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Metabolic abnormalities have been associated with olanzapine treatment. We assessed if olanzapine has dose-dependent effects on metabolic parameters with changes for weight, blood pressure, lipid and glucose profiles being modelled using linear mixed-effects models. The risk of metabolic abnormalities including early weight gain (EWG) (≥5% during first month) was assessed using mixed-effects logistic regression models. In 392 olanzapine-treated patients (median age 38.0 years, interquartile range [IQR] = 26.0-53.3, median dose 10.0 mg/day, IQR = 5.0-10.0 for a median follow-up duration of 40.0 days, IQR = 20.7-112.2), weight gain was not associated with olanzapine dose (p = 0.61) although it was larger for doses versus ≤10 mg/day (2.54 ± 5.55 vs. 1.61 ± 4.51% respectively, p = 0.01). Treatment duration and co-prescription of >2 antipsychotics, antidepressants, benzodiazepines and/or antihypertensive agents were associated with larger weight gain (p < 0.05). Lower doses were associated with increase in total and HDL cholesterol and systolic and diastolic blood pressure (p < 0.05), whereas higher doses were associated with glucose increases (p = 0.01). Patients receiving >10 mg/day were at higher EWG risk (odds risk: 2.15, 1.57-2.97). EWG might be prominent in high-dose olanzapine-treated patients with treatment duration and co-prescription of other medications being weight gain moderators. The lack of major dose-dependent patterns for weight gain emphasizes that olanzapine-treated patients are at weight gain risk regardless of the dose.

International audience; Psychotropic drugs can induce strong metabolic adverse effects, potentially increasing morbidity and/or mortality of patients. Metabolomic profiling, by studying the levels of numerous metabolic intermediates and products in the blood, allows a more detailed examination of metabolism dysfunctions. We aimed to identify blood metabolomic markers associated with weight gain in psychiatric patients. Sixty-two patients starting a treatment known to induce weight gain were recruited. Two hundred and six selected metabolites implicated in various pathways were analyzed in plasma, at baseline and after 1 month of treatment. Additionally, 15 metabolites of the kynurenine pathway were quantified. This latter analysis was repeated in a confirmatory cohort of 24 patients. Among the 206 metabolites, a plasma metabolomic fingerprint after 1 month of treatment embedded 19 compounds from different chemical classes (amino acids, acylcarnitines, carboxylic acids, catecholamines, nucleosides, pyridine, and tetrapyrrole) potentially involved in metabolic disruption and inflammation processes. The predictive potential of such early metabolite changes on 3 months of weight evolution was then explored using a linear mixed-effects model. Of these 19 metabolites, short-term modifications of kynurenine, hexanoylcarnitine, and biliverdin, as well as kynurenine/tryptophan ratio at 1 month, were associated with 3 months weight evolution. Alterations of the kynurenine pathway were confirmed by quantification, in both exploratory and confirmatory cohorts. Our metabolomic study suggests a specific metabolic dysregulation after 1 month of treatment with psychotropic drugs known to induce weight gain. The identified metabolomic signature could contribute in the future to the prediction of weight gain in patients treated with psychotropic drugs.

Few studies have evaluated the influence of valproate on the deterioration of the lipid profile in psychiatric patients. This observational study aimed to compare the evolution of metabolic parameters in a sample of adult patients starting valproate (n = 39) with a control group (n = 39) of patients starting aripiprazole, a drug associated with a low risk of metabolic deterioration. Data were obtained from a prospective study including psychiatric patients with metabolic parameters monitored during the first year of treatment. During the first month of treatment with valproate (median: 31 days [IQR: 25-36]), mean body mass index increased significantly (from 24.8 kg/m 2 at baseline to 25.2 kg/m 2 after one month; P = .03) and mean HDL-C levels decreased significantly (from 1.39 mmol/L to 1.27 mmol/L; P = .02). In comparison, these metabolic variables remained stable during the first month of treatment with aripiprazole. The proportion of patients with early (ie during the first month of treatment) HDL-C decrease of ≥ 5% was significantly higher under valproate (54%) than aripiprazole (15%) treatment (P < .001). These findings remind the importance of a prospective metabolic monitoring in patients who initiate valproate treatment. Further research should be conducted on larger samples and should focus on finding effective interventions to prevent such metabolic adverse effects.

