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PURPOSE: Lamotrigine was previously reported to reduce serum concentration of quetiapine. The aim of this study was to investigate whether lamotrigine dose or quetiapine formulation was of importance for the drug interaction. METHODS: Patients combining lamotrigine with quetiapine (cases) were included retrospectively from a routine therapeutic drug monitoring (TDM) service, as were a control group of patients using quetiapine without any interacting drugs. The case and control groups were divided into groups using immediate release (IR) and extended release (XR) quetiapine. The case group was further split into high-dose (> 200 mg/day) and low-dose (≤ 200 mg/day) lamotrigine users. Quetiapine concentration-to-dose (C/D) ratio and metabolite-to-parent ratio (MPR) were compared between the control group and dose-separated case groups using ANOVA test and t-tests. RESULTS: In total, 406 patients were included. The mean C/D ratio of IR quetiapine was 46% lower in the high-dose lamotrigine group compared with the control group (P < 0.001), while no interaction effect was present in the low dose lamotrigine group (P = 0.7). Regardless of lamotrigine dose, there was no difference in quetiapine C/D ratio for patients using the XR formulation (P = 0.4). The quetiapine MPR was unaffected regardless of formulation and lamotrigine dose (P ≥ 0.06). CONCLUSION: The effect of lamotrigine in reducing quetiapine concentration is only significant for patients using quetiapine IR tablets who are treated with lamotrigine doses > 200 mg/day. Because of high variability in the interaction effect, TDM of quetiapine should be recommended during co-prescription of high-dose lamotrigine.
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Antipsicóticos , Preparaciones de Acción Retardada , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Lamotrigina , Fumarato de Quetiapina , Comprimidos , Humanos , Lamotrigina/farmacocinética , Lamotrigina/administración & dosificación , Lamotrigina/sangre , Lamotrigina/uso terapéutico , Fumarato de Quetiapina/farmacocinética , Fumarato de Quetiapina/administración & dosificación , Fumarato de Quetiapina/sangre , Masculino , Femenino , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacocinética , Antipsicóticos/sangre , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Monitoreo de Drogas/métodos , Triazinas/farmacocinética , Triazinas/sangre , Triazinas/administración & dosificación , AncianoRESUMEN
PURPOSE: The aim of this study was to examine the age of onset for increased dose-adjusted serum concentrations (C/D ratio) of common antidepressant drugs and to explore the potential association with sex and CYP2C19/CYP2D6 genotype. METHODS: Serum concentrations and prescribed daily doses for citalopram, escitalopram, sertraline, venlafaxine and mirtazapine, and CYP genotypes, were obtained from a therapeutic drug monitoring (TDM) service. Segmented linear regression analysis was used to examine the relationship between age and antidepressant log C/D ratio in (i) all individuals, (ii) men and women, and (iii) CYP2D6/CYP2C19 normal metabolizers (NMs) and CYP2D6/CYP2C19 intermediate or poor metabolizers (IMs/PMs). RESULTS: A total of 34,777 individuals were included in the study; CYP genotype was available for 21.3%. An increase in C/D ratio started at 44â55 years of age. Thereafter, the increase progressed more rapidly for citalopram and escitalopram than for venlafaxine and mirtazapine. A doubled C/D ratio was estimated to occur at 79 (citalopram), 81 (escitalopram), 86 (venlafaxine), and 90 years (mirtazapine). For sertraline, only modest changes in C/D ratio were observed. For escitalopram and venlafaxine, the observed increase in C/D ratio started earlier in women than in men. The results regarding CYP genotype were inconclusive. CONCLUSION: The age-related increase in C/D ratio starts in middle-aged adults and progresses up to more than twofold higher C/D ratio in the oldest old. Sertraline seems to be less prone to age-related changes in C/D ratio than the other antidepressants.
