Guía de consenso de expertos para la monitorización terapéutica de drogas en neuropsicofarmacología / Consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology

OBJETIVO: La Monitorización Terapéutica de Drogas (llamada en inglés TDM: therapeutic drug monitoring) combina la cuantificación de las concentraciones de medicamentos en la sangre, la interpretación farmacológica y las directrices de tratamiento. La TDM introduce una herramienta de medicina de precisión en una ípoca de gran conciencia de la necesidad de tratamientos personalizados en neurología y psiquiatría. Las indicaciones claras de la TDM incluyen la ausencia de respuesta clínica en el rango de dosis terapéuticas, la evaluación de la adherencia farmacológica, problemas de tolerancia e interacciones medicamentosas. MÉTODOS: Basándose en la literatura existente, se describieron los rangos de referencia terapéutica recomendables, los valores críticos de laboratorio y los niveles de recomendación para usar la TDM para la optimización de dosis sin indicaciones específicas, se calcularon los factores de conversión, los factores para el cálculo de concentraciones medicamentosas relacionadas con la dosis (en inglés DRC dose-to-ratioconcentration) y el cociente entre el metabolito y el compuesto original (en inglés se llama MPR: metabolite-to-parent ratio). RESULTADOS: Este resumen de las guías actualizadas del consenso por la Task Force del TDM del Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie, ofrece el conocimiento práctico y teórico para la integración de la TDM como parte de la farmacoterapia con medicamentos neuropsiquiátricos en la práctica clínica rutinaria. CONCLUSIONES: La presente traducción en español, de la guía para la aplicación del TDM en medicamentos neuropsiquiátricos, tiene como objetivo ayudar a los clínicos a mejorar la seguridad y la eficacia de los tratamientos

OBJECTIVES: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation, and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalised treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities, and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues, and drug-drug interactions. METHODS: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimisation without specific indications, conversion factors, factors for calculation of dose-related drug concentrations, and metabolite-to-parent ratios were calculated. RESULTS: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuro- psychiatric agents into clinical routine. CONCLUSIONS: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment

[Therapeutic drug monitoring in neuropsychopharmacology : Summary of the consensus guidelines 2017 of the TDM task force of the AGNP]. / Therapeutisches Drug-Monitoring in der Neuropsychopharmakologie : Zusammenfassung der Konsensusleitlinien 2017 der TDM-Arbeitsgruppe der AGNP.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood serum or plasma to optimize pharmacological therapy. TDM is an instrument with which the high interindividual variability of pharmacokinetics of patients can be identified and therefore enables a personalized pharmacotherapy. In September 2017 the TDM task force of the Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) published an update of the consensus guidelines on TDM published in 2011. This article summarizes the essential statements for the clinical practice in psychiatry and neurology.

Influence of Dose and Antiepileptic Comedication on Lacosamide Serum Concentrations in Patients With Epilepsy of Different Ages.

BACKGROUND: Lacosamide (LCM) is a new antiepileptic drug (AED). The purpose of the study was to investigate the effects of LCM dose, body weight, height, sex, age, and concomitant AEDs on LCM trough serum concentrations (at a steady state) in patients with epilepsy. METHODS: A total number of 3154 blood samples of 973 consecutive patients of the Mara Hospital (Bethel Epilepsy Centre) were evaluated. Generalized estimating equation (GEE) models were used for statistical analyses. RESULTS: GEE analyses showed that LCM trough serum concentrations were significantly correlated with the body weight-normalized LCM dose (range: 0.44-25.7 mg/kg; 45-1050 mg) and significantly dependent on comedication and age. Compared with adults (18-60 years), the LCM trough serum concentrations of children aged 6-12 years and children younger than 6 years were significantly lower (-21% to -38%, respectively) and those of elderly patients (>60 years) were significantly higher (+20%). Sex had no significant influence. Carbamazepine, phenytoin, primidone, phenobarbital, and methsuximide decreased LCM trough serum concentrations significantly by 30%, 32%, 34%, 39%, and 41%, respectively, whereas other AEDs (eg, oxcarbazepine, eslicarbazepine acetate, valproate) had no significant or only a minor impact (zonisamide) on LCM trough concentrations. In children, the effect of enzyme-inducing AEDs was more marked. Of note, the number of blood samples (n = 151) of patients younger than 12 (n = 78) was comparatively low. Alternative GEE models confirmed the effect of comedication, whereas the effect of age, especially in children, depended on adjustment of LCM dosage to body weight, body surface area, or approximated volume of distribution. CONCLUSIONS: In accordance with previous therapeutic drug monitoring studies, our results confirmed that enzyme inducers reduce the LCM trough serum concentrations by 30%-40%. In children, the effects of comedication are more pronounced but should be confirmed by further studies.

Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype.

Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3-chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies.

TDM in psychiatry and neurology: A comprehensive summary of the consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology, update 2017; a tool for clinicians.

