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1.
Clin Pharmacokinet ; 62(11): 1621-1637, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37755681

RESUMEN

BACKGROUND AND OBJECTIVE: Escitalopram and sertraline are commonly prescribed for anxiety and depressive disorders in children and adolescents. The pharmacokinetics (PK) of these medications have been evaluated in adults and demonstrate extensive variability, but studies in pediatric patients are limited. Therefore, we performed a population PK analysis for escitalopram and sertraline in children and adolescents to characterize the effects of demographic, clinical, and pharmacogenetic factors on drug exposure. METHODS: A PK dataset was generated by extracting data from the electronic health record and opportunistic sampling of escitalopram- and sertraline-treated psychiatrically hospitalized pediatric patients aged 5-18 years. A population PK analysis of escitalopram and sertraline was performed using NONMEM. Concentration-time profiles were simulated using MwPharm++ to evaluate how covariates included in the final models influence medication exposure and compared to adult therapeutic reference ranges. RESULTS: The final escitalopram cohort consisted of 315 samples from 288 patients, and the sertraline cohort consisted of 265 samples from 255 patients. A one-compartment model with a proportional residual error model best described the data for both medications. For escitalopram, CYP2C19 phenotype and concomitant CYP2C19 inhibitors affected apparent clearance (CL/F), and normalizing CL/F and apparent volume of distribution (V/F) to body surface area (BSA) improved estimations. The final escitalopram model estimated CL/F and V/F at 14.2 L/h/1.73 m2 and 428 L/1.73 m2, respectively. For sertraline, CYP2C19 phenotype and concomitant CYP2C19 inhibitors influenced CL/F, and empirical allometric scaling of patient body weight on CL/F and V/F was significant. The final sertraline model estimated CL/F and V/F at 124 L/h/70 kg and 4320 L/70 kg, respectively. Normalized trough concentrations (Ctrough) for CYP2C19 poor metabolizers taking escitalopram were 3.98-fold higher compared to normal metabolizers (151.1 ng/mL vs 38.0 ng/mL, p < 0.0001), and normalized Ctrough for CYP2C19 poor metabolizers taking sertraline were 3.23-fold higher compared to normal, rapid, and ultrarapid metabolizers combined (121.7 ng/mL vs 37.68 ng/mL, p < 0.0001). Escitalopram- and sertraline-treated poor metabolizers may benefit from a dose reduction of 50-75% and 25-50%, respectively, to normalize exposure to other phenotypes. CONCLUSION: To our knowledge, this is the largest population PK analysis of escitalopram and sertraline in pediatric patients. Significant PK variability for both medications was observed and was largely explained by CYP2C19 phenotype. Slower CYP2C19 metabolizers taking escitalopram or sertraline may benefit from dose reductions given increased exposure.


Asunto(s)
Escitalopram , Sertralina , Adulto , Adolescente , Humanos , Niño , Sertralina/farmacocinética , Sertralina/uso terapéutico , Citocromo P-450 CYP2C19/genética , Inhibidores del Citocromo P-450 CYP2C19 , Fenotipo
2.
Clin Pharmacol Ther ; 112(6): 1280-1290, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36094046

RESUMEN

Major depressive disorder (MDD) is a common disorder in pregnancy. Although sertraline is the most frequently prescribed antidepressant for pregnant people in the United States, limited information about its pharmacokinetics in pregnancy is available. Our objectives were to characterize plasma sertraline concentration to dose (C/D) ratios across pregnancy and postpartum and investigate the effect of pharmacogenetic variability on sertraline elimination. We performed a prospective observational cohort study in people with a singleton pregnancy ≤ 18 weeks gestation and a lifetime diagnosis of MDD at the 3 Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)-funded Obstetrical-Fetal Pharmacology Research Center sites. Subjects (N = 47) were receiving maintenance sertraline therapy and chose to continue it during pregnancy. Blood samples were obtained 24-hours postdose every 4 weeks across pregnancy and twice postpartum for measurement of plasma concentrations of sertraline and desmethylsertraline. Overall mean sertraline C/D ratios were decreased at study onset and remained consistently low until after delivery. During the last 4 weeks of pregnancy the mean sertraline C/D ratio (95% confidence interval (CI)), 0.25 (95% CI, 0.19, 0.3) ng/mL/dose (mg/day), was smaller than the mean ratio at ≥ 8 weeks after delivery, 0.32 (95% CI, 0.27, 0.37) ng/mL/dose (mg/day), a 22% difference. Mean sertraline/desmethylsertraline ratios were highest after birth, which confirmed increased sertraline elimination during pregnancy. Sertraline C/D ratios in participants with functional CYP2C19 activity did not change significantly during pregnancy, whereas ratios in participants with poor or intermediate CYP2C19 activity decreased by 51%. Exploratory pharmacogenomic analysis indicated that pregnant people with poor or intermediate CYP2C19 activity are at risk for subtherapeutic sertraline concentrations during pregnancy.


