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1.
Artigo em Inglês | MEDLINE | ID: mdl-32678694

RESUMO

Purpose: The therapeutic utility of Cannabis in cancer is a topic of intense interest. Dronabinol is synthetic Δ9-tetrahydrocannabinol (THC), the primary psychoactive component of Cannabis sativa, and is approved for treating refractory chemotherapy-induced nausea and vomiting. Little is known about dronabinol prescribing in children and young adults, and no published concentration data are available. This study evaluated national level dronabinol use and assessed concentrations of THC and its primary metabolites in patients with cancer <27 years of age prescribed dronabinol. Methods: Observational review of records from the Pediatric Health Information System (PHIS) and a regional network of hospitals in the Intermountain West, including a tertiary care children's hospital, Primary Children's Hospital (PCH), for inpatients <27 years of age prescribed dronabinol. Prospective blood samples were collected from children with cancer at PCH. Results: Across PHIS institutions, overall dronabinol prescribing aligned with the pharmacy records for those with cancer (p < 0.0001), and of these, 10.4% received dronabinol as inpatients. Blood collected within 72 hours of dronabinol administration was available from 10 children with a median age of 12.5 (range 6-17) years. Quantifiable concentrations were found in 4 (13%), 6 (20%), and 1 (3%) samples assayed for THC, 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (COOH-THC), and 11-hydroxy-Δ9-tetrahydrocannabinol (OH-THC), respectively. THC concentrations ranged between 0.100 and 0.128 ng/mL and were not associated with dose. Conclusion: Dronabinol prescribing appears exclusive to patients diagnosed with cancer, and its use has increased steadily in the past decade. In a small sample of children administered dronabinol, THC and metabolite concentrations were consistently low or undetectable.

2.
Leuk Lymphoma ; : 1-12, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32264729

RESUMO

Pharmacokinetic (PK) conflicts can arise between supportive care medications (SCM) and chemotherapy in children with hematologic malignancy (HM). In this retrospective study, medical records for children (28 days-18 years) diagnosed with HM and receiving an SCM antimicrobial were collected from a hospital network between 1 May 2000 and 31 December 2014. PK drug-gene associations were obtained from a curated pharmacogenomics database. Among 730 patients (median age of 7.5 (IQR 3.7-13.9) years), primarily diagnosed with lymphoid leukemia (52%), lymphoma (28%), or acute myeloid leukemia (16%), chemotherapy was administered in 2846 hospitalizations. SCM accounted for 90.5% (n = 448) of distinct drugs with 93% (n = 679) of children, receiving ≥5 different SCM/hospitalization. Same-day SCM/chemotherapeutic PK gene overlap occurred in 48.3% of hospitalizations and was associated with age (p = 0.026), number of SCM, HM subtype, surgery, and hematopoietic stem cell transplant (p < 0.0001). A high and variable SCM burden among children with HM receiving chemotherapy poses a risk for unanticipated PK conflicts.

3.
J Pharm Biomed Anal ; 184: 113181, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32105943

RESUMO

Valganciclovir (VGC) is an orally available mono-valyl ester pro drug of the nucleoside analog (NA) ganciclovir (GCV) used to treat cytomegalovirus (CMV). Congenital CMV infection in the newborn is associated with progressive sensorineural hearing loss; however, effective CMV therapy with VGC can improve audiologic outcomes. Ongoing studies to demonstrate the effect of VGC in this setting are hampered by a poor understanding of the pharmacology of VGC and GCV in newborns, and the low blood volumes that can be safely collected from this population. We describe a simple method for determining systemic GCV concentrations using dried blood spot (DBS) samples. GCV was extracted from a single 6 mm punch via sonication in methanol, then quantified using liquid chromatography-tandem mass spectrometry. The assay was accurate and precise in the dynamic range of 10-10,000 ng/mL. GCV concentrations determined in DBS agreed well with GCV concentrations observed in serum. The assay was successfully applied to patient samples, and will be used to support pharmacokinetic studies in an ongoing clinical trial of VGC in infants with CMV-mediated hearing loss.

