gestation from 2.21 kg of diet formulated to contain SID Lys/ME of 1.71 g/Mcal. Saliva samples were collected every 2 hr from 0630 to 1830 hours on day 52 and assayed for cortisol using ELISA procedure. Behavior data were collected for 7 d from day 53 of gestation by affixing a remote insights ear tag to each sow. Each sow had 120,960 data points categorized into: “Active”, “Feed,” or “Dormant”. Because of housing constraint, all sows were housed in individual stalls in the same room presenting a potential limitation of the study. The data were analyzed using PROC MIXED and GLIMMIX procedures of SAS 9.4 for cortisol and behavior count data, respectively. Sow was the experimental unit. The area under the curve (AUC) is quantitative evaluation of response as threshold varies over all possible values. The T2 sows had reduced 12-hr cortisol AUC compared with control sows (P = 0.024) and T3 sows (P = 0.004), respectively. The T2 sows had lower 3 hr (P = 0.039) and 5 hr (P = 0.015) postfeeding cortisol AUC compared with control sows. Feed anticipatory activity (FAA), 24-hr total activity, and feeding activities (eating and/or sham chewing) were reduced for T2 sows relative to the control and T3 sows (P &lt; 0.01). Consequently, T2 sows had lower 24-hr total activity (P &lt; 0.001) and feeding activities (P &lt; 0.001) AUC compared with both the control and T3 sows, respectively. The T3 sows had greater FAA (P &lt; 0.001) and 24-hr total activity AUC (P = 0.010) compared with control sows. Our data although inconclusive due to small sample size, twice daily feeding appears to be the threshold that reduces sows’ total activity AUC, feeding activity AUC, and activation of hypothalamic–pituitary–adrenal axis, reduced hunger, and exhibit potential to improve sow welfare in relation to once and thrice daily feeding regimes under isocaloric intake per kilogram live metabolic weight.

Exposure-response (E-R) analysis to facilitate phase III (P3) dose selection for AMG 479 (A479) in combination with gemcitabine (G) to treat metastatic pancreatic cancer (mPC).

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 263-263 ◽  
Author(s):  
J. Lu ◽  
H. Deng ◽  
R. Tang ◽  
C. Hsu ◽  
H. L. Kindler ◽  
...  
Keyword(s):  
Human Monoclonal Antibody ◽  
Safety Data ◽  
Area Under The Curve ◽  
Positive Association ◽  
Phase Iii ◽  
Survival Models ◽  
Confounding Factors ◽  
Dose Selection ◽  
Population Pk ◽  
Selection For

263 Background: A479 is an investigational, fully human monoclonal antibody against IGF1R. In a phase II study, 125 pts with mPC were randomized 1:1:1 to A479, placebo (P), or conatumumab in combination with G. Addition of A479 (12 mg/kg IV, Q2W) to G (1000 mg/m2) showed evidence of improved OS and PFS (Kindler, JCO 2010:28 abstr 4035). An E-R analysis was done to inform P3 dose selection for A479. Methods: A population PK model of A479 was constructed using data from multiple studies. An E-R analysis was performed with pts from the A479+G and P+G arms (∼40 pts/arm). The effect of estimated steady-state area under the curve (AUCss) on OS and PFS was evaluated with a Cox proportional hazard model. Effects of potential confounding factors on OS- AUCss and PFS-AUCss associations were assessed by multivariate analysis. Exposure-safety data were analyzed with descriptive statistics and linear regression. P3 doses for A479 were explored with Monte Carlo simulations using population PK and parametric survival models. Results: There was a positive association between OS or PFS and higher AUCss in the A479+G arm (P<0.001, <0.001) that remained even when data from the A479+G and P+G arms were combined (P=0.033, 0.022). Pts with AUCss ≥ median (19.2 mg·h/μL) had longer median OS and PFS (16.0, 7.6 months) than pts with AUCss < median (4.7, 1.9 months). OS-AUCss and PFS-AUCss associations were significant after adjusting for potential confounding factors. Sensitivity E-R analyses were done to confirm the modeling results. The incidence of most adverse events was similar between the AUCss < and ≥ median groups, although the incidence of grade ≥3 hyperglycemia, neutropenia, and thrombocytopenia trended higher in pts with AUCss ≥ median. Population PK indicated 1.7-fold higher clearance of A479 in mPC than non-mPC pts. No G-A479 PK interactions were identified. PK simulations showed similar AUCss of A479 in mPC pts at 20 mg/kg and in non-mPC pts at 12 mg/kg. Simulations projected improved OS and PFS with 20 mg/kg vs 12 mg/kg A479. Conclusions: Increased exposure to A479 is associated with improved clinical outcomes in mPC. This supports the evaluation of 20 mg/kg A479 in P3. [Table: see text]