OBJECTIVES: Therapeutic drug monitoring (TDM) combines the quantification of drug concentrations in blood, pharmacological interpretation and treatment guidance. TDM introduces a precision medicine tool in times of increasing awareness of the need for personalized treatment. In neurology and psychiatry, TDM can guide pharmacotherapy for patient subgroups such as children, adolescents, pregnant women, elderly patients, patients with intellectual disabilities, patients with substance use disorders, individuals with pharmacokinetic peculiarities and forensic patients. Clear indications for TDM include lack of clinical response in the therapeutic dose range, assessment of drug adherence, tolerability issues and drug-drug interactions. METHODS: Based upon existing literature, recommended therapeutic reference ranges, laboratory alert levels, and levels of recommendation to use TDM for dosage optimization without specific indications, conversion factors, factors for calculation of dose-related drug concentrations and metabolite-to-parent ratios were calculated. RESULTS: This summary of the updated consensus guidelines by the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie offers the practical and theoretical knowledge for the integration of TDM as part of pharmacotherapy with neuropsychiatric agents into clinical routine. CONCLUSIONS: The present guidelines for TDM application for neuropsychiatric agents aim to assist clinicians in enhancing safety and efficacy of treatment.

Assessment of the correlations of lacosamide concentrations in saliva and serum in patients with epilepsy.

Therapeutic drug monitoring of antiepileptic drugs is based on patient serum samples. In this study, we evaluated the correlation between lacosamide (LCM) steady state concentrations in serum and saliva samples. Additionally, we investigated the relation with daily dose, and assessed the feasibility of saliva collection. This was an open-label, single center study including data from 25 patients at the Bethel Epilepsy Center treated with LCM (50-650 mg/d). Samples were collected in the morning (fasting values) and in selected cases at 50 minutes to 5 hours after the morning dose. Nonsignificant differences in the mean LCM morning (trough) concentration in serum and saliva were observed. Serum and saliva concentrations across all samples were highly correlated, (r = .874), with a slightly lower correlation when only fasting values were analyzed (r = .860). Higher correlation with daily dosages was observed in serum samples (r = .773) than in saliva samples (r = .604). Serum and saliva concentrations increased significantly after intake of the LCM morning dose (P < .001). The median absolute and percentage increase of LCM in serum were moderately lower than in saliva samples, with a few outliers in saliva samples. Consequently, saliva could offer great clinical potential to monitor drug concentrations and guide LCM treatment in epileptic patients.

Comparison of lacosamide concentrations in cerebrospinal fluid and serum in patients with epilepsy.

OBJECTIVE: This study was carried out to estimate the exposure of the central nervous system (CNS) to the antiepileptic drug (AED) lacosamide, under steady state conditions, in patients with epilepsy who take oral lacosamide alongside up to three other AEDs. METHODS: Twenty-seven serum and cerebral spinal fluid (CSF) samples were collected from 21 patients receiving lacosamide for the treatment of epilepsy (50-600 mg/day over two or three doses). This included 23 time-matched pairs of serum and CSF samples from 19 patients. The concentration of lacosamide in each sample was determined using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Linear regression was used to characterize the relationship between the CSF-to-serum ratio of lacosamide concentration and the time since dosing, the daily lacosamide dose, or the daily dose normalized by volume of distribution (Vd , approximated to total body water), and between the drug concentrations in each compartment (CSF vs. serum). RESULTS: Concentrations of lacosamide in CSF (mean ± standard deviation [SD] 7.37 ± 3.73 µg/ml, range 1.24-14.95, n = 27) and serum (mean ± SD 8.16 ± 3.82 µg/ml, range 2.29-15.45, n = 27) samples showed a good correlation over the dose range investigated. The mean CSF-to-serum ratio of lacosamide concentrations was 0.897 ± 0.193 (range 0.492-1.254, n = 23 time-matched pairs) and was independent of lacosamide dose. SIGNIFICANCE: Drug concentrations in the CSF are often used to indicate those in the brain interstitial fluid. In patients with epilepsy who follow a stable oral AED dosing regimen, lacosamide concentration in CSF is approximately 85% of that found in serum, suggesting that serum may be a valuable indicator of lacosamide concentration in the CNS.

The antiepileptic drug lamotrigine is a substrate of mouse and human breast cancer resistance protein (ABCG2).

Resistance to antiepileptic drugs (AEDs) is the major problem in the treatment of epilepsy. One hypothesis to explain AED resistance suggests that seizure-induced overexpression of efflux transporters at the blood-brain barrier (BBB) restricts AEDs to reach their brain targets. Various studies examined whether AEDs are substrates of P-glycoprotein (Pgp; MDR1; ABCB1), whereas information about the potential role of breast cancer resistance protein (BCRP; ABCG2) is scanty. We used a highly sensitive in vitro assay (concentration equilibrium transport assay; CETA) with MDCKII cells transduced with murine Bcrp1 or human BCRP to evaluate whether AEDs are substrates of this major efflux transporter. Six of 7 AEDs examined, namely phenytoin, phenobarbital, carbamazepine, levetiracetam, topiramate, and valproate, were not transported by Bcrp at therapeutic concentrations, whereas lamotrigine exhibited a marked asymmetric, Bcrp-mediated transport in the CETA, which could be almost completely inhibited with the Bcrp inhibitor Ko143. Significant but less marked transport of lamotrigine was determined in MDCK cells transfected with human BCRP. Lamotrigine is also a substrate of human Pgp, so that this drug is the first AED that has been identified as a dual substrate of the two major human efflux transporters at the BBB. Previous in vivo studies have demonstrated a synergistic or cooperative role of Pgp and Bcrp in the efflux of dual substrates at the BBB, so that transport of lamotrigine by Pgp and BCRP may be an important mechanism of pharmacoresistance in epilepsy patients in whom both transporters are overexpressed.