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Introduction: Graft survival in pediatric kidney transplant patients has increased significantly within the last three decades, correlating with the discovery and utilization of new immunosuppressants as well as improvements in patient care. Despite these developments in graft survival for patients, there is still improvement needed, particularly in long-term care in pediatric patients receiving grafts from deceased donor patients. Maintenance immunosuppressive therapies have narrow therapeutic indices and are associated with high inter-individual and intra-individual variability.Areas covered: In this review, we examine the impact of pharmacokinetic variability on renal transplantation and its association with age, genetic polymorphisms, drug-drug interactions, drug-disease interactions, renal insufficiency, route of administration, and branded versus generic drug formulation. Pharmacodynamics are outlined in terms of the mechanism of action for each immunosuppressant, potential adverse effects, and the utility of pharmacodynamic biomarkers.Expert opinion: Acquiring abetter quantitative understanding of immunosuppressant pharmacokinetics and pharmacodynamic components should help clinicians implement treatment regimens to maintain the balance between therapeutic efficacy and drug-related toxicity.
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Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/administración & dosificación , Trasplante de Riñón/métodos , Factores de Edad , Niño , Interacciones Farmacológicas , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/farmacocinética , Polimorfismo GenéticoRESUMEN
Lentiviral vectors are increasingly utilized in cell and gene therapy applications because they efficiently transduce target cells such as hematopoietic stem cells and T cells. Large-scale production of current Good Manufacturing Practices-grade lentiviral vectors is limited because of the adherent, serum-dependent nature of HEK293T cells used in the manufacturing process. To optimize large-scale clinical-grade lentiviral vector production, we developed an improved production scheme by adapting HEK293T cells to grow in suspension using commercially available and chemically defined serum-free media. Lentiviral vectors with titers equivalent to those of HEK293T cells were produced from SJ293TS cells using optimized transfection conditions that reduced the required amount of plasmid DNA by 50%. Furthermore, purification of SJ293TS-derived lentiviral vectors at 1 L yielded a recovery of 55% ± 14% (n = 138) of transducing units in the starting material, more than a 2-fold increase over historical yields from adherent HEK293T serum-dependent lentiviral vector preparations. SJ293TS cells were stable to produce lentiviral vectors over 4 months of continuous culture. SJ293TS-derived lentiviral vectors efficiently transduced primary hematopoietic stem cells and T cells from healthy donors. Overall, our SJ293TS cell line enables high-titer vector production in serum-free conditions while reducing the amount of input DNA required, resulting in a highly efficient manufacturing option.
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AIMS: No population pharmacokinetic studies of high-dose methotrexate (HDMTX) have been conducted in infants with brain tumours, which are a vulnerable population. The aim of this study was to evaluate HDMTX disposition in these children to provide a rational basis for MTX dosing. METHODS: Patients received 4 monthly courses of HDMTX (5 g/m2 or 2.5 g/m2 for infants aged ≤31 days) as a 24-h infusion. Serial samples were analysed for MTX by an enzyme immunoassay method. Pharmacokinetic parameters were estimated using nonlinear mixed effects population modelling. Demographics, concomitant medications and genetic polymorphisms were considered as pharmacokinetic covariates while MTX exposure and patient age were considered as covariates for Grade 3 and 4 toxicities. RESULTS: The population pharmacokinetics of HDMTX were estimated in 178 patients (age range 0.02-4.7 years) in 648 courses. The population clearance and volume were 90 mL/min/m2 and 14.4 L/m2 , respectively. Significant covariates on body surface area adjusted MTX clearance included estimated glomerular filtration rate and co-treatment with dexamethasone or vancomycin. No significant association was observed between MTX toxicity and MTX exposure, patient age, leucovorin dosage or duration. MTX clearance in infants ≤31 days at enrolment was 44% lower than in older infants, but their incidence of toxicity was not higher since they also received a lower MTX dosage. CONCLUSIONS: By aggressively following institutional clinical guidelines, HDMTX-related toxicities were low, and using covariates from the population pharmacokinetic model enabled the calculation of a rational dosage for this patient population for future clinical trials.