Asunto(s)
Trastorno Depresivo Mayor , Sertralina , Femenino , Humanos , Embarazo , Citocromo P-450 CYP2C19/genética , Trastorno Depresivo Mayor/tratamiento farmacológico , Periodo Posparto , Estudios Prospectivos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Sertralina/farmacocinética
3.
Biopharm Drug Dispos ; 42(6): 252-262, 2021 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-33851424

RESUMEN

Sertraline is known to undergo changes in pharmacokinetics during pregnancy. CYP 2C19 has been implicated in the interindividual variation in clinical effect associated with sertraline activity. However, knowledge of suitable dose titrations during pregnancy and within CYP 2C19 phenotypes is lacking. A pharmacokinetic modeling virtual clinical trials approach was implemented to: (i) assess gestational changes in sertraline trough plasma concentrations for CYP 2C19 phenotypes, and (ii) identify appropriate dose titration strategies to stabilize sertraline levels within a defined therapeutic range throughout gestation. Sertraline trough plasma concentrations decreased throughout gestation, with maternal volume expansion and reduction in plasma albumin being identified as possible causative reasons. All CYP 2C19 phenotypes required a dose increase throughout gestation. For extensive metabolizer (EM) and ultrarapid metabolizer (UM) phenotypes, doses of 100-150 mg daily are required throughout gestation. For poor metabolizers (PM), 50 mg daily during trimester 1 followed by a dose of 100 mg daily in trimesters 2 and 3 are required.


Asunto(s)
Antidepresivos , Citocromo P-450 CYP2C19 , Modelos Biológicos , Embarazo/metabolismo , Sertralina , Adolescente , Adulto , Antidepresivos/administración & dosificación , Antidepresivos/sangre , Antidepresivos/farmacocinética , Ensayos Clínicos como Asunto , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Femenino , Humanos , Masculino , Fenotipo , Polimorfismo Genético , Sertralina/administración & dosificación , Sertralina/sangre , Sertralina/farmacocinética , Adulto Joven
4.
Eur J Clin Pharmacol ; 77(9): 1323-1331, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-33751155

RESUMEN

PURPOSE: Sertraline, a selective serotonin reuptake inhibitor (SSRI), is one of the most commonly used antidepressant during pregnancy. Plasma sertraline concentrations vary markedly between individuals, partly explained by variability in hepatic drug metabolizing cytochrome P450-enzyme activity. Our purpose was to study the variability in the plasma concentrations in pregnant women and the passage to their infants. METHOD: Pregnant women with moderate untreated depression were recruited in 2016-2019 in Stockholm Region and randomized to treatment with sertraline or placebo. All received Internet-based cognitive behavior therapy as non-medical treatment. Sertraline plasma concentrations were measured around pregnancy weeks 21 and 30, at delivery, 1-month postpartum, in cord blood and at 48 h of age in the infant. The clinical course of the infants was followed. RESULTS: Nine mothers and 7 infants were included in the analysis. Median dose-adjusted sertraline concentration in second trimester was 0.15(ng/mL) /(mg/day), in third trimester and at delivery 0.19 and 1-month postpartum 0.25, with a 67% relative difference between second trimester and postpartum. The interindividual variation was 10-fold. Median concentrations in the infants were 33% and 25% of their mothers', measured in cord blood, and infant plasma, respectively. Only mild and transient adverse effects were seen on the infants. CONCLUSION: Placental passage of sertraline to the infant is low. However, the interindividual variation in maternal concentrations during pregnancy is huge, why therapeutic drug monitoring might assist in finding the poor metabolizers at risk for adversity and increase the safety of the treatment. TRIAL REGISTRATION: The trial was registered at clinicaltrials.gov July 9, 2014 with TRN: NCT02185547.