AIMS: The aims of this study were to characterize escitalopram pharmacokinetic profile, to identify factors influencing drug exposure, notably drug–drug interactions with antiretrovirals, and to simulate expected exposure under standard dosage regimen. METHODS: A population pharmacokinetic analysis was performed using NONMEM. A total of 159 plasma concentration measurements were obtained from 39 human immunodeficiency virus (HIV)‐infected and 71 uninfected psychiatric patients. The influence of age, weight, sex, HIV and psychiatric cohorts, racemic citalopram treatment, and comedications on oral clearance was examined. Simulations served to calculate the percentage of patients expected to be under‐ or over‐exposed, considering established therapeutic targets (15–80 ng/mL). RESULTS: A 1‐compartment model with first‐order absorption and elimination described the data adequately. The average escitalopram clearance and volume of distribution were 23.1 L/h (interindividual variability 51%), and 920 L, respectively. Escitalopram disposition did not differ between HIV‐infected and uninfected patients, and was not affected by antiretroviral treatments. Coadministration of at least 1 proton‐pump inhibitor (CYP2C19 inhibitor) modestly influenced escitalopram elimination (clearance decreased by 19%), with limited clinical relevance. Model‐based simulations showed that, under a standard regimen of 10 mg once daily, a significant proportion of patients (56%) might be under‐exposed. CONCLUSION: The variability in escitalopram disposition is large and poorly explained by demographic, clinical and environmental covariates, thus suggesting a role for dosage individualization based on therapeutic drug monitoring in case of poor clinical response. Escitalopram disposition is modestly impacted by comedications and therefore no a priori dosage adjustments are needed in patients receiving antiretroviral treatments, including boosted regimens.

Background - We previously showed a tumor‐suppressive function of S100A14 in oral squamous cell carcinoma (OSCC). This study aimed to examine the prognostic significance and differentiation‐related function of S100A14 in OSCC. Methods - S100A14 expression was examined in 170 OSCCs from Norwegian and Nepalese populations using immunohistochemistry. Pro‐differentiation function was investigated by overexpressing and silencing S100A14 expression in OSCC‐derived cells. External transcriptomic datasets were used to validate association between S100A14 and differentiation markers in OSCC. Result - Loss of S100A14 expression at the invading tumor fronts significantly correlated with poor differentiation and reduced 10‐years survival of OSCC‐patients. Multivariate Cox analysis identified S100A14 to be an independent prognostic factor. Modulation of S100A14 expression in OSCC‐derived cells positively correlated with the expression of differentiation markers. Analysis of external datasets supported the pro‐differentiation function of S100A14. Conclusion - These results indicate that S100A14 is a pro‐differentiation protein and its expression might be useful as a prognostic marker in OSCC.

Aims The biological response to clopidogrel is highly variable and a poor responsiveness is associated with major adverse cardiac events. Adherence to therapy is a major cause of poor responsiveness but its impact on long-term platelet inhibition is unknown. The objective of the present study was to evaluate the effect of different programmes monitoring adherence to clopidogrel on platelet reactivity. Methods The study took the form of a monocentric, parallel group, randomized controlled trial. Adults treated with clopidogrel 75 mg after elective coronary stenting were randomized into one of three groups: (i) a standard of care group; (ii) a standard of care + adherence electronic monitoring group, in which drug intake was recorded but kept blinded until the study end; or (iii) an integrated care group, with regular feedback on recorded adherence. Clopidogrel response was assessed with the vasodilator-stimulated phosphoprotein–platelet reactivity index (VASP-PRI) at randomization, 3 months and 6 months. Results A total of 123 adults were enrolled and randomized. Baseline VASP-PRI was highly variable, with a mean of 48 ± 18.8%. No difference between groups in VASP-PRI was found at 6 months (P = 0.761), despite better adherence to clopidogrel in the integrated care group. However, adherence (P = 0.035) and baseline VASP-PRI (P = 0.015) were associated with VASP-PRI at 3 months and 6 months. The association between adherence and VASP-PRI was lost in patients with baseline VASP-PRI > 50%. Diabetes, CYP2C19*2 carrier status and body mass index were significant predictors of VASP-PRI. Conclusions The platelet response to clopidogrel during chronic therapy remained highly variable, despite high adherence. Different adherence monitoring programmes did not affect VASP-PRI at 6 months. Poor adherence is associated with lower VASP-PRI only in initial good responders to clopidogrel.

