HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.Computing normalised prediction distribution errors to evaluate nonlinear mixed-effect models: The npde add-on package for R.

We modeled the viral dynamics of 13 untreated patients infected with severe acute respiratory syndrome‐coronavirus 2 to infer viral growth parameters and predict the effects of antiviral treatments. In order to reduce peak viral load by more than two logs, drug efficacy needs to be > 90% if treatment is administered after symptom onset; an efficacy of 60% could be sufficient if treatment is initiated before symptom onset. Given their pharmacokinetic/pharmacodynamic properties, current investigated drugs may be in a range of 6–87% efficacy. They may help control virus if administered very early, but may not have a major effect in severely ill patients.

This article represents the first in a series of tutorials on model evaluation in nonlinear mixed effect models (NLMEMs), from the International Society of Pharmacometrics (ISoP) Model Evaluation Group. Numerous tools are available for evaluation of NLMEM, with a particular emphasis on visual assessment. This first basic tutorial focuses on presenting graphical evaluation tools of NLMEM for continuous data. It illustrates graphs for correct or misspecified models, discusses their pros and cons, and recalls the definition of metrics used.

For external model evaluation, prediction distribution errors are recommended when the aim is to use the model to simulate data. Metrics through hyperparameters should be preferred when the aim is to compare two populations and metrics based on the objective function are useful during the model building process.

word count: 100/100) 38We modeled the viral dynamics of 13 untreated patients infected with SARS-CoV-2 to infer 39 viral growth parameters and predict the effects of antiviral treatments. In order to reduce peak 40 viral load by more than 2 logs, drug efficacy needs to be greater than 80% if treatment is 41 administered after symptom onset; an efficacy of 50% could be sufficient if treatment is 42 initiated before symptom onset. Given their pharmacokinetic/pharmacodynamic properties, 43 current investigated drugs may be in a range of 20-70% efficacy. They may help control virus 44 if administered very early, but may not have a major effect in severe patients. 45 46 All rights reserved. No reuse allowed without permission.was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Model evaluation is an important issue in population analyses. We aimed to perform a systematic review of all population pharmacokinetic and/or pharmacodynamic analyses published between 2002 and 2004 to survey the current methods used to evaluate models and to assess whether those models were adequately evaluated. We selected 324 articles in MEDLINE using defined key words and built a data abstraction form composed of a checklist of items to extract the relevant information from these articles with respect to model evaluation. In the data abstraction form, evaluation methods were divided into three subsections: basic internal methods (goodness-of-fit [GOF] plots, uncertainty in parameter estimates and model sensitivity), advanced internal methods (data splitting, resampling techniques and Monte Carlo simulations) and external model evaluation. Basic internal evaluation was the most frequently described method in the reports: 65% of the models involved GOF evaluation. Standard errors or confidence intervals were reported for 50% of fixed effects but only for 22% of random effects. Advanced internal methods were used in approximately 25% of models: data splitting was more often used than bootstrap and cross-validation; simulations were used in 6% of models to evaluate models by a visual predictive check or by a posterior predictive check. External evaluation was performed in only 7% of models. Using the subjective synthesis of model evaluation for each article, we judged the models to be adequately evaluated in 28% of pharmacokinetic models and 26% of pharmacodynamic models. Basic internal evaluation was preferred to more advanced methods, probably because the former is performed easily with most software. We also noticed that when the aim of modelling was predictive, advanced internal methods or more stringent methods were more often used.

Colistin is an old antibiotic that has recently gained a considerable renewal of interest as the last-line defense therapy against multidrug-resistant Gram-negative bacteria. It is administered as colistin methanesulfonate (CMS), an inactive prodrug, and it was shown that due to slow CMS conversion, colistin plasma concentrations increase very slowly after treatment initiation, which constitutes the rationale for a loading dose in critically ill patients. However, faster CMS conversion was observed in healthy volunteers but using a different CMS brand, which may also have a major impact on colistin pharmacokinetics. Seventythree critically ill patients not undergoing dialysis received multiple doses of CMS. The CMS concentrations were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and a pharmacokinetic analysis was conducted using a population approach. We confirmed that CMS renal clearance and colistin concentrations at steady state are mostly governed by creatinine clearance, but we predict a typical maximum concentration of drug in serum (C max ) of colistin close to 2 mg/liter, occurring 3 h after an initial dose of 2 million international units (MIU) of CMS. Accordingly, the estimated colistin half-life (t 1/2 ) was relatively short (3.1 h), with rapid attainment of steady state. Our results are only partially consistent with other recently published results. We confirm that the CMS maintenance dose should be adjusted according to renal function in critically ill patients. However, much higher than expected colistin concentrations were observed after the initial CMS dose, with rapid steady-state achievement. These discrepancies challenge the pharmacokinetic rationale for a loading dose, which may still be appropriate for rapid bacterial eradication and an improved clinical cure rate. Colistin is an antibiotic that has reemerged because of the increase of bacterial resistance among life-threatening Gramnegative pathogens (1). It is administered intravenously as a prodrug, colistin methanesulfonate (CMS), which is converted within the body into the active moiety. It was shown that colistin concentrations increase slowly after CMS administration in critically ill patients and that it takes 2 days to reach steady state, suggesting the benefits of treatment initiation with a loading dose (2). This front-loading strategy is now well accepted to increase efficacy and avoid the development of resistances (3-5). However, this slow appearance of colistin was not observed in healthy volunteers (6). The objective of this study was therefore to reassess colistin pharmacokinetics (PK) in critically ill patients using the same methodology, including CMS brand, as that for healthy volunteers. MATERIALS AND METHODSStudy design. The study was approved by the ethics committee of the principal investigator hospital. It was an open-label study conducted in 9 sites in France between May 2009 and December 2011. The eligible patients were hospitalized in the intensive care unit (ICU), were Ͼ18 years of age,...

Objective. Interferon regulatory factor 5 (IRF-5) is a transcription factor involved in the regulation of the host defense. Previous studies have demonstrated a significant association of various IRF5 gene polymorphisms with systemic lupus erythematosus (SLE) in Caucasians. The purpose of this case-control study was to investigate whether IRF5 polymorphisms are involved in the genetic predisposition to primary Sjögren's syndrome (SS), an autoimmune disease closely related to SLE.Methods. We analyzed IRF5 rs2004640, rs2070197, rs10954213, and rs2280714 polymorphisms in a cohort of 212 primary SS patients and 162 healthy blood donors, all of whom were of Caucasian origin. The 4 polymorphisms examined were genotyped by competitive allele-specific polymerase chain reaction using fluorescence resonance energy transfer technology.Results. The IRF5 rs2004640 GT or TT genotype (T allele carriers) was identified in 87% of primary SS patients compared with 77% of controls (P ‫؍‬ 0.01, odds ratio [OR] 1.93 [95% confidence interval (95% CI) 1.15-3.42]). The IRF5 rs2004640 T allele was found on 59% of chromosomes from primary SS patients compared with 52% of chromosomes from controls (P ‫؍‬ 0.04, OR 1.36 [95% CI 1.01-1.83]). No significant association of primary SS with rs2070197, rs10954213, or rs2280714 was seen when they were analyzed independently. Nevertheless, haplotype reconstructions based on the 4 polymorphisms examined suggest that various allele combinations of rs2004640 and rs2070197 could define susceptibility or protective haplotypes.Conclusion. This study is the first to demonstrate a significant association between primary SS and the IRF5 rs2004640 T allele. These results, which require further replication on larger populations, suggest that besides their association with identical major histocompatibility complex gene polymorphisms, primary SS and SLE share IRF gene polymorphisms as a common genetic susceptibility factor.