Asunto(s)
Antidepresivos/farmacocinética , Efectos Tardíos de la Exposición Prenatal/sangre , Sertralina/farmacocinética , Adulto , Antidepresivos/sangre , Antidepresivos/uso terapéutico , Terapia Cognitivo-Conductual/métodos , Trastorno Depresivo/tratamiento farmacológico , Método Doble Ciego , Femenino , Sangre Fetal/química , Humanos , Recién Nacido , Masculino , Leche Humana/química , Placenta/química , Periodo Posparto , Embarazo , Trimestres del Embarazo , Sertralina/sangre , Sertralina/uso terapéutico
5.
NPJ Syst Biol Appl ; 6(1): 36, 2020 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-33159093

RESUMEN

Pregnancy is a period of significant change that impacts physiological and metabolic status leading to alterations in the disposition of drugs. Uncertainty in drug dosing in pregnancy can lead to suboptimal therapy, which can contribute to disease exacerbation. A few studies show there are increased dosing requirements for antidepressants in late pregnancy; however, the quantitative data to guide dose adjustments are sparse. We aimed to develop a physiologically based pharmacokinetic (PBPK) model that allows gestational-age dependent prediction of sertraline dosing in pregnancy. A minimal physiological model with defined gut, liver, plasma, and lumped placental-fetal compartments was constructed using the ordinary differential equation solver package, 'mrgsolve', in R. We extracted data from the literature to parameterize the model, including sertraline physicochemical properties, in vitro metabolism studies, disposition in nonpregnant women, and physiological changes during pregnancy. The model predicted the pharmacokinetic parameters from a clinical study with eight subjects for the second trimester and six subjects for the third trimester. Based on the model, gestational-dependent changes in physiology and metabolism account for increased clearance of sertraline (up to 143% at 40 weeks gestational age), potentially leading to under-dosing of pregnant women when nonpregnancy doses are used. The PBPK model was converted to a prototype web-based interactive dosing tool to demonstrate how the output of a PBPK model may translate into optimal sertraline dosing in pregnancy. Quantitative prediction of drug exposure using PBPK modeling in pregnancy will support clinically appropriate dosing and increase the therapeutic benefit for pregnant women.


Asunto(s)
Modelos Biológicos , Sertralina/farmacocinética , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Placenta/efectos de los fármacos , Placenta/metabolismo , Embarazo , Sertralina/farmacología
6.
Chem Res Toxicol ; 33(10): 2584-2592, 2020 10 19.
Artículo en Inglés | MEDLINE | ID: mdl-32957789

RESUMEN

The burden of depression and other mental disorders is on the rise globally, and successful treatment sometimes requires modifications of drugs and/or dose regimens. The development of novel analytical methods for the determination of antidepressant drugs in biological fluids is thus urgently required. Herein, a sensitive, robust, and rapid liquid chromatographic coupled tandem mass spectrometric method was developed and validated for the determination of citalopram (CIT) and sertraline (SER) in rat plasma after oral administration. The analytes of interest and internal standard (duloxetine (DUL)) were extracted from 100 µL of plasma with solid-phase extraction on an Oasis HLB cartridge followed by the separation with gradient elution with water containing 0.1% formic acid and acetonitrile on an Agilent Eclipse Plus ODS (4.6 × 100 mm, 3.5 µm) column at flow rate 0.2 mL min-1. The triple quadrupole mass spectrometry was applied via electrospray ionization source for detection. The fragmentation pattern of the protonated CIT, SER, and DUL was elucidated using multiple reaction monitoring of the transitions of m/z 325.2 to 109, 306.1 to 158.9, and 298.1 to 154.1 as [M + H]+ for CIT, SER, and DUL, respectively. The proposed method has been validated as per US-FDA bioanalytical guidelines in terms of linearity, accuracy, precision, matrix effects, stability, selectivity, and recovery. The method was linear over the concentration range of 1-2000 and 1-1000 ng mL-1 with the lower limit of detection of 0.12 and 0.19 ng mL-1 for CIT and SER, respectively. The interday and intraday precisions and accuracy expressed by the relative standard deviation and the relative standard error were both lower than 11.1% and 2.1%, respectively. The proposed method was successfully applied for the pharmacokinetics and drug monitoring studies of CIT and SER in rat plasma after a single oral dose of 120 mg kg-1 of CIT and SER. Coadministration of SER with CIT has affected the peak plasma concentrations, maximum plasma concentration time, area under the concentration-time curve, and oral clearance of CIT. Molecular modeling study showed that SER could competitively inhibit CYP2D6, the main enzyme involved in CIT metabolism. A possible drug-drug interaction in psychiatric patients undergoing chronic SER and CIT treatment is therefore worthy of more attention in an effort to avoid side effects and serotonin syndrome.