INTRODUCTION Serving as a pilot study of poststroke pharmacotherapy, the present investigation was intended to establish the effect of a single dose of escitalopram on motor task performance in normal volunteers. METHODS Ten healthy volunteers of median age 63 years including four females performed a well-studied tactile manipulation task in two fMRI sessions using a double-blind cross-over design. The sessions began approximately three hours after ingestion of 20 mg escitalopram or placebo presented in pseudorandom order. The fMRI image sequences were submitted to principal component analysis (PCA). RESULTS Based on volume correlations of task-related principal components with the mean component images derived in our previous study, we established the reproducibility of two networks of sensorimotor activity proposed there. The network reflecting motor control (cerebral pattern I) appeared invariably in placebo and verum conditions. In contrast, the other network, attributed to diminished motor control due to distracting mental processing (cerebral pattern II), emerged less regularly and exhibited more variability. Second-level PCAs of both conditions confirmed the findings of the initial analysis. Specifically, it validated the dominant and invariable expression of cerebral pattern I after application of a single dose of escitalopram. Dynamic causal modeling confirmed enhanced motor output as a result of a significantly increased connectivity between primary motor cortex and dorsal premotor cortex. CONCLUSION This pilot study suggests the promise of stimulation by a specific serotonin reuptake inhibitor in regard to recovery and preservation of motor control after stroke.

Aims A large interindividual variability in plasma concentrations has been reported in patients treated with donepezil, the most frequently prescribed antidementia drug. We aimed to evaluate clinical and genetic factors influencing donepezil disposition in a patient population recruited from a naturalistic setting. Methods A population pharmacokinetic study was performed including data from 129 older patients treated with donepezil. The patients were genotyped for common polymorphisms in the metabolic enzymes CYP2D6 and CYP3A, in the electron transferring protein POR and the nuclear factor NR1I2 involved in CYP activity and expression, and in the drug transporter ABCB1. Results The average donepezil clearance was 7.3 l h−1 with a 30% interindividual variability. Gender markedly influenced donepezil clearance (P < 0.01). Functional alleles of CYP2D6 were identified as unique significant genetic covariate for donepezil clearance (P < 0.01), with poor metabolizers and ultrarapid metabolizers demonstrating, respectively, a 32% slower and a 67% faster donepezil elimination compared with extensive metabolizers. Conclusion The pharmacokinetic parameters of donepezil were well described by the developed population model. Functional alleles of CYP2D6 significantly contributed to the variability in donepezil disposition in the patient population and should be further investigated in the context of individual dose optimization to improve clinical outcome and tolerability of the treatment.

Aim Total imatinib concentrations are currently measured for the therapeutic drug monitoring of imatinib, whereas only free drug equilibrates with cells for pharmacological action. Due to technical and cost limitations, routine measurement of free concentrations is generally not performed. In this study, free and total imatinib concentrations were measured to establish a model allowing the confident prediction of imatinib free concentrations based on total concentrations and plasma proteins measurements. Methods One hundred and fifty total and free plasma concentrations of imatinib were measured in 49 patients with gastrointestinal stromal tumours. A population pharmacokinetic model was built up to characterize mean total and free concentrations with inter-patient and intrapatient variability, while taking into account α1-acid glycoprotein (AGP) and human serum albumin (HSA) concentrations, in addition to other demographic and environmental covariates. Results A one compartment model with first order absorption was used to characterize total and free imatinib concentrations. Only AGP influenced imatinib total clearance. Imatinib free concentrations were best predicted using a non-linear binding model to AGP, with a dissociation constant Kd of 319 ng ml−1, assuming a 1:1 molar binding ratio. The addition of HSA in the equation did not improve the prediction of imatinib unbound concentrations. Conclusion Although free concentration monitoring is probably more appropriate than total concentrations, it requires an additional ultrafiltration step and sensitive analytical technology, not always available in clinical laboratories. The model proposed might represent a convenient approach to estimate imatinib free concentrations. However, therapeutic ranges for free imatinib concentrations remain to be established before it enters into routine practice.

