Simultaneous Quantification of Psychotropic Drugs in Human Plasma and Breast Milk and Its Application in Therapeutic Drug Monitoring and Peripartum Treatment Optimization.

BACKGROUND: Therapeutic drug monitoring is recommended for several psychotropic drugs, particularly in sensitive situations such as the peripartum period. This study aimed to develop an ultra-high-performance liquid chromatography-tandem spectrometry method for the simultaneous quantification of 14 psychotropic drugs in human plasma and 4 in breast milk. METHODS: The samples were precipitated with methanol containing the stable isotope-labeled analogs. Chromatographic separation was performed using a Phenomenex Luna Omega Polar C18 column. Detection was performed using a triple-quadrupole mass spectrometer equipped with an electrospray ionization interface. The method was fully validated in plasma according to the European Guidelines on Bioanalytical Method Validation and partially validated in breast milk by determining the intraday precision and accuracy, linearity, lower limit of quantification, and matrix effect. RESULTS: The correlation coefficients of the calibration curves were greater than 0.99. Coefficients of variation ranged from 3.05% to 14.66% and 0.62%-14.90% for internal standard-normalized matrix effect, 1.4%-14.1% and 2.1%-10.4% for intraday precision, and 3.2%-13.9% and 4.1%-9.6% for interday precision, in plasma and milk, respectively. The relative error in accuracy did not exceed ±15% for any analyte. The method was successfully applied clinically to measure the concentrations of psychotropic drugs in 952 plasma samples, among which 43% of the concentrations were out of the therapeutic range, and 13 breast milk samples, with calculated relative infant doses ranging from 0.32% to 8.18%. CONCLUSIONS: To the best of the authors' knowledge, this is the first routine technique validated for the quantification of psychotropic drugs in both plasma and breast milk, allowing for treatment optimization and prevention of adherence issues, including those in breastfeeding patients.

Towards Precision Dosing of Clozapine in Schizophrenia: External Evaluation of Population Pharmacokinetic Models and Bayesian Forecasting.

BACKGROUND: Therapeutic drug monitoring and treatment optimization of clozapine are recommended, owing to its narrow therapeutic range and pharmacokinetic (PK) variability. This study aims to assess the clinical applicability of published population PK models by testing their predictive performance in an external data set and to determine the effectiveness of Bayesian forecasting (BF) for clozapine treatment optimization. METHODS: Available models of clozapine were identified, and their predictive performance was determined using an external data set (53 patients, 151 samples). The median prediction error (PE) and median absolute PE were used to assess bias and inaccuracy. The potential factors influencing model predictability were also investigated. The final concentration was reestimated for all patients using covariates or previously observed concentrations. RESULTS: The 7 included models presented limited predictive performance. Only 1 model met the acceptability criteria (median PE ≤ ±20% and median absolute PE ≤30%). There was no difference between the data used for building the models (therapeutic drug monitoring or PK study) or the number of compartments in the models. A tendency for higher inaccuracy at low concentrations during treatment initiation was observed. Heterogeneities were observed in the predictive performances between the subpopulations, especially in terms of smoking status and sex. For the models included, BF significantly improved their predictive performance. CONCLUSIONS: Our study showed that upon external evaluation, clozapine models provide limited predictive performance, especially in subpopulations such as nonsmokers. From the perspective of model-informed prediction dosing, model predictability should be improved using updating or metamodeling methods. Moreover, BF substantially improved model predictability and could be used for clozapine treatment optimization.

Development and Validation of a Simple and Rapid Ultrahigh-Performance Liquid Chromatography Tandem Spectrometry Method for the Quantification of Hydroxychloroquine in Plasma and Blood Samples in the Emergency Context of SARS-CoV-2 Pandemic.