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Neoplasias Encefálicas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Neoplasias Encefálicas/tratamiento farmacológico , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Leucovorina , MetotrexatoRESUMEN
To understand the systemic impact of breast cancer resistance protein (Bcrp) and P-glycoprotein (Pgp) deletion, untargeted metabolomics was performed on cerebral spinal fluid (CSF) and plasma of wild-type (WT) and Pgp and Bcrp double-knockout (dKO) rats anesthetized with ketamine-xylazine. We unexpectedly found elevated ketamine levels in both CSF and plasma of dKO versus WT rats. Therefore, the effect of these transporters was investigated on the 1) oral and intraperitoneal serum pharmacokinetics (PK) of ketamine, using a liquid chromatography method (high-performance liquid chromatography with ultraviolet detection), and 2) the anesthetic effect of ketamine using a duration of loss-of-righting reflex (dLORR) test in WT, Bcrp knockout (KO), Pgp KO, and Pgp/Bcrp dKO mice. The PK data demonstrated a significantly increased oral bioavailability and serum exposure of ketamine in dKO > Pgp KO > Bcrp KO mice compared with WT mice. Intraperitoneal ketamine-induced dLORR was significantly longer in dKO > Pgp KO > Bcrp KO > WT mice compared with WT mice. Inhibition of Bcrp and Pgp in WT mice using the dual Pgp/Bcrp inhibitor elacridar increased the ketamine-induced dLORR compared with vehicle-treated mice. The ketamine intracellular concentration was significantly decreased in Madin-Darby canine kidney II BCRP/PGP cells compared with the parental cells. In total, these results demonstrate that ketamine appears to be a dual Pgp/Bcrp substrate whose PK and pharmacodynamics are affected by Pgp and Bcrp-mediated efflux.
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Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Ketamina/farmacología , Ketamina/farmacocinética , Proteínas de Transporte de Membrana/metabolismo , Animales , Disponibilidad Biológica , Transporte Biológico/fisiología , Línea Celular , Perros , Células de Riñón Canino Madin Darby , Masculino , Ratones , Ratones Noqueados , Ratas , Ratas Sprague-DawleyRESUMEN
AIMS: Nicotine addiction is an issue faced by millions of individuals worldwide. As a result, nicotine replacement therapies, such as transdermal nicotine patches, have become widely distributed and used. While the pharmacokinetics of transdermal nicotine have been extensively described using noncompartmental methods, there are few data available describing the between-subject variability in transdermal nicotine pharmacokinetics. The aim of this investigation was to use population pharmacokinetic techniques to describe this variability, particularly as it pertains to the absorption of nicotine from the transdermal patch. METHODS: A population pharmacokinetic parent-metabolite model was developed using plasma concentrations from 25 participants treated with transdermal nicotine. Covariates tested in this model included: body weight, body mass index, body surface area (calculated using the Mosteller equation) and sex. RESULTS: Nicotine pharmacokinetics were best described with a one-compartment model with absorption based on a Weibull distribution and first-order elimination and a single compartment for the major metabolite, cotinine. Body weight was a significant covariate on apparent volume of distribution of nicotine (exponential scaling factor 1.42). After the inclusion of body weight in the model, no other covariates were significant. CONCLUSIONS: This is the first population pharmacokinetic model to describe the absorption and disposition of transdermal nicotine and its metabolism to cotinine and the pharmacokinetic variability between individuals who were administered the patch.