Asunto(s)
Antidepresivos/sangre , Citalopram/sangre , Sertralina/sangre , Administración Oral , Animales , Antidepresivos/farmacocinética , Antidepresivos/toxicidad , Cromatografía Liquida , Citalopram/farmacocinética , Citalopram/toxicidad , Interacciones Farmacológicas , Masculino , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Wistar , Síndrome de la Serotonina/inducido químicamente , Sertralina/farmacocinética , Sertralina/toxicidad , Extracción en Fase Sólida , Espectrometría de Masas en Tándem
7.
AAPS J ; 22(4): 73, 2020 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-32430638

RESUMEN

Sertraline pharmacokinetics is poorly understood and highly variable due to large between-subject variability with inconsistent reports for oral bioavailability. The study objective was to characterize sertraline pharmacokinetics by developing and validating a sertraline population pharmacokinetic (PK) model in healthy subjects using published clinical PK data. We carried a systematic literature search in PubMed in October 2015 and identified 27 pharmacokinetic studies of sertraline conducted in healthy adult subjects and reported in the English language. Sixty mean plasma concentration-time profiles made of 748 plasma concentrations following IV, single, and multiple oral doses ranging from 5 to 400 mg were extracted and analyzed for dose proportionality by a log-linear model and fitted to a 2-compartment pharmacokinetic model in NONMEM using a model-based meta-analysis (MBMA) approach. After a single oral dose, sertraline Cmax and AUC∞ increased with dose proportionally between 50 and 200 mg, and bioavailability increased nonlinearly with dose from 5 to 50 mg and plateaued afterwards while Tmax and t1/2 did not change with dose. Following multiple oral doses, Cmax and AUC∞ increased proportionally with dose across the entire dose range (5-200 mg) while bioavailability, Tmax, and t1/2 remained constant with dose. Sertraline absorption was time-dependent and best described by a sigmoidal Emax function of time after dose. Study findings indicate that sertraline PK is linear in healthy adult subjects at doses ≥ 50 mg, and exposures were nonlinear only after single oral doses < 50 mg likely due to reduced bioavailability.


Asunto(s)
Modelos Biológicos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Sertralina/farmacocinética , Administración Intravenosa , Administración Oral , Relación Dosis-Respuesta a Droga , Voluntarios Sanos , Humanos , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/sangre , Sertralina/administración & dosificación , Sertralina/sangre
8.
Basic Clin Pharmacol Toxicol ; 127(4): 303-308, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32307853

RESUMEN

Clozapine is an effective antipsychotic drug for treatment-resistant schizophrenia. Sertraline is a widely prescribed antidepressant and often concomitantly applied to address negative symptoms or depression. However, data on interactions between clozapine and sertraline are inconsistent. The aim of our study was to evaluate pharmacokinetic interactions between clozapine and sertraline analysing a therapeutic drug monitoring database of 1644 clozapine-medicated patients. We compared four groups: non-smokers (n = 250) and smokers (n = 326) with co-medication without known effects on cytochrome P450 and without sertraline, and non-smokers (n = 18) and smokers (n = 17) with sertraline co-medication. Measured and dose-corrected concentrations (C/D) of clozapine were compared between the groups using non-parametrical tests with a significance level of 0.05. Post hoc analyses included pairwise comparisons to account for smoking status. Although we detected significant differences for clozapine levels and C/D values between study groups (P < .001 for Kruskal-Wallis test in both cases), post hoc analyses revealed no differences for concentrations and C/D values of clozapine (P > .05 for Mann-Whitney U test in both cases). A negative correlation between the sertraline dose and the clozapine concentration was found in non-smokers (Spearman's rank correlation, rs = -0.535, P = .048). A potential pharmacokinetic interaction between clozapine and a standard therapeutic sertraline dose seems to be of minor clinical importance.