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Citalopram , Sertralina , Adulto , Masculino , Persona de Mediana Edad , Anciano de 80 o más Años , Femenino , Humanos , Sertralina/uso terapéutico , Clorhidrato de Venlafaxina , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2D6/genética , Mirtazapina , Escitalopram , Edad de Inicio , Antidepresivos/uso terapéutico , GenotipoRESUMEN
PURPOSE: The aim of the present study was to develop a population pharmacokinetic model for methotrexate (MTX) during high-dose treatment (HDMTX) in pediatric patients with acute lymphoblastic leukemia (ALL) and non-Hodgkin's lymphoma (NHL) and to describe the influence of variability factors. METHODS: The study included 50 patients of both sexes (aged 1-18 years) who received 3 or 5 g/m2 of HDMTX. A nonlinear mixed effect modeling approach was applied for data analysis. Parameter estimation was performed by first-order conditional estimation method with interaction (FOCEI), whereas stepwise covariate modeling was used to assess variability factors. RESULTS: The final model is a two-compartment model that incorporates the effect of body surface area and the influence of hemoglobin and serum creatinine on MTX clearance (CL). Population pharmacokinetic values for a typical subject were estimated at 5.75 L/h/m2 for clearance (CL), 21.3 L/m2 for volume of the central compartment (V1), 8.2 L/m2 for volume of the peripheral compartment (V2), and 0.087 L/h/m2 for intercompartmental clearance (Q). According to the final model, MTX CL decreases with increasing serum creatinine, whereas a positive effect was captured for hemoglobin. A difference of almost 32% in MTX CL was observed among patients' hemoglobin values reported in the study. CONCLUSION: The developed population pharmacokinetic model can contribute to the therapy optimization during HDMTX in pediatric patients with ALL and NHL. In addition to renal function and body weight, it describes the influence of hemoglobin on CL, allowing better understanding of its contribution to the disposition of HDMTX.
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Neoplasias Hematológicas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Masculino , Femenino , Humanos , Niño , Metotrexato , Creatinina , Antimetabolitos Antineoplásicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Neoplasias Hematológicas/tratamiento farmacológicoRESUMEN
PURPOSE: The goal of the study was to examine clozapine (CLZ) and norclozapine (NCLZ) therapeutic drug monitoring (TDM) data and associated sources of pharmacokinetic variability, particularly the impact of valproic acid (VPA) use. METHODS: This study included 126 patients with psychiatric disorders on mono- or co-therapy with CLZ. Patients' data during routine TDM were collected retrospectively from clinical records. The descriptive and statistical analysis was computed using IBM SPSS Statistics software (version 22, NY, USA). Multiple linear regression, based on the last observations, was used to assess correlation between demographic characteristics, life habits and co-therapy with dose-corrected serum levels (C/D) of CLZ and NCLZ, as well as CLZ/NCLZ. RESULTS: A total of 295 CLZ concentrations were measured in 126 patients, with a mean of 275.5 ± 174.4 µg/L, while 124 NCLZ concentrations were determined in 74 patients, with a mean of 194.6 ± 149.8 µg/L. A statistically significant effect on ln-transformed CLZ C/D was confirmed for sex and smoking, whereas sex, smoking and VPA therapy were associated with ln-transformed NCLZ C/D. According to the final models, lower values of NCLZ C/D for about 45.9% can be expected in patients receiving VPA. Concomitant use of VPA was the only factor detected to contribute in CLZ/NCLZ variability. CONCLUSION: The results of this study may help clinicians interpret TDM data and optimize CLZ dosing regimens, especially in patients concomitantly treated with VPA. Our results show that VPA primarily decreases NCLZ levels, while alteration of the parent drug is not statistically significant.
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Clozapina , Trastornos Mentales , Humanos , Clozapina/uso terapéutico , Clozapina/farmacocinética , Ácido Valproico/uso terapéutico , Estudios Retrospectivos , Trastornos Mentales/tratamiento farmacológicoRESUMEN
Inflammation is characterized by an increased secretion of proinflammatory cytokines known to alter the expression and functionality of drug transporters. Since P-glycoprotein (P-gp) plays a key role in the pharmacokinetics of several drugs, these modulations could further affect drug exposure. In this context, this study aims to investigate the impact of in vitro cytokine exposure on the expression and activity of P-gp using the intestinal model Caco-2 and the human renal cells RPTEC/TERT1. Cells were exposed to various concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-1ß for 24 or 72 h. Gene expression was then assessed by RT-qPCR followed by absolute quantification of P-gp using liquid chromatography coupled with mass spectrometry. Then, the activity of P-gp was assessed by the intracellular accumulation of rhodamine 123. TNF-α increased both the gene expression and P-gp activity by 15-40% in each model. Minor modulations were observed at the protein level with increases of up to 8% for RPTEC/TERT1 cells and 24% for Caco-2 cells. Conversely, IL-1ß led to a downregulation of gene, protein, and functionality by 48 and 25% in intestinal and renal cells, respectively. Taken together, these data highlighted that gene expression levels and functional activity of P-gp are altered by the pro-inflammatory cytokines in intestinal and renal cells. Such pronounced changes in human P-gp could result in altered exposure to drug substrates. Further in vivo studies are needed to confirm the impact of inflammation on drug pharmacokinetics.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Interleucina-1beta , Factor de Necrosis Tumoral alfa , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Células CACO-2 , Citocinas/metabolismo , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Interleucina-1beta/farmacología , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Formulating poorly water soluble, weakly basic drugs with consistent exposure is often a challenge due to pH-dependent solubility. When the oral formulation is exposed to different pH ranges in the gastrointestinal (GI) tract, drug precipitation, or incomplete dissolution may occur resulting in decreased drug absorption and higher intra- and inter-patient pharmacokinetic (PK) variabilities. In the present study, a series of enhanced formulations containing organic acids and/or surfactants were developed and compared with conventional formulations with respect to their in vitro dissolution performance. The formulation containing 5% citric acid and 1% sodium lauryl sulfate (SLS) showed much less variations in dissolution performance at different pH conditions than a conventional formulation. The combination of citric acid and SLS demonstrated a synergistic effect as compared to use of citric acid alone or in combination with PEG4000 as a precipitation inhibitor. When compared with a conventional formulation and a spray-dried amorphous solid dispersion (ASD) formulation in a dog PK study, the enhanced formulation demonstrated the least AUC and Cmax variability between the two gastric pH-controlled groups. In conclusion, an enhanced formulation using a combination of organic acid and surfactant is recommended for weakly basic drug compounds to minimize drug PK variabilities in clinical studies.