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Modelos Biológicos , Nicotina/administración & dosificación , Nicotina/farmacocinética , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/farmacocinética , Dispositivos para Dejar de Fumar Tabaco , Administración Cutánea , Adulto , Ensayos Clínicos como Asunto , Femenino , Humanos , Masculino , Nicotina/sangre , Agonistas Nicotínicos/sangre , Estudios Retrospectivos , Absorción Cutánea , Parche Transdérmico , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Monitoring renal function is critical in treating pediatric patients, especially when dosing nephrotoxic agents. We evaluated the validity of the bedside Schwartz and Brandt equations in pediatric oncology patients and developed new equations for estimated glomerular filtration rate (eGFR) in these patients. METHODS: A retrospective analysis was conducted comparing eGFR using the bedside Schwartz and Brandt equations to measured GFR (mGFR) from technetium-99m diethylenetriamine pentaacetic acid (99mTc-DTPA) between January 2007 and August 2013. An improved equation to estimate GFR was developed, simplified, and externally validated in a cohort of patients studied from September 2013 to June 2015. Carboplatin doses calculated from 99mTc-DTPA were compared with doses calculated by GFR-estimating equations. RESULTS: Overall, the bedside Schwartz and Brandt equations did not precisely or accurately predict measured GFR (mGFR). Using a data subset, we developed a five-covariate equation, which included height, serum creatinine, age, blood urea nitrogen (BUN), and gender, and a simplified version (two-covariates), which contained height and serum creatinine. These equations were used to estimate GFR in 2036 studies, resulting in precise and accurate predictors of mGFR values. Equations were validated in an external cohort of 570 studies; both new equations were more accurate in calculating carboplatin doses than either the bedside Schwartz or Brandt equation. CONCLUSIONS: Two new equations were developed to estimate GFR in pediatric oncology patients, both of which did a better job at estimating mGFR than published equations.
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Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Pruebas de Función Renal/métodos , Modelos Biológicos , Neoplasias/tratamiento farmacológico , Adolescente , Antineoplásicos/farmacocinética , Carboplatino/farmacocinética , Niño , Preescolar , Femenino , Tasa de Filtración Glomerular , Humanos , Lactante , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Neoplasias/fisiopatología , Radiofármacos/administración & dosificación , Eliminación Renal , Insuficiencia Renal Crónica , Estudios Retrospectivos , Pentetato de Tecnecio Tc 99m/administración & dosificaciónRESUMEN
The epicutaneous histamine (EH) test is the current gold standard method for the clinical evaluation of allergic conditions. However, the EH method is limited in providing an objective and qualitative assessment of histamine pharmacodynamic response. The histamine iontophoresis with laser Doppler (HILD) monitoring method, an alternative method, allows a fixed dose of histamine to be delivered and provides an objective, continuous, and dynamic measurement of histamine epicutaneous response in children and adults. However, due to the high sampling frequency (up to 40 Hz), the output files are usually too cumbersome to be directly used for further analysis. In this study, we developed an averaging algorithm that efficiently reduces the HILD data in size. The reduced data was further analyzed and a population linked effect pharmacokinetic/pharmacodynamic (PK/PD) model was developed to describe the local histamine response. The model consisted of a one-compartment PK model and a direct-response fractional maximum effect (Emax) model. The parameter estimates were obtained as follows: absorption rate constant (ka), 0.094/min; absorption lag time (Tlag), 2.72 min; partitioning clearance from local depot to systemic circulation (CLpar), 0.0006 L/min; baseline effect (E0), 13.1 flux unit; Emax, 13.4; concentration at half maximum effect (EC50) 31.1 mg/L. Covariate analysis indicated that age and race had significant influence on Tlag and EC50, respectively.
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Asma/tratamiento farmacológico , Antagonistas de los Receptores Histamínicos , Histamina , Iontoforesis , Flujometría por Láser-Doppler/métodos , Modelos Biológicos , Adolescente , Adulto , Algoritmos , Asma/metabolismo , Velocidad del Flujo Sanguíneo , Niño , Femenino , Histamina/administración & dosificación , Histamina/farmacocinética , Histamina/farmacología , Antagonistas de los Receptores Histamínicos/administración & dosificación , Antagonistas de los Receptores Histamínicos/farmacocinética , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , MasculinoRESUMEN
Lung inflammation in premature infants contributes to the development of bronchopulmonary dysplasia (BPD), a chronic lung disease with long-term sequelae. Pilot studies administering budesonide suspended in surfactant have found reduced BPD without the apparent adverse effects that occur with systemic dexamethasone therapy. Our objective was to determine budesonide potency, stability, and antiinflammatory effects in human fetal lung. We cultured explants of second-trimester fetal lung with budesonide or dexamethasone and used microscopy, immunoassays, RNA sequencing, liquid chromatography/tandem mass spectrometry, and pulsating bubble surfactometry. Budesonide suppressed secreted chemokines IL-8 and CCL2 (MCP-1) within 4 hours, reaching a 90% decrease at 12 hours, which was fully reversed 72 hours after removal of the steroid. Half-maximal effects occurred at 0.04-0.05 nM, representing a fivefold greater potency than for dexamethasone. Budesonide significantly induced 3.6% and repressed 2.8% of 14,500 sequenced mRNAs by 1.6- to 95-fold, including 119 genes that contribute to the glucocorticoid inflammatory transcriptome; some are known targets of nuclear factor-κB. By global proteomics, 22 secreted inflammatory proteins were hormonally regulated. Two glucocorticoid-regulated genes of interest because of their association with lung disease are CHI3L1 and IL1RL1. Budesonide retained activity in the presence of surfactant and did not alter its surface properties. There was some formation of palmitate-budesonide in lung tissue but no detectable metabolism to inactive 16α-hydroxy prednisolone. We concluded that budesonide is a potent and stable antiinflammatory glucocorticoid in human fetal lung in vitro, supporting a beneficial antiinflammatory response to lung-targeted budesonide:surfactant treatment of infants for the prevention of BPD.