Asunto(s)
Clozapina/farmacocinética , Sertralina/farmacocinética , Fumar/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Antidepresivos/farmacocinética , Antipsicóticos/farmacocinética , Clozapina/sangre , Sistema Enzimático del Citocromo P-450 , Bases de Datos Factuales , Interacciones Farmacológicas , Monitoreo de Drogas/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , No Fumadores/estadística & datos numéricos , Estudios Retrospectivos , Sertralina/sangre , Fumadores/estadística & datos numéricos
9.
Clin Pharmacol Ther ; 108(1): 136-144, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32128758

RESUMEN

Significant in vitro and in vivo evidence supports the potential use of sertraline as an anticancer and antimicrobial agent. Yet, it is unknown whether effective sertraline concentrations are clinically achieved at therapeutic doses. The study objectives were to develop a physiologically-based pharmacokinetic (PBPK) model of sertraline and estimate the probability of achieving effective concentrations in various human tissues. A generic PBPK model consisting of perfusion-limited compartments representing the body organs linked together by blood flows and incorporated with clearance, tissue distribution, and absorption models was implemented in R using the mrgsolve package. Sertraline clearance and volume of distribution were first optimized from i.v. plasma concentration data then absorption and bioavailability were optimized from oral data. Predicted unbound sertraline concentrations at steady-state in human tissues did not reach concentrations determined in vitro, indicating therapeutic doses of sertraline are unlikely to produce concentrations required for anticancer and antimicrobial activities in humans.


Asunto(s)
Modelos Biológicos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Sertralina/farmacocinética , Administración Oral , Disponibilidad Biológica , Humanos , Distribución Tisular
12.
J Pharmacokinet Pharmacodyn ; 46(6): 565-576, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31584146

RESUMEN

The ASTRO-CM dose-finding pilot study investigated the role of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis in HIV-infected Ugandan patients. The present study is a post hoc pharmacokinetic-pharmacodynamic analysis of the ASTRO-CM pilot study to provide insight into sertraline exposure-response-outcome relationships. We performed a population pharmacokinetic analysis using sertraline plasma concentration data and correlated various predicted PK-PD indices with the percentage change in log10 CFU/mL from baseline. Sertraline clearance was 1.95-fold higher in patients receiving antiretroviral (ART), resulting in 49% lower drug exposure. To quantify the clinical benefit of sertraline, we estimated rates of fungal clearance from cerebrospinal fluid (CSF) of ASTRO-CM patients using Poisson model and compared the clearance rates to a historical control study (COAT) in which patients received standard Cryptococcus therapy of amphotericin B (0.7-1.0 mg/kg per day) and fluconazole (800 mg/day) without sertraline. Adjunctive sertraline significantly increased CSF fungal clearance rate compared to COAT trial and sertraline effect was dose-independent with no covariate found to affect fungal clearance including ART. Study findings suggest sertraline response could be mediated by different mechanisms than directly inhibiting the initiation of protein translation as previously suggested; this is supported by the prediction of unbound sertraline concentrations is unlikely to reach MIC concentrations in the brain. Study findings also recommend against the use of higher doses of sertraline, especially those greater than the maximum FDA-approved daily dose (200 mg/day), since they unlikely provide any additional benefits and come with greater costs and risk of adverse events.