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Excipientes , Tensoactivos , Animales , Ácido Cítrico , Perros , Excipientes/química , Humanos , Dodecil Sulfato de Sodio/química , Solubilidad , Tensoactivos/químicaRESUMEN
INTRODUCTION: Eslicarbazepine acetate (ESL) is a sodium channel blocker indicated for partial-onset seizures with or without secondary generalization, at a single daily dose. There are very few publications on the levels of ESL metabolites in real clinical practice. OBJECTIVE: To describe the serum levels of licarbazepine (main metabolite of ESL) in patients with refractory epilepsy in real clinical practice. To evaluate the influence of age, sex, and polytherapy on levels and adverse effects. METHODS: This study involved a retrospective analysis of patients diagnosed with epilepsy treated with ESL for whom plasma levels of licarbazepine were available, measured by spectrophotometry. RESULTS: Sixty-four patients were included. One patient had licarbazepine levels of 0 (admitted not taking the drug) was not analyzed. Mean licarbazepine levels of 7.66⯵g/mL (400â¯mg/day dose), 16.56⯵g/mL (800-mg dose), and 20.80⯵g/mL (1200â¯mg) were significantly different. There was a significant correlation between daily dose and serum levels (pâ¯<â¯0.05) and between the concentration/dose ratio and lower to higher doses (pâ¯<â¯0.05). Pharmacokinetic variability (coefficient of variation for the concentration/dose ratio) was 33.2%. We found a decrease in the concentration/dose ratio in the 1200â¯mg/day dose, compared to lower doses. We did not find differences by sex or intake of other antiepileptic inducers or metabolic inhibitors. Fifteen patients (23.8%) had mild nonsymptomatic hyponatremia. CONCLUSION: These results suggest that it is not necessary to routinely determine licarbazepine levels. In specific cases, licarbazepine levels can be useful to assess adherence to treatment and for personalized dose adjustment.
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PURPOSE: The aim of this work was to identify whether biochemical and physiological sources of mAb pharmacokinetic sex-effects could be identified in the rat model where target-mediated disposition is avoided. METHODS: Plasma and lymphatic pharmacokinetics of the humanised anti-EGFR antibody cetuximab, along with potential physiological and biochemical drivers of pharmacokinetic sex differences, were examined in male and female rats. Cetuximab was used as a model mAb since plasma clearance is slower in female patients. RESULTS: When plasma concentrations were normalised to dose, female rats displayed slower plasma clearance than males, but no significant differences were observed in liver and spleen biodistribution. Sex differences in apparent plasma clearance, however, were abolished after normalisation to body weight, surface area or fat-free mass. Significant sex differences were observed in plasma testosterone, endogenous IgG and fat free mass, but did not correlate with apparent clearance. Females did, however, show two-fold higher lymphatic exposure compared to males. CONCLUSIONS: These data suggested that mAbs more efficiently access lymph in females, but this does not affect plasma pharmacokinetics or biodistribution. Further, the data suggest that sex differences observed in humans could be a function of antigen density.