ABSTRACT: Therapeutic drug monitoring of hydroxychloroquine (HCQ) has been recommended to optimize the treatment of patients with COVID-19. The authors describe an ultrahigh-performance liquid chromatography tandem spectrometry method developed in a context of emergency, to analyze HCQ in both human plasma and blood samples. After adding the labeled internal standard and simple protein precipitation, plasma samples were analyzed using a C18 column. Blood samples required evaporation before analysis. The total chromatographic run time was 4 minutes (including 1.5 minutes of column equilibration). The assay was linear over the calibration range (r2 > 0.99) and up to 1.50 mcg/mL for the plasma samples (5.00 mcg/mL for the blood matrix). The limit of quantification was 0.0150 mcg/mL for plasma samples (0.05 mcg/mL blood matrix) with accuracy and precision ranging from 91.1% to 112% and from 0.750% to 11.1%, respectively. Intraday and interday precision and accuracy values were within 15.0%. No significant matrix effect was observed in the plasma or blood samples. This method was successfully applied to patients treated for COVID-19 infection. A simple and rapid ultrahigh-performance liquid chromatography tandem spectrometry method adapted to HCQ therapeutic drug monitoring in the context of SARS-CoV-2 infection was successfully developed and validated.

Replication study of plasma proteins relating to Alzheimer's pathology.

INTRODUCTION: This study sought to discover and replicate plasma proteomic biomarkers relating to Alzheimer's disease (AD) including both the "ATN" (amyloid/tau/neurodegeneration) diagnostic framework and clinical diagnosis. METHODS: Plasma proteins from 972 subjects (372 controls, 409 mild cognitive impairment [MCI], and 191 AD) were measured using both SOMAscan and targeted assays, including 4001 and 25 proteins, respectively. RESULTS: Protein co-expression network analysis of SOMAscan data revealed the relation between proteins and "N" varied across different neurodegeneration markers, indicating that the ATN variants are not interchangeable. Using hub proteins, age, and apolipoprotein E ε4 genotype discriminated AD from controls with an area under the curve (AUC) of 0.81 and MCI convertors from non-convertors with an AUC of 0.74. Targeted assays replicated the relation of four proteins with the ATN framework and clinical diagnosis. DISCUSSION: Our study suggests that blood proteins can predict the presence of AD pathology as measured in the ATN framework as well as clinical diagnosis.

TMEM106B and CPOX are genetic determinants of cerebrospinal fluid Alzheimer's disease biomarker levels.

INTRODUCTION: Neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and synaptic degeneration, respectively. METHODS: We performed genome-wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF-AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates. RESULTS: We identify novel genome-wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL-40. We confirm previous work suggesting that YKL-40 levels are associated with DNA variants in CHI3L1. DISCUSSION: Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD-related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.

Modular slowing of resting-state dynamic functional connectivity as a marker of cognitive dysfunction induced by sleep deprivation.

Dynamic Functional Connectivity (dFC) in the resting state (rs) is considered as a correlate of cognitive processing. Describing dFC as a flow across morphing connectivity configurations, our notion of dFC speed quantifies the rate at which FC networks evolve in time. Here we probe the hypothesis that variations of rs dFC speed and cognitive performance are selectively interrelated within specific functional subnetworks. In particular, we focus on Sleep Deprivation (SD) as a reversible model of cognitive dysfunction. We found that whole-brain level (global) dFC speed significantly slows down after 24h of SD. However, the reduction in global dFC speed does not correlate with variations of cognitive performance in individual tasks, which are subtle and highly heterogeneous. On the contrary, we found strong correlations between performance variations in individual tasks -including Rapid Visual Processing (RVP, assessing sustained visual attention)- and dFC speed quantified at the level of functional sub-networks of interest. Providing a compromise between classic static FC (no time) and global dFC (no space), modular dFC speed analyses allow quantifying a different speed of dFC reconfiguration independently for sub-networks overseeing different tasks. Importantly, we found that RVP performance robustly correlates with the modular dFC speed of a characteristic frontoparietal module.

Amygdalar nuclei and hippocampal subfields on MRI: Test-retest reliability of automated volumetry across different MRI sites and vendors.