Asunto(s)
Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Infecciones por VIH/microbiología , Meningitis Criptocócica/tratamiento farmacológico , Sertralina/farmacocinética , Sertralina/uso terapéutico , Adulto , Anfotericina B/uso terapéutico , Encéfalo/efectos de los fármacos , Líquido Cefalorraquídeo/efectos de los fármacos , Femenino , Fluconazol/uso terapéutico , Humanos , Masculino , Proyectos Piloto , Uganda
13.
Pharm Nanotechnol ; 7(2): 162-176, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30919786

RESUMEN

OBJECTIVE: To circumvent the aforementioned problems and for the successful delivery of those newly discovered poorly soluble compounds, researchers have focused on the feasibility of biocompatible lipids such as Solid lipid nanoparticles (SLN) as carrier system. BACKGROUND: Sertraline (SRT) is commercially available as hydrochloride salt. Poor bioavailability (around 44%) of hydrochloride salt is considered to be conversion of salts to free base in the gastrointestinal tract which retard it's absorption. METHODS: Different batches of solid lipid nanoparticles (SLN) were prepared and on the basis of particle size, polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), and drug loading capacity (L) an optimum system was designed. RESULTS: The optimized formulation contains; 5% (w/v) Compritol® E ATO as lipids, 2.5% (w/v) Tween® 80 as surfactant and 0.1% (w/v) SRT as actives. The formulation was freeze-dried using mannitol as a cryoprotectant to control the aggregation of particles during redispersion process. SLN with <110 nm size, <0.2 PDI, >36 mV ZP, >72% EE, and nearly 0.7% L can be formed at appropriate formulation process conditions; homogenization time (HT) and sonication time (ST) at 5 min and 10 min, respectively. XRD studies indicated the presence of amorphous form of drug that is completely encapsulated within the nanoparticulate matrix system. The optimized SLN formulation have shown the highest value of zeta potential (-36.5 mV) confers stability of nanodispersion. Release of drug encapsulated in SLN showed a biphasic pattern and was extended upto 12 hours. The maximum plasma concentration (Cmax) and area under the curve (AUC) in case of sertraline loaded SLN were found 10-fold and 6-fold higher, respectively compared to pure drug. CONCLUSION: The result depicted enhanced extent of absorption of sertraline from SLN compared to plain sertraline. Furthermore, sertraline-loaded SLN were found to be stable at 4°C for 6 months of study period. Hence, the SLN can be used as a potential carrier for successful delivery of poorly water-soluble drugs associated with poor oral bioavailability like sertraline.


Asunto(s)
Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Lípidos/química , Nanocápsulas/química , Sertralina/química , Sertralina/farmacocinética , Animales , Disponibilidad Biológica , Composición de Medicamentos , Liberación de Fármacos , Masculino , Ratas , Ratas Sprague-Dawley
14.
J Child Adolesc Psychopharmacol ; 29(5): 340-347, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30817183

RESUMEN

Objective: Cytochrome P4502C19 (CYP2C19) is a highly polymorphic gene that encodes an enzyme that metabolizes escitalopram and sertraline, two selective serotonin reuptake inhibitors (SSRIs) that are FDA approved for pediatric use and commonly used to treat anxiety and depressive disorders in youth. Using pharmacokinetic (PK) models in adolescents, we sought to (1) model SSRI dosing across CYP2C19 phenotypes to compare SSRI exposure (area under curve, AUC) and maximum concentration (Cmax), (2) evaluate the impact of b.i.d. dosing (in rapid metabolizers [RM] and ultrarapid metabolizers [UM]) on SSRI exposure and Cmax, and (3) determine pharmacogenomically-informed dosing strategies to provide similar exposure across CYP2C19 phenotypes in adolescents. Methods: Using PK parameters in CYP2C19 phenotype groups and previously reported pediatric PK data for escitalopram and sertraline, we modeled exposure (AUC0-24) and Cmax and determined CYP2C19-guided dosing strategies. Results: Compared with normal CYP2C19 metabolizers treated with either escitalopram or sertraline, Cmax and AUC0-24 were higher in slower metabolizers and lower in patients with increased CYP2C19 activity, although the magnitude of these differences was more pronounced for escitalopram than for sertraline. For escitalopram, poor metabolizers (PMs) require 10 mg/day and UMs require 30 mg/day to achieve an exposure that is equivalent to 20 mg/day in a normal metabolizer (NM). For sertraline, to achieve AUC0-24 and Cmax similar to NMs receiving 150 mg/day, PMs require 100 mg/day, whereas a dose of 200 mg/day was required in rapid and UMs. For UMs, b.i.d. escitalopram dosing was necessary to achieve comparable trough levels and exposure to NMs. Conclusions: This simulation study raises the possibility that achieving similar escitalopram and sertraline plasma concentrations could require dose adjustments in CYP2C19 poor metabolizers and UMs, although the magnitude of these differences were more pronounced for escitalopram than for sertraline. However, prospective trials of pharmacogenomically guided dosing in the pediatric population are needed to extend the findings of these modeling studies.