4.
Pediatr Res ; 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32006953

RESUMO

BACKGROUND: Initial trials of lung-targeted budesonide (0.25 mg/kg) in surfactant to prevent bronchopulmonary dysplasia (BPD) in premature infants have shown benefit; however, the optimal safe dose is unknown. METHODS: Dose-escalation study of budesonide (0.025, 0.05, 0.10 mg/kg) in calfactatant in extremely low gestational age neonates (ELGANs) requiring intubation at 3-14 days. Tracheal aspirate (TA) cytokines, blood budesonide concentrations, and untargeted blood metabolomics were measured. Outcomes were compared with matched infants receiving surfactant in the Trial Of Late SURFactant (TOLSURF). RESULTS: Twenty-four infants with mean gestational age 25.0 weeks and 743 g birth weight requiring mechanical ventilation were enrolled at mean age 6 days. Budesonide was detected in the blood of all infants with a half-life of 3.4 h. Of 11 infants with elevated TA cytokine levels at baseline, treatment was associated with sustained decrease (mean 65%) at all three dosing levels. There were time- and dose-dependent decreases in blood cortisol concentrations and changes in total blood metabolites. Respiratory outcomes did not differ from the historic controls. CONCLUSIONS: Budesonide/surfactant had no clinical respiratory benefit at any dosing levels for intubated ELGANs. One-tenth the dose used in previous trials had minimal systemic metabolic effects and appeared effective for lung-targeted anti-inflammatory action.

5.
Epilepsia ; 60(9): 1829-1837, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31329272

RESUMO

OBJECTIVE: Pharmacokinetics (PK) of antiseizure drugs differ considerably between rats and humans. Rodents require larger and more frequent doses to maintain therapeutic drug levels. This study uses the antiseizure drug (ASD) carbamazepine (CBZ) to validate the application of a previously described automated drug delivery system for delivering chronic oral medication to rats. METHODS: Treatment-naive, male Sprague-Dawley rats were treated with oral CBZ, 75 mg/kg every 6 hours for 10 days, via the automated feeder. Blood samples were collected on day 0 (acute), day 2 (steady-state), and day 9 (chronic) and used to measure plasma CBZ and carbamazepine-10,11-epoxide (CBZ-E) concentrations via high-performance liquid chromatography. The PK of CBZ and CBZ-E were modeled using Monolix v2018R1. The acute and chronic tolerability of CBZ was evaluated using the open field test. RESULTS: CBZ and CBZ-E concentrations were best described by a one-compartment parent-metabolite model with first-order absorption and elimination kinetics. Observed and predicted CBZ concentrations were maintained within the therapeutic window (4-12 µg/mL) for the duration of the study. There was no change in open-field test activity following acute or chronic oral dosing of 75 mg/kg CBZ compared to a pretreatment baseline (P > 0.4). SIGNIFICANCE: Oral administration of CBZ dosed q.i.d. in rats using an automated drug delivery system results in therapeutic concentrations of CBZ and its active metabolite. This study represents the first PK validation for this previously described preclinical drug delivery system.


Assuntos
Anticonvulsivantes/farmacocinética , Carbamazepina/farmacocinética , Sistemas de Liberação de Medicamentos , Administração Oral , Animais , Masculino , Ratos , Ratos Sprague-Dawley
6.
J Clin Pharmacol ; 59(7): 997-1005, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30776089