BACKGROUND: The amygdala and the hippocampus are two limbic structures that play a critical role in cognition and behavior, however their manual segmentation and that of their smaller nuclei/subfields in multicenter datasets is time consuming and difficult due to the low contrast of standard MRI. Here, we assessed the reliability of the automated segmentation of amygdalar nuclei and hippocampal subfields across sites and vendors using FreeSurfer in two independent cohorts of older and younger healthy adults. METHODS: Sixty-five healthy older (cohort 1) and 68 younger subjects (cohort 2), from the PharmaCog and CoRR consortia, underwent repeated 3D-T1 MRI (interval 1-90 days). Segmentation was performed using FreeSurfer v6.0. Reliability was assessed using volume reproducibility error (ε) and spatial overlapping coefficient (DICE) between test and retest session. RESULTS: Significant MRI site and vendor effects (p â€‹< â€‹.05) were found in a few subfields/nuclei for the ε, while extensive effects were found for the DICE score of most subfields/nuclei. Reliability was strongly influenced by volume, as ε correlated negatively and DICE correlated positively with volume size of structures (absolute value of Spearman's r correlations >0.43, p â€‹< â€‹1.39E-36). In particular, volumes larger than 200 â€‹mm3 (for amygdalar nuclei) and 300 â€‹mm3 (for hippocampal subfields, except for molecular layer) had the best test-retest reproducibility (ε â€‹< â€‹5% and DICE â€‹> â€‹0.80). CONCLUSION: Our results support the use of volumetric measures of larger amygdalar nuclei and hippocampal subfields in multisite MRI studies. These measures could be useful for disease tracking and assessment of efficacy in drug trials.

An Alzheimer Disease Challenge Model: 24-Hour Sleep Deprivation in Healthy Volunteers, Impact on Working Memory, and Reversal Effect of Pharmacological Intervention: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study.

PURPOSE/BACKGROUND: Alzheimer disease (AD) is a public health issue because of the low number of symptomatic drugs and the difficulty to diagnose it at the prodromal stage. The need to develop new treatments and to validate sensitive tests for early diagnosis could be met by developing a challenge model reproducing cognitive impairments of AD. Therefore, we implemented a 24-hour sleep deprivation (SD) design on healthy volunteers in a randomized, double-blind, placebo-controlled, crossover study on 36 healthy volunteers. METHODS/PROCEDURE: To validate the SD model, cognitive tests were chosen to assess a transient worsening of cognitive functions after SD and a restoration under modafinil as positive control (one dose of 200 mg). Then, the same evaluations were replicated after 15 days of donepezil (5 mg/d) or memantine (10 mg/d). The working memory (WM) function was assessed by the N-back task and the rapid visual processing (RVP) task. FINDINGS/RESULTS: The accuracy of the N-back task and the reaction time of the RVP revealed the alteration of the WM with SD and its restoration with modafinil (changes in score after SD compared with baseline before SD), respectively, in the placebo group and in the modafinil group (-0.2% and +1.0% of satisfactory answers, P = 0.022; +21.3 and +1.9 milliseconds of reaction time, P = 0.025). Alzheimer disease drugs also tended to reverse this deterioration: the accuracy of the N-back task was more stable through SD (compared with -3.0% in the placebo group, respectively, in the memantine group and in the donepezil group: -1.4% and -1.6%, P = 0.027 and P = 0.092) and RVP reaction time was less impacted (compared with +41.3 milliseconds in the placebo group, respectively, in the memantine group and in the donepezil group: +16.1 and +29.3 milliseconds, P = 0.034 and P = 0.459). IMPLICATIONS/CONCLUSIONS: Our SD challenge model actually led to a worsening of WM that was moderated by both modafinil and AD drugs. To use this approach, the cognitive battery, the vulnerability of the subjects to SD, and the expected drug effect should be carefully considered.

Evaluation of current dosing guidance for oral rifampicin treatment in adult patients with osteoarticular infections.