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Antineoplásicos Inmunológicos/farmacocinética , Cetuximab/farmacocinética , Sistema Linfático/metabolismo , Administración Intravenosa , Animales , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/sangre , Cetuximab/administración & dosificación , Cetuximab/sangre , Femenino , Masculino , Tasa de Depuración Metabólica , Ratas Sprague-Dawley , Factores Sexuales , Distribución TisularRESUMEN
BACKGROUND: There is a general dearth of information on extrapulmonary tuberculosis (EPTB). Here, we investigated Mycobacterium tuberculosis (Mtb) drug resistance and transmission patterns in EPTB patients treated in the Tshwane metropolitan area, in South Africa. METHODS: Consecutive Mtb culture-positive non-pulmonary samples from unique EPTB patients underwent mycobacterial genotyping and were assigned to phylogenetic lineages and transmission clusters based on spoligotypes. MTBDRplus assay was used to search mutations for isoniazid and rifampin resistance. Machine learning algorithms were used to identify clinically meaningful patterns in data. We computed odds ratio (OR), attributable risk (AR) and corresponding 95% confidence intervals (CI). RESULTS: Of the 70 isolates examined, the largest cluster comprised 25 (36%) Mtb strains that belonged to the East Asian lineage. East Asian lineage was significantly more likely to occur within chains of transmission when compared to the Euro-American and East-African Indian lineages: OR = 10.11 (95% CI: 1.56-116). Lymphadenitis, meningitis and cutaneous TB, were significantly more likely to be associated with drug resistance: OR = 12.69 (95% CI: 1.82-141.60) and AR = 0.25 (95% CI: 0.06-0.43) when compared with other EPTB sites, which suggests that poor rifampin penetration might be a contributing factor. CONCLUSIONS: The majority of Mtb strains circulating in the Tshwane metropolis belongs to East Asian, Euro-American and East-African Indian lineages. Each of these are likely to be clustered, suggesting on-going EPTB transmission. Since 25% of the drug resistance was attributable to sanctuary EPTB sites notorious for poor rifampin penetration, we hypothesize that poor anti-tuberculosis drug dosing might have a role in the development of resistance.
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Farmacorresistencia Bacteriana/genética , Mycobacterium tuberculosis/genética , Tuberculosis/transmisión , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Genotipo , Humanos , Lactante , Isoniazida/uso terapéutico , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Mutación , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Filogenia , Rifampin/uso terapéutico , Sudáfrica , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Tuberculosis Pulmonar/microbiología , Adulto JovenRESUMEN
Once regarded obscure and underappreciated, the gut microbiota (the microbial communities colonizing the gastrointestinal tract) is gaining recognition as an influencer of many aspects of human health. Also increasingly apparent is the breadth of interindividual variation in these co-evolved microbial-gut associations, presenting novel quests to explore implications for disease and therapeutic response. In this respect, the unearthing of the drug-metabolizing capacity of the microbiota has provided impetus for the integration of microbiological and pharmacological research. This review considers a potential mechanism, 'microbial bile acid metabolism', by which the intricate interplay between the host and gut bacteria may influence drug pharmacokinetics. Bile salts traditionally regarded as biological surfactants, synthesized by the host and biotransformed by gut bacteria, are now also recognized as signalling molecules that affect diverse physiological processes. Accumulating data indicate that bile salts are not equivalent with respect to their physicochemical properties, micellar solubilization capacities for poorly water-soluble drugs, crystallization inhibition tendencies nor potencies for bile acid receptor activation. Herein, the origin, physicochemical properties, physiological functions, plasticity and pharmaceutical significance of the human bile acid pool are discussed. Microbial dependant differences in the composition of the human bile acid pool, simulated intestinal media and commonly used preclinical species is highlighted to better understand in vivo performance predictiveness. While the precise impact of an altered gut microbiome, and consequently bile acid pool, in the biopharmaceutical setting remains largely elusive, the objective of this article is to aid knowledge acquisition through a detailed review of the literature.
