Population Pharmacokinetics of Vixotrigine in Healthy Volunteers and Subjects with Trigeminal Neuralgia, Painful Lumbosacral Radiculopathy and Erythromelalgia

Naik, Himanshu; Forrestal, Fiona; Cleall, Simon; Bockbrader, Howard N.; Chapel, Sunny

doi:10.1007/s13318-021-00678-0

Cited by 4 publications

(2 citation statements)

References 14 publications

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“…However, when built PPK model from BSI patients, a full PPK model with covariates could not be built possibly due to a small number of patients. Considering plenty of studies built PPK models by combining data from all available trials (Lu et al, 2019;Gaudy et al, 2020;Naik et al, 2021), and population pharmacokinetic guidance by FDA also encourages combining data from early-and late-stages of trials to build models using the non-linear mixed-effects modeling approach (https://www.fda.gov/media/128793/download).We therefore Frontiers in Pharmacology frontiersin.org included all plasma concentrations acquired from healthy subjects and BSI patients in the PPK model. Not surprisingly, BSI was included as a category covariate on the volume of the central compartment (V1), whereas CLcr before and during treatment was not included as a covariate in the model.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae

Liu

et al. 2022

Front. Pharmacol.

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Introduction: Polymyxin B is a last-line therapy for carbapenem-resistant microorganisms. However, a lack of clinical pharmacokinetic/pharmacodynamic (PK/PD) data has substantially hindered dose optimization and breakpoint setting.Methods: A prospective, multi-center clinical trial was undertaken with polymyxin B [2.5 mg/kg loading dose (3-h infusion), 1.25 mg/kg/12 h maintenance dose (2-h infusion)] for treatment of carbapenem-resistant K. pneumoniae (CRKP) bloodstream infections (BSI). Safety, clinical and microbiological efficacy were evaluated. A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was applied to determine the concentrations of polymyxin B in blood samples. Population pharmacokinetic (PK) modeling and Monte Carlo simulations were conducted to examine the susceptibility breakpoint for polymyxin B against BSI caused by CRKP.Results: Nine patients were enrolled and evaluated for safety. Neurotoxicity (5/9), nephrotoxicity (5/9), and hyperpigmentation (1/9) were recorded. Blood cultures were negative within 3 days of commencing therapy in all 8 patients evaluated for microbiological efficacy, and clinical cure or improvement occurred in 6 of 8 patients. Cmax and Cmin following the loading dose were 5.53 ± 1.80 and 1.62 ± 0.41 mg/L, respectively. With maintenance dosing, AUCss,24 h was 79.6 ± 25.0 mg h/L and Css,avg 3.35 ± 1.06 mg/L. Monte Carlo simulations indicated that a 1 mg/kg/12-hourly maintenance dose could achieve >90% probability of target attainment (PTA) for isolates with minimum inhibitory concentration (MIC) ≤1 mg/L. PTA dropped substantially for MICs ≥2 mg/L, even with a maximally recommended daily dose of 1.5 mg/kg/12-hourly.Conclusion: This is the first clinical PK/PD study evaluating polymyxin B for BSI. These results will assist to optimize polymyxin B therapy and establish its breakpoints for CRKP BSI.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae

Liu

et al. 2022

Front. Pharmacol.

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“…With respect to published studies 61 , 62 , 63 , 64 , 65 , 66 , 67 that have undertaken individual PK data meta‐analyses, diversity on the methods used can be observed. There are clear differences on the way the data are obtained, with the majority of studies using pooled analysis with available data in house, or from different selected studies, whereas only few of the reported studies actually perform a literature search to identify available studies to include in their analysis.…”

Section: Further Recommendationsmentioning

confidence: 99%

Pharmacokinetic analysis across studies to drive knowledge‐integration: A tutorial on individual patient data meta‐analysis (IPDMA)

Wijk

Imperial

Savic

et al. 2023

CPT Pharmacom & Syst Pharma

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Answering challenging questions in drug development sometimes requires pharmacokinetic (PK) data analysis across different studies, for example, to characterize PKs across diverse regions or populations, or to increase statistical power for subpopulations by combining smaller size trials. Given the growing interest in data sharing and advanced computational methods, knowledge integration based on multiple data sources is increasingly applied in the context of model‐informed drug discovery and development. A powerful analysis method is the individual patient data meta‐analysis (IPDMA), leveraging systematic review of databases and literature, with the most detailed data type of the individual patient, and quantitative modeling of the PK processes, including capturing heterogeneity of variance between studies. The methodology that should be used in IPDMA in the context of population PK analysis is summarized in this tutorial, highlighting areas of special attention compared to standard PK modeling, including hierarchical nested variability terms for interstudy variability, and handling between‐assay differences in limits of quantification within a single analysis. This tutorial is intended for any pharmacological modeler who is interested in performing an integrated analysis of PK data across different studies in a systematic and thorough manner, to answer questions that transcend individual primary studies.

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Evaluation of the Effect of Uridine Diphosphate-Glucuronosyltransferases (UGT) Inhibition by Valproic Acid on Vixotrigine Pharmacokinetics in Healthy Volunteers

et al. 2022

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Population Pharmacokinetics of Vixotrigine in Healthy Volunteers and Subjects with Trigeminal Neuralgia, Painful Lumbosacral Radiculopathy and Erythromelalgia

Cited by 4 publications

References 14 publications

Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae

Pharmacokinetics/pharmacodynamics of polymyxin B in patients with bloodstream infection caused by carbapenem-resistant Klebsiella pneumoniae

Pharmacokinetic analysis across studies to drive knowledge‐integration: A tutorial on individual patient data meta‐analysis (IPDMA)

Evaluation of the Effect of Uridine Diphosphate-Glucuronosyltransferases (UGT) Inhibition by Valproic Acid on Vixotrigine Pharmacokinetics in Healthy Volunteers

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