BACKGROUND AND PURPOSE: There is high interindividual variability in the activity of drug-metabolizing enzymes catalysing the oxidation of oxycodone [cytochrome P450 (CYP) 2D6 and 3A], due to genetic polymorphisms and/or drug-drug interactions. The effects of CYP2D6 and/or CYP3A activity modulation on the pharmacokinetics of oxycodone remains poorly explored. EXPERIMENTAL APPROACH: A randomized crossover double-blind placebo-controlled study was performed with 10 healthy volunteers genotyped for CYP2D6 [six extensive (EM), two deficient (PM/IM) and two ultrarapid metabolizers (UM)]. The volunteers randomly received on five different occasions: oxycodone 0.2 mg x kg(-1) and placebo; oxycodone and quinidine (CYP2D6 inhibitor); oxycodone and ketoconazole (CYP3A inhibitor); oxycodone and quinidine+ketoconazole; placebo. Blood samples for plasma concentrations of oxycodone and metabolites (oxymorphone, noroxycodone and noroxymorphone) were collected for 24 h after dosing. Phenotyping for CYP2D6 (with dextromethorphan) and CYP3A (with midazolam) were assessed at each session. KEY RESULTS: CYP2D6 activity was correlated with oxymorphone and noroxymorphone AUCs and C(max) (-0.71 < Spearman correlation coefficient rhos < -0.92). Oxymorphone C(max) was 62% and 75% lower in PM than EM and UM. Noroxymorphone C(max) reduction was even more pronounced (90%). In UM, oxymorphone and noroxymorphone concentrations increased whereas noroxycodone exposure was halved. Blocking CYP2D6 (with quinidine) reduced oxymorphone and noroxymorphone C(max) by 40% and 80%, and increased noroxycodone AUC(infinity) by 70%. Blocking CYP3A4 (with ketoconazole) tripled oxymorphone AUC(infinity) and reduced noroxycodone and noroxymorphone AUCs by 80%. Shunting to CYP2D6 pathway was observed after CYP3A4 inhibition. CONCLUSIONS AND IMPLICATIONS: Drug-drug interactions via CYP2D6 and CYP3A affected oxycodone pharmacokinetics and its magnitude depended on CYP2D6 genotype.

BACKGROUND AND PURPOSE: The major drug-metabolizing enzymes for the oxidation of oxycodone are CYP2D6 and CYP3A. A high interindividual variability in the activity of these enzymes because of genetic polymorphisms and/or drug-drug interactions is well established. The possible role of an active metabolite in the pharmacodynamics of oxycodone has been questioned and the importance of CYP3A-mediated effects on the pharmacokinetics and pharmacodynamics of oxycodone has been poorly explored. EXPERIMENTAL APPROACH: We conducted a randomized crossover (five arms) double-blind placebo-controlled study in 10 healthy volunteers genotyped for CYP2D6. Oral oxycodone (0.2 mg x kg(-1)) was given alone or after inhibition of CYP2D6 (with quinidine) and/or of CYP3A (with ketoconazole). Experimental pain (cold pressor test, electrical stimulation, thermode), pupil size, psychomotor effects and toxicity were assessed. KEY RESULTS: CYP2D6 activity was correlated with oxycodone experimental pain assessment. CYP2D6 ultra-rapid metabolizers experienced increased pharmacodynamic effects, whereas cold pressor test and pupil size were unchanged in CYP2D6 poor metabolizers, relative to extensive metabolizers. CYP2D6 blockade reduced subjective pain threshold (SPT) for oxycodone by 30% and the response was similar to placebo. CYP3A4 blockade had a major effect on all pharmacodynamic assessments and SPT increased by 15%. Oxymorphone C(max) was correlated with SPT assessment (rho(S)= 0.7) and the only independent positive predictor of SPT. Side-effects were observed after CYP3A4 blockade and/or in CYP2D6 ultra-rapid metabolizers. CONCLUSIONS AND IMPLICATIONS: The modulation of CYP2D6 and CYP3A activities had clear effects on oxycodone pharmacodynamics and these effects were dependent on CYP2D6 genetic polymorphism.

AIMS: The aims of this observational study were to assess the variability in imatinib pharmacokinetics and to explore the relationship between its disposition and various biological covariates, especially plasma alpha1-acid glycoprotein concentrations. METHODS: A population pharmacokinetic analysis was performed using NONMEM based on 321 plasma samples from 59 patients with either chronic myeloid leukaemia or gastrointestinal stromal tumours. The influence of covariates on oral clearance and volume of distribution was examined. Furthermore, the in vivo intracellular pharmacokinetics of imatinib was explored in five patients. RESULTS: A one-compartment model with first-order absorption appropriately described the data, giving a mean (+/-SEM) oral clearance of 14.3 l h-1 (+/-1.0) and a volume of distribution of 347 l (+/-62). Oral clearance was influenced by body weight, age, sex and disease diagnosis. A large proportion of the interindividual variability (36% of clearance and 63% of volume of distribution) remained unexplained by these demographic covariates. Plasma alpha1-acid glycoprotein concentrations had a marked influence on total imatinib concentrations. Moreover, we observed an intra/extracellular ratio of 8, suggesting substantial uptake of the drug into the target cells. CONCLUSION: Because of the high pharmacokinetic variability of imatinib and the reported relationships between its plasma concentration and efficacy and toxicity, the usefulness of therapeutic drug monitoring as an aid to optimizing therapy should be further investigated. Ideally, such an approach should take account of either circulating alpha1-acid glycoprotein concentrations or free imatinib concentrations.