Population Pharmacokinetics of Levetiracetam: a Systematic Review

2021 ◽  
Vol 16 ◽  
Author(s):  
Janthima Methaneethorn ◽  
Nattawut Leelakanok
Keyword(s):  
Systematic Review ◽  
Sample Size ◽  
Small Sample Size ◽  
Compartment Model ◽  
Small Sample ◽  
Future Research ◽  
Population Pharmacokinetic ◽  
Pharmacokinetic Studies ◽  
Clinical Implementation ◽  
Mixed Effect

Background: The use of levetiracetam (LEV) has been increasing given its favorable pharmacokinetic profile. Numerous population pharmacokinetic studies for LEV have been conducted. However, there are some discrepancies regarding factors affecting its pharmacokinetic variability. Therefore, this systematic review aimed to summarize significant predictors for LEV pharmacokinetics as well as the need for dosage adjustments. Methods: We performed a systematic search for population pharmacokinetic studies of LEV conducted using a nonlinear-mixed effect approach from PubMed, Scopus, CINAHL Complete, and Science Direct databases from their inception to March 2020. Information on study design, model methodologies, significant covariate-parameter relationships, and model evaluation was extracted. The quality of the reported studies was also assessed. Results: A total of 16 studies were included in this review. Only two studies were conducted with a two-compartment model, while the rest were performed with a one-compartment structure. Bodyweight and creatinine clearance were the two most frequently identified covariates on LEV clearance (CLLEV). Additionally, postmenstrual age (PMA) or postnatal age (PNA) were significant predictors for CLLEV in neonates. Only three studies externally validated the models. Two studies conducted pharmacodynamic models for LEV with relatively small sample size. Conclusion: Significant predictors for LEV pharmacokinetics are highlighted in this review. For future research, a population pharmacokinetic-pharmacodynamic model using a larger sample size should be conducted. From a clinical perspective, the published models should be externally evaluated before clinical implementation.

Board composition, sustainability committee and corporate social and environmental performance in Australia

2018 ◽  
Vol 30 (4) ◽  
pp. 517-540 ◽  
Author(s):  
Pallab Kumar Biswas ◽  
Mansi Mansi ◽  
Rakesh Pandey
Keyword(s):  
Environmental Performance ◽  
Small Sample Size ◽  
Positive Association ◽  
Small Sample ◽  
Gender Composition ◽  
Board Independence ◽  
Content Type ◽  
Social And Environmental Performance ◽  
Corporate Social ◽  
The Relationship

PurposeThe purpose of this study is to examine the impacts of board gender composition, board independence and the existence of a board sustainability committee on the corporate social and environmental performance of Australian firms.Design/methodology/approachThe dataset comprises 2,188 Australian Securities Exchange listed firm-year observations (407 individual firms) from 2004 to 2015. The ASSET4 environmental, social and governance database is used to measure corporate social and environmental performance and their sub-dimensions.FindingsOur results show that firms with higher board gender composition, greater board independence and sustainability committees tend to have better social and environmental performance. This paper also provides empirical evidence of the positive association of these variables on the sub-dimensions of social and environmental performance. The results are robust after controlling for self-selection and various forms of endogeneity.Originality/valueThis is the first study that examines the relationship between sustainability committees and corporate social and environmental performance in the context of Australia. This study also overcomes the relatively small sample size and shorter study period issues of similar studies in Australia that provide inconclusive evidence on the relationship between each of board gender composition, board independence and corporate social and environmental performance.

scholarly journals 0755 Pitolisant (Wakix) is an Effective Anti-Cataplexy Agent in Narcolepsy Type 1

SLEEP ◽  
2020 ◽  
Vol 43 (Supplement_1) ◽  
pp. A287-A287
Author(s):  
G J Meskill
Keyword(s):  
Clinical Judgment ◽  
Small Sample Size ◽  
Treatment Options ◽  
Standard Of Care ◽  
The United States ◽  
Substantial Improvement ◽  
Small Sample ◽  
Adult Patients