For management of osteoarticular infections, rifampicin appears to be the key antibiotic. We aimed to evaluate the actual rifampicin dosing regimens using a population pharmacokinetic model of rifampicin in patients with osteoarticular infections. A Monte Carlo simulation study was performed to simulate steady-state plasma concentrations for 1000 randomly sampled subjects using a total daily dose between 600 and 1200 mg (600 and 900 mg once daily, 450 and 600 mg twice daily, or 300 mg 3 times daily). When rifampicin was administered with fusidic acid, the pharmacokinetic/pharmacodynamic (PK/PD) target (area under the curve/minimum inhibitory concentration ≥952) was achieved with all tested dosing regimen, except 600 mg once daily for Staphylococcus epidermidis infections. Without coadministration of fusidic acid, none of tested dosing regimens achieved this PK/PD target. Most recommended drug-dosing regimens allow attaining the fixed area under the curve/minimum inhibitory concentration target for Staphylococcus aureus and coagulase-negative staphylococcal osteoarticular infections. In future studies, PK/PD target for osteoarticular infections in human should also be confirmed.

Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum.

INTRODUCTION: We investigated relations between amyloid-ß (Aß) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau). METHODS: We included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aß status (Aß- vs. Aß+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition. RESULTS: Ng and T-tau distinguished between Aß+ from Aß- individuals in each clinical group, whereas NFL and YKL-40 were associated with Aß+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aß+ individuals. NFL was the best predictor of cognitive decline in Aß+ individuals across the cognitive spectrum. DISCUSSION: Axonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.

Discovery and validation of plasma proteomic biomarkers relating to brain amyloid burden by SOMAscan assay.

INTRODUCTION: Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins. METHODS: 4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid. RESULTS: A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization. DISCUSSION: The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.

Inflammatory biomarkers in Alzheimer's disease plasma.

INTRODUCTION: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a "Holy Grail" of AD research and intensively sought; however, there are no well-established plasma markers. METHODS: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. RESULTS: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APOε4 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). DISCUSSION: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation.

Primary fatty amides in plasma associated with brain amyloid burden, hippocampal volume, and memory in the European Medical Information Framework for Alzheimer's Disease biomarker discovery cohort.

INTRODUCTION: A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers. METHODS: This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis. RESULTS: Eight metabolites were associated with amyloid ß and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory. DISCUSSION: PFAMs have been found increased and associated with amyloid ß burden in CSF and clinical measures.

Brain Networks are Independently Modulated by Donepezil, Sleep, and Sleep Deprivation.

Resting-state connectivity has been widely studied in the healthy and pathological brain. Less well-characterized are the brain networks altered during pharmacological interventions and their possible interaction with vigilance. In the hopes of finding new biomarkers which can be used to identify cortical activity and cognitive processes linked to the effects of drugs to treat neurodegenerative diseases such as Alzheimer's disease, the analysis of networks altered by medication would be particularly interesting. Eleven healthy subjects were recruited in the context of the European Innovative Medicines Initiative 'PharmaCog'. Each underwent five sessions of simultaneous EEG-fMRI in order to investigate the effects of donepezil and memantine before and after sleep deprivation (SD). The SD approach has been previously proposed as a model for cognitive impairment in healthy subjects. By applying network based statistics (NBS), we observed altered brain networks significantly linked to donepezil intake and sleep deprivation. Taking into account the sleep stages extracted from the EEG data we revealed that a network linked to sleep is interacting with sleep deprivation but not with medication intake. We successfully extracted the functional resting-state networks modified by donepezil intake, sleep and SD. We observed donepezil induced whole brain connectivity alterations forming a network separated from the changes induced by sleep and SD, a result which shows the utility of this approach to check for the validity of pharmacological resting-state analysis of the tested medications without the need of taking into account the subject specific vigilance.

Population pharmacokinetic model for tumescent lidocaine in women undergoing breast cancer surgery.