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Antiinflamatorios/farmacología , Budesonida/farmacología , Feto/efectos de los fármacos , Pulmón/embriología , Antiinflamatorios/metabolismo , Budesonida/metabolismo , Quimiocinas/metabolismo , Dexametasona/farmacología , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Humanos , Pulmón/efectos de los fármacos , Neumonía/genética , Neumonía/patología , Tensión Superficial/efectos de los fármacos , Factores de TiempoRESUMEN
For infants and very young children with brain tumors, chemotherapy after surgical resection is the main treatment due to neurologic and neuroendocrine adverse effects from whole brain irradiation. Topotecan, an anticancer drug with antitumor activity against pediatric brain tumors, can be given intravenous or orally. However, high interpatient variability in oral drug bioavailability is common in children less than 3 years old. Therefore, this study aimed to determine the population pharmacokinetics of oral topotecan in infants and very young children, specifically evaluating the effects of age and ABCG2 and ABCB1 on the absorption rate constant (Ka), as well as other covariate effects on all pharmacokinetic parameters. A nonlinear mixed effects model was implemented in Monolix 4.3.2 (Lixoft, Orsay, France). A one-compartment model with first-order input and first-order elimination was found to adequately characterize topotecan lactone concentrations with population estimates as [mean (S.E.)]; Ka = 0.61 (0.11) h(-1), apparent volume of distribution (V/F) = 40.2 (7.0) l, and apparent clearance (CL/F) = 40.0 (2.9) l/h. After including the body surface area in the V/F and CL/F as a power model centered on the population median, the ABCG2 rs4148157 allele was found to play a significant role in the value of Ka Patients homozygous or heterozygous for G>A demonstrated a Ka value 2-fold higher than their GG counterparts, complemented with a 2-fold higher maximal concentration as well. These results demonstrate a possible role for the ABCG2 rs4148157 allele in the pharmacokinetics of oral topotecan in infants and very young children, and warrants further investigation.
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Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Neoplasias Encefálicas/tratamiento farmacológico , Absorción Gastrointestinal , Proteínas de Neoplasias/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Inhibidores de Topoisomerasa I/administración & dosificación , Inhibidores de Topoisomerasa I/farmacocinética , Topotecan/administración & dosificación , Topotecan/farmacocinética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/metabolismo , Administración Oral , Factores de Edad , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Preescolar , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Lactante , Masculino , Modelos Biológicos , Proteínas de Neoplasias/metabolismo , Farmacogenética , FenotipoRESUMEN
The administration of drugs to neonates poses significant challenges. The aim of this review was to provide insight into some of these challenges and resolutions that may be encountered with several of the most commonly used routes of administration and dosage forms in neonatal care, including oral, parenteral, transdermal, intrapulmonary, and rectal. Important considerations include fluctuations in stomach pH hours to years after birth, the logistics of setting up an intravenous infusion, the need for reduced particle size for aerosol delivery to the developing neonatal lung, and variation in perirectal venous drainage. Additionally, some of the recently developed technologies for use in neonatal care are described. While the understanding of neonatal drug delivery has advanced over the past several decades, there is still a deficiency of technologies and formulations developed specifically for this population.