Abstract Introduction Harmony Biosciences initiated the Pitolisant Expanded Access Clinical Evaluation (PEACE) program to allow treatment with pitolisant in adult patients with narcolepsy while pitolisant was an investigational medication in the United States. Starting in March 2019, Comprehensive Sleep Medicine Associates (CSMA) offered enrollment to patients who met the inclusion/exclusion criteria and who were deemed appropriate based on clinical judgment. All patients who enrolled were taking at least one standard-of-care agent for narcolepsy at enrollment. Many of the enrolled patients had refractory/challenging cases of narcolepsy. On August 14, 2019, Wakix received FDA approval for the treatment of excessive daytime sleepiness in adult patients with narcolepsy, which contrasts with the European label that states that Wakix is indicated for the treatment of narcolepsy in adults with or without cataplexy. Methods CSMA enrolled 21 patients in the PEACE program. The charts for all 10 narcolepsy type 1 (NT1) patients were reviewed. The 2 patients who did not have follow up after starting pitolisant were excluded. Results Of the 8 NT1 patients who had at least one follow up visit after initiating pitolisant, 6 reported substantial improvement or complete resolution of cataplexy compared to baseline. For example, one patient’s wife stated, “I forgot my husband was funny because he would avoid telling jokes until he started pitolisant.” Another stated, “I have not had an episode of cataplexy since starting pitolisant.” 5 of these patients were taking an anti-cataplectic agent at the time of starting pitolisant (sodium oxybate 3, venlafaxine 2). Conclusion While a relatively small sample size, these results demonstrate that in a “real world” uncontrolled population of refractory/challenging NT1 patients, pitolisant is an effective anti-cataplectic agent. As there are relatively few treatment options for NT1, clinicians should consider use of pitolisant for patients with cataplexy, and further consideration for adding an indication for pitolisant to treat cataplexy is warranted. Support Harmony Biosciences (PEACE trial)

scholarly journals Development of the infant gut microbiome predicts temperament across the first year of life

2021 ◽  
pp. 1-12
Author(s):  
Molly Fox ◽  
S. Melanie Lee ◽  
Kyle S. Wiley ◽  
Venu Lagishetty ◽  
Curt A. Sandman ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Emotion Dysregulation ◽  
Small Sample Size ◽  
Positive Association ◽  
Illumina Miseq ◽  
Small Sample ◽  
Microbiome Composition ◽  
Sensitive Periods ◽  
Infant Gut Microbiome ◽  
First Year Of Life

Abstract Perturbations to the gut microbiome are implicated in altered neurodevelopmental trajectories that may shape life span risk for emotion dysregulation and affective disorders. However, the sensitive periods during which the microbiome may influence neurodevelopment remain understudied. We investigated relationships between gut microbiome composition across infancy and temperament at 12 months of age. In 67 infants, we examined if gut microbiome composition assessed at 1–3 weeks, 2, 6, and 12 months of age was associated with temperament at age 12 months. Stool samples were sequenced using the 16S Illumina MiSeq platform. Temperament was assessed using the Infant Behavior Questionnaire-Revised (IBQ-R). Beta diversity at age 1–3 weeks was associated with surgency/extraversion at age 12 months. Bifidobacterium and Lachnospiraceae abundance at 1–3 weeks of age was positively associated with surgency/extraversion at age 12 months. Klebsiella abundance at 1–3 weeks was negatively associated with surgency/extraversion at 12 months. Concurrent composition was associated with negative affectivity at 12 months, including a positive association with Ruminococcus-1 and a negative association with Lactobacillus. Our findings support a relationship between gut microbiome composition and infant temperament. While exploratory due to the small sample size, these results point to early and late infancy as sensitive periods during which the gut microbiome may exert effects on neurodevelopment.

scholarly journals Radiomics machine learning study with small sample size: single random training-test set split may result in unreliable results

2020 ◽  
Author(s):  
Chansik An ◽  
Yae Won Park ◽  
Sung Soo Ahn ◽  
Kyunghwa Han ◽  
Hwiyoung Kim ◽  
...  
Keyword(s):  
Machine Learning ◽  
Sample Size ◽  
Small Sample Size ◽  
Area Under The Curve ◽  
Small Sample ◽  
Simple Task ◽  
Test Set ◽  
Magnetic Resonance Imaging Mri ◽  
Selection Operator ◽  
Set Splitting