RESUMO

Concern for bacterial resistance and treatment failure with vancomycin trough concentrations < 10 µg/mL have led guidelines to increase goal concentrations. There is a paucity of data evaluating vancomycin dosage necessary to achieve goals in the neonatal intensive care unit (NICU). We aimed to evaluate the implementation of a new vancomycin dosing guideline in improving trough target attainment. This retrospective study evaluated neonates in the NICU treated with vancomycin between January 2009 and December 2015. Therapeutic trough concentration attainment (10-20 µg/mL) was compared between neonates receiving vancomycin per old versus new dosing guidelines. Vancomycin trough concentrations, modeled pharmacodynamic target attainment, and nephrotoxicity were compared between groups. A total of 212 vancomycin trough concentrations (n = 91 old and n = 121 new guideline) were evaluated in 182 unique neonates. The mean ± standard deviation trough concentration achieved was 18.0 ± 7.3 µg/mL vs 8.9 ± 4.8 µg/mL in the new and old guidelines, respectively (P < .01). The new guideline resulted in a higher percentage of neonates achieving trough concentrations of 10 to 20 µg/mL (62% vs 29%; P < .01) and decreased the percentage of neonates with subtherapeutic trough concentrations (9% vs 69%; P < .01). Pharmacokinetic modeling identified postmenstrual age, days of life, and urine output as predictors of vancomycin clearance and resultant trough and area under the curve values (P < .01 for all). Trough concentrations >10 µg/mL ensured area under the curve /minimum inhibitory concentration >400 in >90% of neonates when bacteria minimum inhibitory concentration was ≤ 1 µg/mL. Nephrotoxicity was similar between groups (8.3% vs 7.7%; P = .99). In conclusion, a vancomycin nomogram designed to achieve trough concentration of 10 to 20 µg/mL improves pharmacodynamic target attainment in neonates in the NICU.

7.
J Pharm Biomed Anal ; 167: 7-14, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738243

RESUMO

Budesonide is a potential therapeutic option for the prevention of bronchopulmonary dysplasia in mechanically ventilated premature neonates. The dose and concentrations of budesonide that drive effective prophylaxis are unknown, due in part to the difficulty in obtaining serial blood samples from this fragile population. Of primary concern is the limited total blood volume available for collection for the purposes of a pharmacokinetic study. Dried blood spots (DBS), which require the collection of <200 µL whole blood to fill an entire card, are an attractive low-blood volume alternative to traditional venipuncture sampling. We describe a simple and sensitive method for determining budesonide concentrations in DBS using an ultra-high-performance liquid chromatography - tandem mass spectrometry assay. Budesonide was liberated from a single 6 mm punch using a basified methyl tert-butyl ether extraction procedure. The assay was determined to be accurate and precise in the dynamic range of 1 to 50 ng/mL. The validated assay was then successfully applied to DBS collected as part of a multi-center, dose-escalation study of budesonide administered in surfactant via intra-tracheal instillation to premature neonates between 23 and 28 weeks gestational age. These findings show that DBS are a useful technique for collecting pharmacokinetic samples in premature neonates and other pediatric populations.


Assuntos
Budesonida/sangue , Teste em Amostras de Sangue Seco/métodos , Monitoramento de Medicamentos/métodos , Lactente Extremamente Prematuro/sangue , Bioensaio , Displasia Broncopulmonar/sangue , Displasia Broncopulmonar/prevenção & controle , Calibragem , Cromatografia Líquida de Alta Pressão , Teste em Amostras de Sangue Seco/instrumentação , Monitoramento de Medicamentos/instrumentação , Idade Gestacional , Humanos , Recém-Nascido , Limite de Detecção , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
8.
Eur J Clin Pharmacol ; 75(1): 59-66, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30259065

RESUMO

PURPOSE: Intravenous (IV) magnesium sulfate (MgSO4) is clinically useful as adjunct therapy in treating acute asthma exacerbations. Despite its clinical utility, the disposition of magnesium in children is poorly described. The purpose of this study is to describe the pharmacokinetics (PK) of ionized and total serum magnesium following IV MgSO4 administration in children with severe acute asthma. METHODS: Thirty-two children receiving 50 mg/kg IV MgSO4 for acute asthma exacerbations at Primary Children's Hospital in Salt Lake City, UT, were prospectively enrolled in the study. Blood samples were collected before, as well as 30 min and 2 h after each child's IV MgSO4 dose, and used to determine total serum and ionized magnesium concentrations. The collected data were analyzed using population PK techniques using NONMEM® software. RESULTS: Total serum magnesium concentrations were used to externally validate our previously published model constructed with retrospective data (median prediction error 10.3%, median absolute prediction error 18.1%). The mean (%CV) observed endogenous ionized magnesium concentration was calculated to be 6.0 mg/L (12%), approximately one third of the same value for endogenous total serum magnesium (17.6 mg/L (22%)) in this dataset. Weight was a significant predictor of both clearance and volume in a population PK model describing ionized magnesium concentrations. No adverse events were observed in this pediatric cohort. CONCLUSIONS: This prospective study supports and extends our previous PK analysis of total serum magnesium concentrations. Ionized and total serum magnesium followed similar PK profiles following IV MgSO4 administration in children. A single bolus infusion of IV MgSO4 was safe in this small sample of children receiving it for acute asthma.