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Ácidos y Sales Biliares/metabolismo , Microbioma Gastrointestinal , Mucosa Intestinal/metabolismo , Preparaciones Farmacéuticas/metabolismo , Animales , Humanos , Absorción IntestinalRESUMEN
AIMS: Serelaxin is a recombinant human relaxin-2 peptide being developed for the treatment of acute heart failure (AHF). The present analyses aimed to evaluate serelaxin pharmacokinetics following intravenous administration and to identify covariates that may explain pharmacokinetic variability in healthy subjects and patients. METHODS: Serum concentration-time data for 613 subjects from nine phase I and II studies were analysed using a nonlinear mixed-effects model to estimate population pharmacokinetics and identify significant covariates. A quantile regression analysis was also conducted to assess the relationship between clearance and covariates by including sparse data from a phase III study. RESULTS: A three-compartment disposition model was established to describe serelaxin pharmacokinetics. Three out of 23 covariates, including baseline body mass index (BMI) and estimated glomerular filtration rate (eGFR) and study A1201, were identified as significant covariates for clearance but with a moderate impact on steady-state concentration, reducing the intersubject variability from 44% in the base model to 41% in the final model with covariates. The steady-state volume of distribution (Vss) was higher in patients with AHF (544 ml kg-1 ) or chronic heart failure (434 ml kg-1 ), compared with typical nonheart failure subjects (347 ml kg-1 ). Quantile regression analysis showed that a 20% increase in BMI or a 20% decrease in eGFR decreased serelaxin clearance by 9.2% or 5.2%, respectively. CONCLUSIONS: Patients with HF showed higher Vss but similar clearance (and therefore steady-state exposure) vs. non nonheart failure subjects. BMI and eGFR were identified as the main covariates explaining intersubject variability in clearance; however, the impact of these covariates on steady-state concentration was moderate and therefore unlikely to be clinically relevant.
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Tasa de Filtración Glomerular , Insuficiencia Cardíaca/tratamiento farmacológico , Modelos Biológicos , Relaxina/administración & dosificación , Enfermedad Aguda , Administración Intravenosa , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad Crónica , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Hipertensión Portal/complicaciones , Hepatopatías/complicaciones , Masculino , Persona de Mediana Edad , Dinámicas no Lineales , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacocinética , Relaxina/farmacocinética , Insuficiencia Renal/complicaciones , Distribución Tisular , Adulto JovenRESUMEN
The purpose was to investigate pharmacokinetic variability of valproic acid (VPA) in women of childbearing age by therapeutic drug monitoring (TDM) data to elucidate the variable relationship between dose and serum concentrations with the ultimate aim of facilitating safer use of VPA. Anonymized retrospective data from the TDM database (2006-2015) at the National Center for Epilepsy in Norway were used. Trough total concentrations of VPA at assumed steady state in women aged 14-46 years were analyzed. Data from 643 nonpregnant women of childbearing age (mean age = 27 years) were included. Mean dose and serum concentration of VPA were 968 (standard deviation [SD] = 453) mg/day and 411 (SD = 138) µmol/L, respectively, and 59% used polytherapy. The pharmacokinetic variability in serum concentration/dose (C/D) ratios between women was extensive. For doses <700 mg/day (n = 202; 32%; 150-625 mg/day), mean serum concentration was 336 µmol/L and variability in C/D ratio was 10-fold. The variability decreased with increasing dose to eightfold (≥700 to <1,500 mg/day, n = 358) and fourfold (≥1,500 mg/day, n = 96). This study demonstrates the extensive pharmacokinetic variability of VPA among women of childbearing age, which is most pronounced at low doses. In future studies, serum concentrations of VPA, rather than dosage, should be used as a guide for exposure of VPA and possible risks of teratogenicity to evaluate safety aspects of VPA in women.
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Anticonvulsivantes/farmacocinética , Epilepsia/metabolismo , Ácido Valproico/farmacocinética , Adolescente , Adulto , Anticonvulsivantes/uso terapéutico , Monitoreo de Drogas , Epilepsia/tratamiento farmacológico , Femenino , Humanos , Persona de Mediana Edad , Noruega , Estudios Retrospectivos , Ácido Valproico/uso terapéutico , Adulto JovenRESUMEN
Lacosamide (LCM) is a new antiepileptic drug (AED). Experience from therapeutic drug monitoring (TDM) in clinical practice is limited. The purpose of this study is to evaluate the pharmacokinetic variability of LCM in relation to efficacy and tolerability in patients with refractory epilepsy in a real-life setting. Variables included age, gender, daily doses and serum concentrations of LCM and other AEDs from the TDM-database at the National Center for Epilepsy in Norway. Clinical data regarding efficacy and tolerability were collected from medical records. The Norwegian Prescription Database (NorPD) was used to include population-based numbers of users. TDM-data from 344 patients were included. The median dose, serum concentration, and concentration/dose (C/D)-ratio of LCM was 350 (range 25-700) mg/day, 19.7 (range 8.1-56.2) µmol/L, and 0.06 (0.02-0.82) µmol/L/mg, respectively. Serum concentrations were reduced by 28% by concomitant use of enzyme inducers and increased by 30% in patients aged >65 years. Efficacy and tolerability were assessed in 227 patients: 29% had >50% seizure reduction (eight seizure free), 30% had no effect, and 44% reported adverse effects. In Norway, there were on average 500 patients per year using LCM in this period based on NorPD. The study demonstrated pharmacokinetic variability and use of TDM of LCM in Norway. Data were collected from multiple sources for improved pharmacovigilance. Serum concentrations were influenced by enzyme inducers and ageing, indicating the usefulness of TDM. Effect and tolerability were favorable within a suggested reference range of 10-40 µmol/L given drug-fasting conditions.