Asunto(s)
Trastornos de Ansiedad/tratamiento farmacológico , Citalopram/farmacocinética , Citocromo P-450 CYP2C19/genética , Trastorno Depresivo Mayor/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Sertralina/farmacocinética , Adolescente , Citalopram/uso terapéutico , Femenino , Humanos , Masculino , Pruebas de Farmacogenómica , Fenotipo , Polimorfismo Genético , Inhibidores Selectivos de la Recaptación de Serotonina/uso terapéutico , Sertralina/uso terapéutico
15.
Arch Womens Ment Health ; 22(3): 383-390, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30116895

RESUMEN

Despite increasing prescription rates of antidepressants in pregnant and breastfeeding women over the past decades, evidence of drug exposure for neonates through lactation is very sparse. Concentrations of three antidepressants citalopram, sertraline, and venlafaxine were measured in maternal blood and breast milk in 17 women receiving antidepressant therapy during breastfeeding period. We also computed concentration-by-dose-ratios (C/D) and milk to serum (plasma) penetration ratios (M/P). Non-parametric tests were applied. Serum concentration of citalopram and daily dosage correlated positively while daily dosage and mother milk concentration did not (rho = 0.939, p = 0.005, and rho = 0.772, p > 0.05 respectively). A significant correlation was also found between serum and milk concentrations (rho = 0.812, p = 0.05). Venlafaxine daily dosage correlated positively with the active moiety milk concentration (rho = 0.949, p = 0.014). No significant correlations were reported for sertraline. The amount of antidepressant concentrations to which neonates may be exposed, assessed as absolute infant dose (AID), was particularly low with the highest median AID being 0.16 mg/kg/day for venlafaxine. No significant difference was detected for the M/P ratios between different drugs (p > 0.05), whereas the comparison of C/D ratios revealed lower values in the sertraline group, with the highest values reported for citalopram group (p = 0.007 for serum concentrations and p = 0.008 for mother milk). Findings suggest that breastfeeding under antidepressant treatment constantly exposes children with measurable drug concentrations. As daily dosage and serum concentration of the antidepressants did not predict drug concentrations in mother milk, measuring of drug concentrations in milk helps to quantify drug exposure during breastfeeding. More data-even data of drug concentrations in breastfed children-are needed to better assess the effects of drug exposure on children's development.


Asunto(s)
Antidepresivos/farmacocinética , Leche Humana/química , Adulto , Antidepresivos/análisis , Lactancia Materna/efectos adversos , Desarrollo Infantil/efectos de los fármacos , Citalopram/análisis , Citalopram/farmacocinética , Depresión/tratamiento farmacológico , Femenino , Humanos , Lactante , Leche Humana/metabolismo , Embarazo , Inhibidores Selectivos de la Recaptación de Serotonina/análisis , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Inhibidores de Captación de Serotonina y Norepinefrina/análisis , Inhibidores de Captación de Serotonina y Norepinefrina/farmacocinética , Sertralina/análisis , Sertralina/farmacocinética , Clorhidrato de Venlafaxina/análisis , Clorhidrato de Venlafaxina/farmacocinética , Adulto Joven
16.
Basic Clin Pharmacol Toxicol ; 122(5): 501-511, 2018 May.
Artículo en Inglés | MEDLINE | ID: mdl-29136336