Aims To identify the molecular basis for a low CYP1A2 metabolic status, as determined by a caffeine phenotyping test, in a 71-year-old, nonsmoking, Caucasian woman who presented with very high clozapine concentrations despite being administered a standard dose of the drug. Methods The nucleotide sequence of the 7 exons, exon-intron boundaries and 5′-flanking region of the CYP1A2 gene was analysed by direct sequencing. Results Only one heterozygous point mutation was identified in the donor splice site of intron 6 (3534G > A) of CYP1A2. This mutation could cause abnormal RNA splicing and therefore lead to a truncated nonfunctional enzyme. No other carrier of this mutation was identified in a population of 100 unrelated healthy Caucasians. Conclusions This is the first report of a splice-site mutation affecting the CYP1A2 gene. This polymorphism is a likely explanation for the low CYP1A2 activity associated with high clozapine concentrations in this patient.

Many antidepressants have been introduced as racemic drugs, the enantiomers of which may differ in some of their pharmacodynamic and pharmacokinetic properties. This review argues that each enantiomer of a chiral antidepressant should be evaluated according to its individual characteristics rather than by extrapolation from the racemate, or by assumptions based on the stereoselective characteristics of other enantiomeric drugs. For example, in some cases the enantiomers' pharmacodynamic and therapeutic properties can be complementary, which suggests that the racemate should be used clinically. In other cases where enantiomers show qualitatively similar but quantitatively different properties to the racemate, using a single enantiomer might be more appropriate. In yet further cases, a distomer may induce the metabolism of the eutomer, enantiomers may be metabolised by different enzymes, there may be a different profile of drug-drug interactions, and therapeutic drug monitoring may be simpler. Therefore, this review exemplifies the principle that each enantiomer of a chiral antidepressant should be evaluated according to its individual pharmacological, pharmacokinetic and pharmacogenetic characteristics. These factors are discussed in relation to five chiral antidepressants: trimipramine, mianserin, mirtazapine, fluoxetine and citalopram. It is hoped that an appreciation of the stereoselective differences between enantiomers will facilitate improvements in the benefit:risk ratio of drugs used in the management of depression. Copyright 2001 John Wiley & Sons, Ltd.

An HPLC method is presented which allows the measurement in the same run of the enantiomers of mianserin, desmethylmianserin, and 8-hydroxymianserin in plasma and urine of mianserin-treated patients. Limits of quantitation for the (S)- and (R)- enantiomers of mianserin and desmethylmianserin were 4 and 2.5 ng/ml, respectively, in plasma, and for the (S)- and (R)-enantiomers of mianserin, desmethylmianserin, and 8-hydroxymianserin 5, 2.5, and 5 ng/ml, respectively, in urine. The measured ratios of (S)-mianserin/(R)-mianserin and (S)-desmethylmianserin/(R)-desmethylmianserin in the plasmas of 10 mianserin-treated patients, all extensive metabolizers of debrisoquine as determined by CYP2D6 genotyping, varied, respectively, from 1.0 to 4.06 and from 0.19 to 0.64. As the enantiomers of mianserin differ in their pharmacological profile, these results could partially explain why, until now, no consistent relationship has been established between the therapeutic response and total [(S) + (R)] plasma levels of this antidepressant. © 1994 Wiley-Liss, Inc.

A method allowing a clear separation of the different variants of desialylated alpha 1-acid glycoprotein (orosomucoid) has been developed using isoelectric focusing in immobilized pH gradients, supplemented with 8 M urea and 2% v/v 2-mercaptoethanol. Immunoblotting with two antibody-steps afforded high sensitivity and permitted the detection of about 700 pg of alpha 1-acid glycoprotein in a 20 microL plasma sample diluted 1:28 672. A one year old bloodstrain, kept at room temperature, could easily be phenotyped.