PURPOSE: Tumescent lidocaine anesthesia (TLA) is an opportunity to perform mastectomy for breast cancer without general anesthesia in elderly women. Few reports are available on the pharmacokinetics of lidocaine in a context of TLA during a unilateral mastectomy. The aim of this study was to describe lidocaine pharmacokinetics in elderly women undergoing breast cancer surgery after TLA and to explore the risk of the toxicity of this technique. METHODS: A prospective study was conducted to examine the pharmacokinetics of lidocaine in women undergoing TLA. TLA consists of an intradermal lidocaine instillation (20 mL, 1% [200 mg]) followed by a tumescent lidocaine infiltration (100 mL of 1% lidocaine [1000 mg] and 0.5 mg epinephrine to 1 L Ringer's lactate) via an infusion pump. A population pharmacokinetic (popPK) analysis was performed using the nonlinear mixed effects model (NONMEM). RESULTS: The analysis included 116 observations from 17 women with a median (range) age of 83.4 (60.5-90.0). The median tumescent lidocaine dose was 800 mg (range 375-1000 mg) infused over 48.0 ± 11.0 min. A one-compartment disposition model with first order absorption, two input compartments, and a central elimination best described the pharmacokinetics of lidocaine. The estimates (between subject variability; relative standard error, %) of apparent volume, apparent clearance, tumescent absorption rate, and instillation absorption rate were 195.0 (46.3; 14.5%) L, 24.7 (48.9; 13.3%) L h-1, 0.28 (39.6; 13.8%) h-1, and 2.56 (135.3; 44.9%) h-1, respectively. CONCLUSIONS: This is the first popPK model developed to describe kinetic profiles of TLA. These findings confirm the slow diffusion of lidocaine from the tumescent deposit.

Population pharmacokinetics of rifampicin in adult patients with osteoarticular infections: interaction with fusidic acid.

AIMS: Rifampicin represents the key antibiotic for the management of osteoarticular infections. An important pharmacokinetic variability has already been described, particularly for absorption and metabolism. All previous pharmacokinetic studies have been focused only on patients treated for tuberculosis. The objective of the present study was to describe a population pharmacokinetic model of rifampicin in patients with staphylococcal osteoarticular infections, which has not been investigated to date. METHOD: Rifampicin concentrations were collected retrospectively from 62 patients treated with oral rifampicin 300 mg three times daily. Plasma concentration-time data were analysed using NONMEM to estimate population pharmacokinetic parameters. Demographic data, infection characteristics and antibiotics taken in addition to rifampicin antibiotics were investigated as covariates. RESULTS: A one-compartment model, coupled to a transit absorption model, best described the rifampicin data. Fusidic acid coadministration was identified as a covariate in rifampicin pharmacokinetic parameters. The apparent clearance and apparent central volume of distribution mean values [95% confidence interval (CI)] were 5.1 1 h-1 (1.2, 8.2 1 h-1 )/23.8 l (8.9, 38.7 l) and 13.7 1 h-1 (10.6, 18.0 1 h-1 )/61.1 1 (40.8, 129.0 1) for patients with and without administration of fusidic acid, respectively. Interindividual variability (95% CI) in the apparent clearance and apparent central volume of distribution were 72.9% (49.5, 86.0%) and 59.1% (5.5, 105.4%), respectively. Residual variability was 2.3 mg l-1 (1.6, 2.6 mg l-1 ). CONCLUSION: We developed the first population pharmacokinetic model of rifampicin in patients with osteoarticular infections. Our model demonstrated that fusidic acid affects rifampicin pharmacokinetics, leading to potential high drug exposure. This finding suggests that fusidic acid dosing regimens should be reconsidered.

Dissociating Bottom-Up and Top-Down Mechanisms in the Cortico-Limbic System during Emotion Processing.