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Acetamidas/sangre , Acetamidas/uso terapéutico , Anticonvulsivantes/sangre , Anticonvulsivantes/uso terapéutico , Epilepsia Refractaria/sangre , Epilepsia Refractaria/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticonvulsivantes/efectos adversos , Niño , Preescolar , Monitoreo de Drogas/métodos , Epilepsia Refractaria/epidemiología , Femenino , Humanos , Lacosamida , Masculino , Persona de Mediana Edad , Noruega/epidemiología , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration-time curves (AUC0-24) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (MICs). Thus, each child will achieve different AUC0-24/MIC ratios when treated with the same dose. METHODS: We used 10 000-subject Monte Carlo experiments to identify the oral doses of linezolid, moxifloxacin, and faropenem that would achieve optimal target exposures associated with optimal efficacy in children with disseminated tuberculosis. The linezolid and moxifloxacin exposure targets were AUC0-24/MIC ratios of 62 and 122, and a faropenem percentage of time above MIC >60%, in combination therapy. A linezolid AUC0-24 of 93.4 mg × hour/L was target for toxicity. Population pharmacokinetic parameters of each drug and between-child variability, as well as MIC distribution, were used, and the cumulative fraction of response (CFR) was calculated. We also considered drug penetration indices into meninges, bone, and peritoneum. RESULTS: The linezolid dose of 15 mg/kg in full-term neonates and infants aged up to 3 months and 10 mg/kg in toddlers, administered once daily, achieved CFR ≥ 90%, with <10% achieving linezolid AUC0-24 associated with toxicity. The moxifloxacin dose of 25 mg/kg/day achieved a CFR > 90% in infants, but the optimal dose was 20 mg/kg/day in older children. The faropenem medoxomil optimal dosage was 30 mg/kg 3-4 times daily. CONCLUSIONS: The regimen and doses of linezolid, moxifloxacin, and faropenem identified are proposed to be adequate for all disseminated tuberculosis syndromes, whether drug-resistant or -susceptible.
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Antituberculosos/administración & dosificación , Fluoroquinolonas/administración & dosificación , Linezolid/administración & dosificación , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , beta-Lactamas/administración & dosificación , Antituberculosos/farmacocinética , Área Bajo la Curva , Niño , Preescolar , Simulación por Computador , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Fluoroquinolonas/farmacocinética , Humanos , Lactante , Recién Nacido , Linezolid/farmacocinética , Pruebas de Sensibilidad Microbiana , Modelos Estadísticos , Método de Montecarlo , Moxifloxacino , beta-Lactamas/farmacocinéticaRESUMEN
BACKGROUND: The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown. METHODS: Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables. RESULTS: Among the 143 children with known outcomes, there was high between-child variability of isoniazid, rifampin, and pyrazinamide concentrations: 110 (77%) completed therapy, 24 (17%) failed therapy, and 9 (6%) died. The main predictors of therapy failure or death were a pyrazinamide peak concentration <38.10 mg/L and rifampin peak concentration <3.01 mg/L. The relative risk of these poor outcomes below these peak concentration thresholds was 3.64 (95% confidence interval [CI], 2.28-5.83). Isoniazid had concentration-dependent antagonism with rifampin and pyrazinamide, with an adjusted odds ratio for therapy failure of 3.00 (95% CI, 2.08-4.33) in antagonism concentration range. In regard to death alone as an outcome, the same drug concentrations, plus z scores (indicators of malnutrition), and age <3 years, were highly ranked predictors. In children <3 years old, isoniazid 0- to 24-hour area under the concentration-time curve <11.95 mg/L × hour and/or rifampin peak <3.10 mg/L were the best predictors of therapy failure, with relative risk of 3.43 (95% CI, .99-11.82). CONCLUSIONS: We have identified new antibiotic target concentrations, which are potential biomarkers associated with treatment failure and death in children with tuberculosis.