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Sistemas de Liberación de Medicamentos , Vías de Administración de Medicamentos , Humanos , Recién Nacido , Preparaciones Farmacéuticas/administración & dosificaciónRESUMEN
OBJECTIVES: The aims of this study were to develop a population pharmacokinetic model for intravenous paracetamol in preterm and term neonates and to assess the generalizability of the model by testing its predictive performance in an external dataset. METHODS: Nonlinear mixed-effects models were constructed from paracetamol concentration-time data in NONMEM 7.2. Potential covariates included body weight, gestational age, postnatal age, postmenstrual age, sex, race, total bilirubin, and estimated glomerular filtration rate. An external dataset was used to test the predictive performance of the model through calculation of bias, precision, and normalized prediction distribution errors. RESULTS: The model-building dataset included 260 observations from 35 neonates with a mean gestational age of 33.6 weeks [standard deviation (SD) 6.6]. Data were well-described by a one-compartment model with first-order elimination. Weight predicted paracetamol clearance and volume of distribution, which were estimated as 0.348 L/h (5.5 % relative standard error; 30.8 % coefficient of variation) and 2.46 L (3.5 % relative standard error; 14.3 % coefficient of variation), respectively, at the mean subject weight of 2.30 kg. An external evaluation was performed on an independent dataset that included 436 observations from 60 neonates with a mean gestational age of 35.6 weeks (SD 4.3). The median prediction error was 10.1 % [95 % confidence interval (CI) 6.1-14.3] and the median absolute prediction error was 25.3 % (95 % CI 23.1-28.1). CONCLUSIONS: Weight predicted intravenous paracetamol pharmacokinetics in neonates ranging from extreme preterm to full-term gestational status. External evaluation suggested that these findings should be generalizable to other similar patient populations.
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Acetaminofén/administración & dosificación , Acetaminofén/farmacocinética , Analgésicos no Narcóticos/administración & dosificación , Modelos Biológicos , Administración Intravenosa , Analgésicos no Narcóticos/farmacocinética , Peso Corporal , Cálculo de Dosificación de Drogas , Humanos , Recién Nacido , Recien Nacido Prematuro , Dinámicas no Lineales , Estudios ProspectivosRESUMEN
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of premature human infants, which may persist through adulthood. Airway inflammation has been firmly established in the pathogenesis of BPD. Previous studies to reduce airway inflammation with high-dose dexamethasone demonstrated adverse neurological outcomes, despite lower incidences of BPD. Instillation of budesonide and surfactant can facilitate early extubation and reduce the incidence of BPD and death among very low birth weight infants. However, the pharmacokinetics of budesonide and its distribution into the lung and brain are unknown. Therefore, 5 premature lambs were administered 0.25 mg/kg budesonide, with surfactant as the vehicle. Plasma and tissue samples were taken from the lambs for measurement of budesonide, 16α- hydroxy prednisolone, and budesonide palmitate using LC/MS/MS. Peak plasma budesonide concentrations were inversely correlated with the oxygenation index (correlation coefficient of -0.75). plasma budesonide concentrations were extremely low (~10% of expected) for two lambs that had high oxygenation indices and were excluded from further analyses. For the remaining 5 premature lambs, a non-compartmental analysis demonstrated an AUCinf of 148.77 ± 28.16 h*µg/L, half-life of 4.76 ± 1.79 h, and Cmax of 46.17 ± 17.71 µg/L. Using population pharmacokinetic methods, a onecompartment model with exponential residual error and first-order absorption adequately described the data. The apparent clearance and apparent volume of distribution of budesonide were estimated at 6.29 L/h (1.99 L/h/kg) and 29.1 L (9.2 L/kg), respectively. Budesonide and budesonide palmitate, but not 16α-hydroxy prednisolone, were detected in lung tissue. In this study, budesonide and its metabolites were not detected in the brain, which suggests that intratracheal instillation suggests that after local pulmonary deposition, there is no evidence of budesonide accumulation in the central nervous system. Overall, these results show that peak plasma budesonide concentrations are inversely correlated with the oxygenation index and that lung-specific delivery of budesonide avoids accumulation of budesonide in the brain.