The cortico-limbic system is critically involved in emotional responses and resulting adaptive behaviors. Within this circuit, complementary regions are believed to be involved in either the appraisal or the regulation of affective state. However, the respective contribution of these bottom-up and top-down mechanisms during emotion processing remains to be clarified. We used a new functional magnetic resonance imaging (fMRI) paradigm varying 3 parameters: emotional valence, emotional congruency, and allocation of attention, to distinguish the functional variation in activity and connectivity between amygdala, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Bottom-up appraisal of negative compared with positive stimuli led to a greater amygdala response and stronger functional interaction between amygdala and both dorsal ACC and DLPFC. Top-down resolution of emotional conflict was associated with increased activity within ACC and higher functional connectivity between this structure, and both the amygdala and DLPFC. Finally, increased top-down attentional control caused greater engagement of the DLPFC, accompanied by increased connectivity between DLPFC and dorsal ACC. This novel task provides an efficient tool for exploring bottom-up and top-down processes underlying emotion and may be particularly helpful for investigating the neurofunctional underpinnings of psychiatric disorders.

Levodopa in Parkinson's Disease: A Review of Population Pharmacokinetics/Pharmacodynamics Analysis.

BACKGROUND: Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease. Although levodopa remains the single effective agent in the management of Parkinson's disease, the accurate determination of this optimal dosage is complicated by marked between-subject and between-occasion variability in this population.  This review presents a synthesis of the population pharmacokinetic and pharmacodynamic models of levodopa described in Parkinson's disease. METHODS: A literature search was conducted from the PubMed database, from their inception through April 2016, using the following terms: levodopa, pharmacokinetic(s), pharmacodynamic(s) population, model(ling) and nonlinear mixed effect. Articles were excluded if they were not pertinent. References of all selected articles were also evaluated. RESULTS: A total of 12 articles were finally retained. The following covariates were selected as interindividual variability factors: body weight, age, sex, creatinine clearance and levodopa dose. The clinical response versus effect site concentration relationship was described with different sigmoidal Emax models. Different pharmacodynamic effects were described: UPDRS, Tapping, Dyskinesia, CURSΣ and treatment response scale. DISCUSSION: This review allows us to realize interpretation of a patient's clinical picture and confirmed the appropriateness of the pharmacokinetic-pharmacodynamic modeling for levodopa. External evaluation of previous published models should be also continued to evaluate these previous studies. New pharmacokinetic and/or pharmacodynamic population modelling studies could be consider to improve future models and decrease variability, to better understand the evolution of patients with Parkinson's disease treated by levodopa. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Investigating patient narratives posted on Internet and their informativeness level for pharmacovigilance purpose: The example of comments about statins.

AIM OF THE STUDY: Health-related networks like patient health forums may be considered as potential sources of information to early detect pharmacovigilance issues or complete data on drug safety. However, the clinical and pharmacological relevancy of such a source has not been clearly explored. We aimed to describe the characteristics and the informativeness level of Internet narratives posted by patients and mentioning adverse drug reactions (ADRs) related to statins. METHODS: A retrospective cross-sectional study was conducted on an Internet website dedicated to share experience on medicines. One day of December 2012, postings about simvastatin, rosuvastatin and atorvastatin publicly available on the website were collected. Their informativeness according to 16 key elements of information (including drug start and stop date, duration of treatment, time to onset and duration of the ADR, outcome, medical history, concomitant medication) was assessed. General information about reported ADRs was also investigated. RESULTS: Among the 96 postings related to statins, 72 (40 women, 32 men; mean age: 59 [40-78]) mentioned at least one ADR accounting for a total of 176 ADRs. Musculoskeletal and connective tissue disorders (42.6%) and nervous system disorders (15.3%) were the main represented ADRs. Only 2 patients mentioned ADRs that could be considered as serious but 24 patients mentioned they stopped or switched their treatment toward another lipid modifying agent because of the ADR. Mean number of available key elements of information per narrative was 6/16. Time to onset and duration of the ADR were respectively available in only 31% and 3% of the narratives. Medical history and concomitant medication were respectively lacking in 87% and 86% of the narratives. Outcome was found only in 39% of the narratives. CONCLUSION: Patient narratives posted on Internet include mainly non-serious expected ADR. However, their informativeness level is very incomplete and makes difficult their assessment and use for pharmacovigilance purpose.