RESUMEN

Sertraline is a selective serotonin reuptake inhibitor widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P-glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of this study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty-six healthy volunteers (24 men and 22 women) receiving a 100-mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP-binding cassette subfamily B member 1 (ABCB1), solute carrier family 6 member 4 (SLC6A4), 5-hydroxytryptamine receptor 2A (HTR2A) and 5-hydroxytryptamine receptor 2C (HTR2C) genes. Pharmacokinetic and pharmacodynamic parameters were similar in men and women. Polymorphisms in CYP2C19 and CYP2B6 genes influenced sertraline pharmacokinetics, with a greater effect of CYP2C19. Individuals carrying defective alleles for CYP2C19 and CYP2B6 showed higher area under the curve (AUC) and half-life (T1/2 ). Moreover, CYP2C19*17 was related to a decreased AUC and T1/2 . No significant effect was found for polymorphisms in CYP2C9, CYP2D6 and ABCB1 on sertraline pharmacokinetics. Sertraline had a small heart rate-lowering effect, directly related to maximum concentration (Cmax ) and the presence of ABCB1 minor alleles. Sertraline had no significant effect on blood pressure and QTc. There was a tendency to present more adverse drug reactions in women and individuals with higher AUC of sertraline, such as CYP2C19 intermediate metabolizers and CYP2B6 G516T T/T individuals.


Asunto(s)
Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2C19/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Sertralina/farmacocinética , Administración Oral , Adolescente , Adulto , Presión Sanguínea/efectos de los fármacos , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Femenino , Genotipo , Voluntarios Sanos , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética , Fenotipo , Medición de Riesgo , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Sertralina/administración & dosificación , Sertralina/efectos adversos , Adulto Joven
18.
Breastfeed Med ; 12(6): 377-380, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28481632

RESUMEN

BACKGROUND: Hypernatremic dehydration is well described in exclusively breastfed neonates, although life-threatening complications are rarely reported. MATERIALS AND METHODS: The present article describes a case of severe hypernatremic dehydration in a previously healthy term neonate. Other published cases of severe complications of hypernatremic dehydration are discussed. RESULTS: The exclusively breastfed neonate described had severe hypernatremic dehydration because of inadequate milk intake, with disseminated intravascular coagulation and right lower limb gangrene that required amputation of all five toes and surgical debridement of the metatarsals. The usual etiology of hypernatremic dehydration in this age group is insufficient breast milk intake. Here, the infant's mother was treated for bipolar disorder with lamotrigine 250 mg orally once daily, aripiprazole 15 mg orally once daily, and sertraline 100 mg orally once daily. CONCLUSIONS: Awareness of these complications should prompt close follow-up of the infant with poor weight gain. The role of maternal medication as a risk factor for hypernatremic dehydration among exclusively breastfed infants needs to be further explored.


Asunto(s)
Antidepresivos/efectos adversos , Lactancia Materna/efectos adversos , Deshidratación/inducido químicamente , Gangrena/inducido químicamente , Hipernatremia/inducido químicamente , Extremidad Inferior/patología , Leche Humana/química , Adulto , Amputación Quirúrgica , Antidepresivos/administración & dosificación , Antidepresivos/farmacocinética , Aripiprazol/efectos adversos , Aripiprazol/farmacocinética , Trastorno Bipolar/tratamiento farmacológico , Desbridamiento , Deshidratación/complicaciones , Deshidratación/fisiopatología , Femenino , Gangrena/complicaciones , Gangrena/patología , Gangrena/cirugía , Humanos , Hipernatremia/complicaciones , Hipernatremia/fisiopatología , Recién Nacido , Lamotrigina , Extremidad Inferior/cirugía , Masculino , Madres , Sertralina/efectos adversos , Sertralina/farmacocinética , Dedos del Pie/patología , Dedos del Pie/cirugía , Triazinas/efectos adversos , Triazinas/farmacocinética
20.
CPT Pharmacometrics Syst Pharmacol ; 5(10): 505-515, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27642087

RESUMEN

This subteam under the Drug Metabolism Leadership Group (Innovation and Quality Consortium) investigated the quantitative role of circulating inhibitory metabolites in drug-drug interactions using physiologically based pharmacokinetic (PBPK) modeling. Three drugs with major circulating inhibitory metabolites (amiodarone, gemfibrozil, and sertraline) were systematically evaluated in addition to the literature review of recent examples. The application of PBPK modeling in drug interactions by inhibitory parent-metabolite pairs is described and guidance on strategic application is provided.


Asunto(s)
Amiodarona/farmacocinética , Gemfibrozilo/farmacocinética , Sertralina/farmacocinética , Animales , Área Bajo la Curva , Descubrimiento de Drogas , Interacciones Farmacológicas , Humanos , Modelos Biológicos
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