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Budesonida/farmacocinética , Tensoactivos/farmacocinética , Administración por Inhalación , Animales , Animales Recién Nacidos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Budesonida/administración & dosificación , Ensayos Clínicos como Asunto/métodos , Femenino , Humanos , Recién Nacido , Masculino , Embarazo , Nacimiento Prematuro/tratamiento farmacológico , Nacimiento Prematuro/metabolismo , Ovinos , Tensoactivos/administración & dosificaciónRESUMEN
BACKGROUND: The incidence of nephrotoxicity among vancomycin-treated neonates has been reported to range from 2% to 20%. These widely varying estimates have led to confusion and controversy regarding the safety of vancomycin among neonates. OBJECTIVE: Evaluate the incidence of nephrotoxicity among neonates receiving vancomycin concomitantly with gentamicin. DESIGN: Retrospective observational cohort study using propensity score matching to provide covariate balance between neonates who did or did not receive vancomycin based on factors known to be related to the development of renal dysfunction. SETTING: Hospitals (n=22) throughout the Intermountain West, including a quaternary care children's hospital. PATIENTS: Neonates ≤44 postmenstrual weeks (median gestational age: 31 (IQR 28-36) weeks) receiving intravenous gentamicin with or without exposure to vancomycin from January 2006 to December 2012. MAIN OUTCOME MEASURES: Nephrotoxicity based on the modified Acute Kidney Injury Network criteria for acute kidney injury (AKI) or serum creatinine concentration ≥1.5â mg/dL persisting for ≥48â h. RESULTS: The final cohort was comprised of 1066 neonates (533 receiving vancomycin and gentamicin vs 533 receiving gentamicin). In a propensity score-matched cohort that was well balanced across 16 covariates, AKI was not associated with vancomycin use (16 neonates receiving vancomycin vs 7 controls experienced AKI; OR 1.5; 95% CI 0.6 to 4.0). However, the presence of a patent ductus arteriosus, concomitant non-steroidal anti-inflammatory drug use, ≥1 positive blood cultures, low birth weight and higher severity of illness and risk of mortality scores were associated with an increased risk of nephrotoxicity. CONCLUSIONS: These results corroborate several earlier reports and much anecdotal evidence describing the infrequent occurrence of nephrotoxicity in neonates receiving concomitant vancomycin and gentamicin.
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Lesión Renal Aguda/inducido químicamente , Antibacterianos/efectos adversos , Vancomicina/efectos adversos , Lesión Renal Aguda/epidemiología , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/efectos adversos , Bacteriemia/epidemiología , Estudios de Cohortes , Creatinina/sangre , Quimioterapia Combinada , Conducto Arterioso Permeable/epidemiología , Femenino , Gentamicinas/administración & dosificación , Humanos , Recién Nacido de Bajo Peso , Recién Nacido , Masculino , Puntaje de Propensión , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Estados Unidos/epidemiologíaRESUMEN
A rapid and robust method for measuring methotrexate (MTX) and its two primary metabolites, 7-hydroxymethotrexate (7-OHMTX) and 2,4-diamino-N10-methylpteroic acid (DAMPA), was developed for use in pharmacokinetic studies of plasma and cerebrospinal fluid samples collected from infants with malignant brain tumors. Sample aliquots (100µL) were prepared for bioanalysis of MTX and metabolites using a Waters Oasis HLB microelution SPE plate. Chromatography was performed using a Phenomenex Synergi Polar-RP 4µ 75 × 2.0mm ID column heated to 40°C. A rapid gradient elution on a Shimadzu HPLC system was used, with mobile phase A consisting of water/formic acid (100/0.1 v/v) and mobile phase B consisting of acetonitrile/formic acid (100/0.1 v/v). Column eluent was analyzed using AB Sciex QTRAP 5500 instrumentation in electrospray ionization mode. The ion transitions (m/z) monitored were 455.2â308.1, 471.1â324.1, and 326.2â175.1 for MTX, 7-OHMTX, and DAMPA respectively. The method was linear over a range of 0.0022 - 5.5 µM for MTX, 0.0085 - 21 µM for 7-OHMTX, and 0.0031 - 7.7 µM for DAMPA. The method was applied to the analysis of serial plasma samples obtained from infants diagnosed with malignant brain tumors receiving high-dose MTX and results were compared to MTX concentrations from a TDx-FLx FPIA.