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Antituberculosos/farmacocinética , Antituberculosos/uso terapéutico , Tuberculosis/tratamiento farmacológico , Tuberculosis/mortalidad , Adolescente , Biomarcadores , Niño , Preescolar , Coinfección , Monitoreo de Drogas , Quimioterapia Combinada , Femenino , Infecciones por VIH/tratamiento farmacológico , Humanos , Lactante , Aprendizaje Automático , Masculino , Modelos Estadísticos , Pronóstico , Sensibilidad y Especificidad , Insuficiencia del Tratamiento , Resultado del Tratamiento , Tuberculosis/diagnósticoRESUMEN
BACKGROUND: Based on a hollow-fiber system model of tuberculosis, we hypothesize that microbiologic failure and acquired drug resistance are primarily driven by low drug concentrations that result from pharmacokinetic variability. METHODS: Clinical and pharmacokinetic data were prospectively collected from 142 tuberculosis patients in Western Cape, South Africa. Compartmental pharmacokinetic parameters of isoniazid, rifampin, and pyrazinamide were identified for each patient. Patients were then followed for up to 2 years. Classification and regression tree analysis was used to identify and rank clinical predictors of poor long-term outcome such as microbiologic failure or death, or relapse. RESULTS: Drug concentrations and pharmacokinetics varied widely between patients. Poor long-term outcomes were encountered in 35 (25%) patients. The 3 top predictors of poor long-term outcome, by rank of importance, were a pyrazinamide 24-hour area under the concentration-time curve (AUC) ≤ 363 mg·h/L, rifampin AUC ≤ 13 mg·h/L, and isoniazid AUC ≤ 52 mg·h/L. Poor outcomes were encountered in 32/78 patients with the AUC of at least 1 drug below the identified threshold vs 3/64 without (odds ratio = 14.14; 95% confidence interval, 4.08-49.08). Low rifampin and isoniazid peak and AUC concentrations preceded all cases of acquired drug resistance. CONCLUSIONS: Low drug AUCs are predictive of clinical outcomes in tuberculosis patients.
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Antituberculosos/farmacocinética , Isoniazida/farmacocinética , Pirazinamida/farmacocinética , Rifampin/farmacocinética , Tuberculosis Pulmonar/tratamiento farmacológico , Adolescente , Adulto , Anciano , Antituberculosos/sangre , Área Bajo la Curva , Femenino , Humanos , Isoniazida/sangre , Masculino , Pruebas de Sensibilidad Microbiana , Persona de Mediana Edad , Mycobacterium tuberculosis/efectos de los fármacos , Estudios Prospectivos , Pirazinamida/sangre , Rifampin/sangre , Resultado del Tratamiento , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/mortalidad , Adulto JovenRESUMEN
Introduction: Cannabidiol (CBD) is a widely utilized nonpsychoactive cannabinoid available as a prescriptive drug treatment and over-the-counter supplement. In humans, CBD is metabolized and forms the major active metabolite 7-hydroxy-cannabidiol (7-OH-CBD), which is further metabolized to 7-carboxy-cannabidiol (7-COOH-CBD). In the current study, plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD were measured, and the potential influences of sex, race, and body mass index (BMI) on the pharmacokinetic variability were assessed. Methods: Blood samples from a previously conducted CBD drug interaction study in healthy volunteers (n = 12) were utilized. The subjects received orally administered CBD (Epiodiolex®), 750 mg twice daily for 3 days and a single dose on the 4th day. Nine plasma samples were collected, and plasma concentrations of CBD, 7-OH-CBD, and 7-COOH-CBD were analyzed by LC-MS/MS. Peak plasma concentration (Cmax), time to Cmax (Tmax), area under the curve (AUC), and metabolite-to-parent drug exposure ratios (MPR) were calculated. Statistical analysis was performed to determine the correlations of Cmax, AUC, and MPR of CBD, 7-OH-CBD, and 7-COOH-CBD in different sex, race, BMI, and body weight. Results: For CBD, the mean Cmax was 389.17 ± 153.23 ng/mL, and the mean AUC was 1,542.19 ± 488.04 ng/mL*h. For 7-OH-CBD, the mean Cmax was 81.35 ± 36.64 ng/mL, the mean AUC was 364.70 ± 105.59 ng/mL*h, and the mean MPR was 0.25 ± 0.07. For 7-COOH-CBD, the mean Cmax was 1,717.33 ± 769.22 ng/mL, the mean AUC was 9,888.42 ± 3,961.47 ng/mL*h, and the mean MPR was 7.11 ± 3.48. For 7-COOH-CBD, a 2.25-fold higher Cmax was observed in female subjects (p = 0.0155) and a 1.97-fold higher AUC for female subjects (p = 0.0285) with the normalization of body weight. A significant linearity (p = 0.0135) of 7-OH-CBD AUC with body weight in females was observed. No significant differences were identified in Cmax, AUC, and PMR with race and BMI. Conclusion: Observed differences in sex were in agreement with previously reported findings. A larger population pharmacokinetics study is warranted to validate the observed higher Cmax and AUC in females and significant linearity with body weight in females from the current study.