Assuntos
Antiasmáticos/administração & dosagem , Asma/tratamento farmacológico , Sulfato de Magnésio/administração & dosagem , Modelos Biológicos , Doença Aguda , Adolescente , Antiasmáticos/efeitos adversos , Antiasmáticos/farmacocinética , Asma/fisiopatologia , Criança , Pré-Escolar , Feminino , Hospitalização , Humanos , Infusões Intravenosas , Sulfato de Magnésio/efeitos adversos , Sulfato de Magnésio/farmacocinética , Masculino , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores de Tempo
9.
BMJ Paediatr Open ; 1: e000147, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29177199

RESUMO

Objective: Immunosuppressant therapy plays a pivotal role in transplant success and longevity. Tacrolimus, a primary immunosuppressive agent, is well known to exhibit significant pharmacological interpatient and intrapatient variability. This variability necessitates the collection of serial trough concentrations to ensure that the drug remains within therapeutic range. The objective of this study was to build a population pharmacokinetic (PK) model and use it to determine the minimum number of trough samples needed to guide the prediction of an individual's future concentrations. Design setting and patients: Retrospective data from 48 children who received tacrolimus as inpatients at Primary Children's Hospital in Salt Lake City, Utah were included in the study. Data were collected within the first 6 weeks after heart transplant. Outcome measures: Data analysis used population PK modelling techniques in NONMEM. Predictive ability of the model was determined using median prediction error (MPE, a measure of bias) and median absolute prediction error (MAPE, a measure of accuracy). Of the 48 children in the study, 30 were used in the model building dataset, and 18 in the model validation dataset. Results: Concentrations ranged between 1.5 and 37.7 µg/L across all collected data, with only 40% of those concentrations falling within the targeted concentration range (12 to 16 µg/L). The final population PK model contained the impact of age (on volume), creatinine clearance (on elimination rate) and fluconazole use (on elimination rate) as covariates. Our analysis demonstrated that as few as three concentrations could be used to predict future concentrations, with negligible bias (MPE (95% CI)=0.10% (-2.9% to 3.7%)) and good accuracy (MAPE (95% CI)=24.1% (19.7% to 27.7%)). Conclusions: The use of PK in dose guidance has the potential to provide significant benefits to clinical care, including dose optimisation during the early stages of therapy, and the potential to limit the need for frequent drug monitoring.

10.
Br J Clin Pharmacol ; 83(12): 2709-2717, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28771779

RESUMO

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.


Assuntos
Modelos Biológicos , Nicotina/administração & dosagem , Nicotina/farmacocinética , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/farmacocinética , Dispositivos para o Abandono do Uso de Tabaco , Administração Cutânea , Adulto , Ensaios Clínicos como Assunto , Feminino , Humanos , Masculino , Nicotina/sangue , Agonistas Nicotínicos/sangue , Estudos Retrospectivos , Absorção Cutânea , Adesivo Transdérmico , Adulto Jovem
11.
J Clin Pharmacol ; 57(1): 77-84, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27291466