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AIM: To develop a vancomycin population pharmacokinetic model and assess the probability of attaining a pharmacodynamic target associated with clinical and microbiological success, a ratio of the 24-hour area under the concentration-time curve to the minimum inhibitory concentration (MIC) ≥ 400, in a 5-year clinical cohort of preterm and term neonatal patients with late-onset staphylococcal sepsis. METHODS: Therapeutic drug monitoring data were obtained from septic neonates with ≥1 vancomycin concentration(s) from January 2006 to September 2011. Only neonates with a postnatal age of >72 hours and a positive microbiological culture were included. Population pharmacokinetic model was developed using nonlinear mixed effects modeling (NONMEM 7.2). Eleven demographic characteristics were evaluated as covariates. Probabilities of achieving the pharmacodynamic target were evaluated. RESULTS: A 1-compartment model with first-order elimination was constructed from 528 vancomycin concentrations collected from 152 preterm and term neonates. Body weight, creatinine clearance (CL), and postmenstrual age were identified as significant covariates. Estimated vancomycin CL and volume of distribution for typical neonates were 0.068 ± 0.03 L·h·kg and 0.62 ± 0.13 L/kg, respectively. Coagulase-negative staphylococci (85.5%) and Staphylococcus aureus (14.5%) were the common pathogenic organisms. The distribution of vancomycin MIC breakpoints was composed of approximately 70% MIC breakpoint of ≤2 mcg/mL. Approximately 54% of neonates, with a median serum creatinine concentration of 0.44 mg/dL, achieved the target ratio of 24-hour area under the concentration-time curve to the MIC ≥ 400 with a median daily dose of 30 (interquartile range, 21-42) mg/kg. CONCLUSIONS: Body weight, creatinine CL, and postmenstrual age significantly influenced vancomycin CL. The current vancomycin doses are acceptable at MICs ≤1 mcg/mL because they are likely to achieve the pharmacodynamic target in the majority of neonatal patients, although higher doses may be considered for more resistant staphylococcal infections.
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Antibacterianos/administración & dosificación , Modelos Biológicos , Sepsis/tratamiento farmacológico , Vancomicina/administración & dosificación , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Humanos , Recién Nacido , Enfermedades del Recién Nacido/tratamiento farmacológico , Enfermedades del Recién Nacido/microbiología , Masculino , Pruebas de Sensibilidad Microbiana , Dinámicas no Lineales , Estudios Retrospectivos , Sepsis/microbiología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Distribución Tisular , Vancomicina/farmacocinética , Vancomicina/farmacologíaRESUMEN
BACKGROUND AND OBJECTIVE: Hair is an attractive matrix for amphetamine drug testing; however, little is known about the rate at which amphetamines are deposited into hair. Therefore, the purpose of this study was to determine the pharmacokinetics of oral dextroamphetamine in plasma and quantify the rate of deposition into hair in healthy adults using a linked population pharmacokinetic model. METHODS: Healthy adults >18 years of age received dextroamphetamine 10 mg orally for 7 days. Plasma samples were collected over 48 h following the final dose, and hair was collected 5 weeks following the first dose. NONMEM 7.2 was used to estimate dextroamphetamine oral absorption rate constant, apparent clearance and volume of distribution of the plasma compartment, the plasma to hair incorporation rate constant, and the apparent volume of distribution in the hair compartment. RESULTS: Dextroamphetamine pharmacokinetics were well-described by a one-compartment model with combined additive and proportional error for the plasma compartment, which was linked to a single compartment for the hair. Apparent clearance and volume of distribution in the plasma compartment were scaled by current body weight (centered on the mean). Melanin hair concentration was included as a significant covariate on the hair compartment. Absorption rate constant, clearance, and volume of distribution for the plasma compartment were estimated as 0.527 h(-1) (95% CI 0.467-0.586), 28.7 L/h (95% CI 27.1-30.3), and 377 L (95% CI 326-428), respectively. The incorporation rate constant from plasma to hair was 1.60e(-6) h(-1) (95% CI 1.06e(-6)-2.14e(-6)) and apparent volume of distribution in hair was 17.7 mg (95% CI 12.5-22.8). CONCLUSIONS: A one-compartment plasma model linked to a single compartment for hair successfully described the pharmacokinetics of dextroamphetamine in healthy adults. The volume of distribution and clearance of dextroamphetamine increased with weight, and the volume of distribution of the hair compartment increased with greater melanin concentrations.