Abstract Objective: This study aims to determine how randomly splitting a dataset into training and test sets affects the estimated performance of a machine learning model under different conditions, using real-world brain tumor radiomics data.Materials and Methods: We conducted two classification tasks of different difficulty levels with magnetic resonance imaging (MRI) radiomics features: (1) “Simple” task, glioblastomas [n=109] vs. brain metastasis [n=58] and (2) “difficult” task, low- [n=163] vs. high-grade [n=95] meningiomas. Additionally, two undersampled datasets were created by randomly sampling 50% from these datasets. We performed random training-test set splitting for each dataset repeatedly to create 1,000 different training and test set pairs. For each dataset pair, the least absolute shrinkage and selection operator model was trained by five-fold cross-validation (CV) or nested CV with or without repetitions in the training set and tested with the test set, using the area under the curve (AUC) as an evaluation metric.Results: The AUCs in CV and testing varied widely based on data composition, especially with the undersampled datasets and the difficult task. The mean (±standard deviation) AUC difference between CV and testing was 0.029 (±0.022) for the simple task without undersampling and 0.108 (±0.079) for the difficult task with undersampling. In a training-test set pair, the AUC was high in CV but much lower in testing (0.840 and 0.650, respectively); in another dataset pair with the same task, however, the AUC was low in CV but much higher in testing (0.702 and 0.836, respectively). None of the CV methods helped overcome this issue.Conclusions: Machine learning after a single random training-test set split may lead to unreliable results in radiomics studies, especially when the sample size is small.

846 Effects of Ceragenins on Pseudomonas Aeruginosa Biofilm Formation in Burn Wounds in a Porcine Model

2020 ◽  
Vol 41 (Supplement_1) ◽  
pp. S262-S263
Author(s):  
Paul B Savage
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Fungal Infections ◽  
Small Sample Size ◽  
Positive Control ◽  
Small Sample ◽  
High Morbidity ◽  
Post Inoculation ◽  
Protective Function ◽  
Bacterial Counts ◽  
Burn Wounds

Abstract Introduction Damage from burn wounds compromises the protective function of the skin, increasing susceptibility to bacterial and fungal infections and sepsis. Pseudomonas aeruginosa is commonly infects burn injuries and is associated with high morbidity, especially in large total burn surface area injuries. Silver sulfadiazine (SSD), the standard topical antimicrobial used for burn wounds, has been associated with irritation, scarring and other adverse effects creating a need for alternative treatment options. Ceragenins are small-molecule mimics of endogenous antimicrobial peptides. In this pilot study, two ceragenins, CSA-44 and CSA-144 were assessed for their ability to reduce P. aeruginosa in a porcine burn wound model. Methods One pathogen-free female pig was appropriately prepared and 48 burn wounds were generated, under general anesthesia, on the back and flank area by direct contact with a heated brass rod. Wounds were inoculated with P. aeruginosa and biofilm was allowed to form for 24 hours. Four of the wounds were analyzed 24 hours post inoculation to establish baseline bacterial counts. R emaining wounds were treated with a vehicle control, SSD (positive control) or formulations of CSA-44 and CSA-144 in gel, cream and aqueous forms. After 7 days of treatment, tissue samples from the wounds were excised and bacterial counts were determined (colony forming units per milliliter of tissue). Percent decreases in bacterial counts were evaluated for each wound. The wounds were also observed for erythema and irritation over the course of the study. Results The greatest reductions in bacterial counts after treatment were seen in wounds treated with aqueous CSA-44 at 0.05 % (99.6% reduction) and aqueous CSA-144 at 0.05% (98.4% reduction), which were both greater than the bacterial reductions seen in wounds treated with SSD. Additionally, after the second day of treatment, wounds treated with aqueous CSA-44 and CSA-144 showed reduced erythema, while wounds treated with SSD continued to show swelling and redness. Conclusions This study demonstrates the effective antimicrobial action of aqueous formulations of ceragenins CSA-44 and CSA-144. The bacterial reduction seen with aqueous CSA-44 and CSA-144 were greater than the positive control (SSD). Furthermore, treatment with CSA-44 showed reduced signs of irritation, which were not observed with SSD. Even within this small sample size, the superior antimicrobial ability of ceragenins, without the negative effects of SSD becomes apparent. Applicability of Research to Practice Ceragenins provide a means of replacing endogenous defenses against infection in burn wounds.

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