RESUMO

Vancomycin is a first-line treatment for ß-lactam-resistant Gram-positive bacterial infections. Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of vancomycin in an adolescent population is of clinical importance in this often overlooked pediatric population. This retrospective study investigated vancomycin PK-PD in an adolescent cohort (12 to 18 years of age) of 463 patients (57% male, 81% white) admitted to the Intermountain Healthcare System between January 2006 and December 2013. Population PK modeling was performed in NONMEM 7.3. Vancomycin PK was well described with a 1-compartment model that identified both body weight (WT) and creatinine clearance (CRCL) as covariates significantly impacting vancomycin disposition. The model was then utilized to determine dosing strategies that achieved the targeted area under the 24-hour time curve vs minimum inhibitory concentration (AUC0-24 /MIC) ratio of ≥400. Additionally, these data were correlated with minimum steady-state concentrations (Css,min ) to find an acceptable target trough concentration range in adolescents. This analysis demonstrated that Css,min ranging from 10 to 12.5 mg/L were highly predictive of achieving an AUC0-24 /MIC ≥400 when the MIC was ≤1 mg/L. These results suggest that the target trough concentration for adolescents may be lower than that for adults.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Sepse/sangue , Vancomicina/administração & dosagem , Vancomicina/sangue , Adolescente , Criança , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Estudos Retrospectivos , Sepse/diagnóstico , Sepse/tratamento farmacológico
12.
Eur J Clin Pharmacol ; 73(3): 325-331, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27909740

RESUMO

PURPOSE: Intravenous (IV) magnesium sulfate (MgSO4) is used as adjunct therapy to treat acute asthma exacerbations. Despite its clinical use, there is a limited understanding of the disposition of magnesium in children. METHODS: To explore the pharmacokinetics (PK) of IV MgSO4 in this population, we collected retrospective data from 54 children who received IV MgSO4 for treatment of an acute asthma exacerbation at Primary Children's Hospital in Salt Lake City, UT. These data were analyzed using population PK modeling techniques in NONMEM® to determine sources of variability affecting the disposition of magnesium, as well as to predict the dose of IV MgSO4 needed to achieve clinical benefit. RESULTS: The covariate analysis found that only weight was a significant predictor of magnesium concentrations in children. Estimated model parameters suggested that magnesium exhibits a short serum half-life (2.7 h) in children. The average endogenous magnesium concentration (prior to administration of IV MgSO4) was estimated to be 21 mg/L. Simulated data suggested that doses between 50 and 75 mg/kg are required to achieve concentration-time profiles within a hypothesized target therapeutic range between 25 and 40 mg/L. CONCLUSIONS: These results provide new insight into the disposition of IV MgSO4 in children and provide dosing guidelines for future prospective studies of IV MgSO4 in children with acute asthma.


Assuntos
Asma/tratamento farmacológico , Sulfato de Magnésio/farmacocinética , Doença Aguda , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Sulfato de Magnésio/uso terapêutico , Masculino , Índice de Gravidade de Doença
13.
AIDS Res Hum Retroviruses ; 32(10-11): 981-991, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27526873

RESUMO

The pharmacokinetics (PK) of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP), the active anabolites of tenofovir disoproxil fumarate (TDF), and emtricitabine (FTC) in blood, genital, and rectal compartments was determined in HIV-positive and seronegative adults who undertook a 60-day intensive PK study of daily TDF/FTC (plus efavirenz in HIV positives). Lymphocyte cell sorting, genital, and rectal sampling occurred once per subject, at staggered visits. Among 19 HIV-positive (3 female) and 21 seronegative (10 female) adults, TFV-DP in peripheral blood mononuclear cells (PBMC) accumulated 8.6-fold [95% confidence interval (CI): 7.2-10] from first-dose to steady-state concentration (Css) versus 1.7-fold (95% CI: 1.5-1.9) for FTC-TP. Css was reached in ∼11 and 3 days, respectively. Css values were similar between HIV-negative and HIV-positive individuals. Css TFV-DP in rectal mononuclear cells (1,450 fmol/106 cells, 898-2,340) was achieved in 5 days and was >10 times higher than PBMC (95 fmol/106 cells, 85-106), seminal cells (22 fmol/106 cells, 6-79), and cervical cells (111 fmol/106 cells, 64-194). FTC-TP Css was highest in PBMC (5.7 pmol/106 cells, 5.2-6.1) and cervical cells (7 pmol/106 cells, 2-19) versus rectal (0.8 pmol/106 cells, 0.6-1.1) and seminal cells (0.3 pmol/106 cells, 0.2-0.5). Genital drug concentrations on days 1-7 overlapped with estimated Css, but accumulation characteristics were based on limited data. TFV-DP and FTC-TP in cell sorted samples were highest and achieved most rapidly in CD14+ compared with CD4+, CD8+, and CD19+ cells. Together, these findings demonstrate cell-type and tissue-dependent cellular pharmacology, preferential accumulation of TFV-DP in rectal mononuclear cells, and rapid distribution into rectal and genital compartments.