Asunto(s)
Dextroanfetamina/sangre , Dextroanfetamina/farmacocinética , Cabello/metabolismo , Adulto , Femenino , Voluntarios Sanos , Humanos , Masculino , Melaninas/metabolismo , Modelos Biológicos , Detección de Abuso de Sustancias/métodos , Adulto JovenRESUMEN
BACKGROUND: Despite therapeutic hypothermia, neonates with encephalopathy (NE) have high rates of death or disability. Darbepoetin alfa (Darbe) has comparable biological activity to erythropoietin, but has extended circulating half-life (t(1/2)). Our aim was to determine Darbe safety and pharmacokinetics as adjunctive therapy to hypothermia. STUDY DESIGN: Thirty infants (n = 10/arm) ≥36 wk gestation undergoing therapeutic hypothermia for NE were randomized to receive placebo, Darbe low dose (2 µg/kg), or high dose (10 µg/kg) given intravenously within 12 h of birth (first dose/hypothermia condition) and at 7 d (second dose/normothermia condition). Adverse events were documented for 1 mo. Serum samples were obtained to characterize Darbe pharmacokinetics. RESULTS: Adverse events (hypotension, altered liver and renal function, seizures, and death) were similar to placebo and historical controls. Following the first Darbe dose at 2 and 10 µg/kg, t(1/2) was 24 and 32 h, and the area under the curve (AUC(inf)) was 26,555 and 180,886 h*mU/ml*, respectively. In addition, clearance was not significantly different between the doses (0.05 and 0.04 l/h). At 7 d, t(1/2) was 26 and 35 h, and AUC(inf) was 10,790 and 56,233 h*mU/ml*, respectively (*P < 0.01). CONCLUSION: Darbe combined with hypothermia has similar safety profile to placebo with pharmacokinetics sufficient for weekly administration.
Asunto(s)
Encefalopatías/tratamiento farmacológico , Darbepoetina alfa/farmacocinética , Darbepoetina alfa/uso terapéutico , Hipotermia Inducida , Adolescente , Adulto , Área Bajo la Curva , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Eritropoyetina/uso terapéutico , Femenino , Humanos , Hipotermia/tratamiento farmacológico , Recién Nacido , Imagen por Resonancia Magnética , Masculino , Adulto JovenRESUMEN
AIM: The aim of this study was to determine the population pharmacokinetics of darbepoetin alfa in hypothermic neonates with hypoxic-ischemic encephalopathy treated with hypothermia. METHODS: Neonates ≥36 weeks gestation and <12 h postpartum with moderate to severe hypoxic-ischemic encephalopathy who were undergoing hypothermia treatment were recruited in this randomized, multicenter, investigational, new drug pharmacokinetic study. Two intravenous darbepoetin alfa treatment groups were evaluated: 2 and 10 µg/kg. Serum erythropoietin concentrations were measured using an enzyme-linked immunosorbent assay. Monolix 4.3.1 was used to estimate darbepoetin alfa clearance and volume of distribution. Covariates tested included: birthweight, gestational age, postnatal age, postmenstrual age, sex, Sarnat score, and study site. RESULTS: Darbepoetin alfa pharmacokinetics were well described by a one-compartment model with exponential error. Clearance and the volume of distribution were scaled by birthweight (centered on the mean) a priori. Additionally, gestational age (also centered on the mean) significantly affected darbepoetin alfa clearance. Clearance and volume of distribution were estimated as 0.0465 L/h (95% confidence interval 0.0392-0.0537) and 1.58 L (95% confidence interval 1.29-1.87), respectively. CONCLUSIONS: A one-compartment model successfully described the pharmacokinetics of darbepoetin alfa among hypothermic neonates treated for hypoxic-ischemic encephalopathy. Clearance decreased with increasing gestational age.