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Background: Over the last years, there is a dramatic increase in the use of medical cannabis products for an expanding range of clinical indications. The type of the drug product and its administration route affect substantially the rate and the extent of absorption of cannabinoids and the effects induced by them in the patients. The current challenge for the cannabis pharmaceutical industry is to develop formulations that allow predictable and stable absorption of cannabinoids. This article reports the results of the clinical trial that investigated the pharmacokinetics (PKs) of innovative cannabis products in healthy volunteers. Materials and Methods: This was a single-center study with a single-dose, randomized, crossover, partially blinded controlled design. Each of the 12 healthy volunteers received 8 different products, of the 10 products that were assessed in this trial: novel sublingual (SL) tablet, vaporizer, and rectal products, comparator products (Sativex® and oil-based oromucosal products), and placebo products. Serial blood samples were collected, plasma concentrations of the THC, 11-OH-THC, and CBD were quantified and subjected to noncompartmental PK analysis. Results: Novel medical cannabis products that were investigated in the study induced substantial exposure of the volunteers to the active ingredients, had more rapid absorption, and in some cases also less variable absorption of THC and CBD, in comparison with the approved comparison products. The bioavailability of the novel SL tablet-based and suppositories products was somewhat lower than that of the oromucosal products. The vaporizer provided immediate systemic absorption with highest maximal concentration. The safety profile of the novel cannabis products, namely vaporizer, SL tablets, and suppositories, was not inferior to the Sativex and oil-based oromucosal formulations. Conclusions: The novel cannabis products that were assessed in this study have PK properties that may be advantageous for management of specific medical conditions or in specific subgroups of patients that are prescribed medical cannabis.
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BACKGROUND: Etoposide is a chemotherapeutic agent, widely used for the treatment of various malignancies, including small cell lung cancer (SCLC), an aggressive disease with poor prognosis. Oral etoposide administration exhibits advantages for the quality of life of the patient as well as economic benefits. However, widespread use of oral etoposide is limited by incomplete and variable bioavailability. Variability in bioavailability was observed both within and between patients. This suggests that some patients may experience suboptimal tumor cytotoxicity, whereas other patients may be at risk for excess toxicity. CONCLUSIONS: The article highlights dilemmas as well as solutions regarding oral treatment with etoposide by presenting and analyzing relevant literature data. Numerous studies have shown that bioavailability of etoposide is influenced by genetic, physiological and environmental factors. Several strategies were explored to improve bioavailability and to reduce pharmacokinetic variability of oral etoposide, including desired and undesired drug interactions (e.g. with ketoconazole), development of suitable drug delivery systems, use of more water-soluble prodrug of etoposide, and influence on gastric emptying. In addition to genotype-based dose administration, etoposide is suitable for pharmacokinetically guided dosing, which enables dose adjustments in individual patient. Further, it is established that oral and intravenous schedules of etoposide in SCLC patients do not result in significant differences in treatment outcome, while results of toxicity are inconclusive. To conclude, the main message of the article is that better prediction of the pharmacokinetics of oral etoposide may encourage its wider use in routine clinical practice.
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Antiseizure medications (ASMs) are the cornerstone of treatment for patients with epilepsy. Several new ASMs have recently been introduced to the market, making it possible to better tailor the treatment of epilepsy, as well as other indications (psychiatry and pain disorders). For this group of drugs there are numerous pharmacological challenges, and updated knowledge on their pharmacodynamic and pharmacokinetic properties is, therefore, crucial for an optimal treatment outcome. This review focuses on educational approaches to the following learning outcomes as described by the International League Against Epilepsy (ILAE): To demonstrate knowledge of pharmacokinetics and pharmacodynamics, drug interactions with ASMs and with concomitant medications, and appropriate monitoring of ASM serum levels (therapeutic drug monitoring, TDM). Basic principles in pharmacology, pharmacokinetic variability, and clinically relevant approaches to manage drug interactions are discussed. Furthermore, recent improvements in analytical technology and sampling are described. Future directions point to the combined implementation of TDM with genetic panels for proper diagnosis, pharmacogenetic tests where relevant, and the use of biochemical markers that will all contribute to personalized treatment. These approaches are clinically relevant for an optimal treatment outcome with ASMs in various patient groups.