Assuntos
Fármacos Anti-HIV/farmacocinética , Emtricitabina/farmacocinética , Genitália/química , Leucócitos Mononucleares/química , Reto/química , Tenofovir/farmacocinética , Adolescente , Adulto , Fármacos Anti-HIV/administração & dosagem , Emtricitabina/administração & dosagem , Células Epiteliais/química , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Espermatozoides/química , Tenofovir/administração & dosagem , Fatores de Tempo , Adulto Jovem
14.
Expert Rev Anti Infect Ther ; 14(8): 731-46, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27355512

RESUMO

INTRODUCTION: Voriconazole is a broad-spectrum antifungal agent commonly used to treat invasive fungal infections (IFI), including aspergillosis, candidiasis, Scedosporium infection, and Fusarium infection. IFI often occur in immunocompromised patients, leading to increased morbidity and mortality. AREAS COVERED: The objective of this review is to summarize the pharmacodynamic properties of voriconazole and to provide considerations for potential optimal dosing strategies. Studies have demonstrated superior clinical response when an AUC/MIC >25 or Cmin/MIC >1 is attained in adult patients, correlating to a trough concentration range as narrow as 2-4.5 mg/L; however, these targets are poorly established in the pediatric population. Topics in this discussion include voriconazole use in multiple age groups, predisposing patient factors for IFI, and considerations for clinicians managing IFI. Expert commentary: The relationship between voriconazole dosing and exposure is not well defined due to the large inter- and intra-subject variability. Development of comprehensive decision support tools for individualizing dosing, particularly in children who require higher dosing, will help to increase the probability of achieving therapeutic efficacy and decrease sub-therapeutic dosing and adverse events.


Assuntos
Antifúngicos/uso terapêutico , Infecções Fúngicas Invasivas/tratamento farmacológico , Voriconazol/uso terapêutico , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Antifúngicos/farmacologia , Área Sob a Curva , Relação Dose-Resposta a Droga , Predisposição Genética para Doença , Humanos , Infecções Fúngicas Invasivas/genética , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/microbiologia , Testes de Sensibilidade Microbiana , Modelos Biológicos , Voriconazol/administração & dosagem , Voriconazol/farmacocinética , Voriconazol/farmacologia
15.
Pediatr Pulmonol ; 51(12): 1414-1421, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27218606

RESUMO

BACKGROUND: Asthma is the most common pediatric chronic disease and currently affects 7.1 million children in the United States. Many children experience acute asthma exacerbations. Many children also require hospitalization despite treatment in an emergency department with current standard therapy (corticosteroids, albuterol, and ipratropium). These hospitalizations may be avoided if effective adjunctive therapies can be developed to adequately treat severe exacerbations. METHODS: Publications were searched in the PubMed database using the following keywords: magnesium AND asthma AND children AND randomized controlled trial. A total of 30 publications were returned. References of relevant articles were also screened. We included publications of controlled randomized trials where intravenous magnesium sulfate was studied in children (age < 18 years) with acute asthma (n = 7). We excluded studies in adults or trials with other formulations of magnesium (e.g., nebulized). RESULTS: Previous studies have demonstrated that intravenous magnesium sulfate (IV MgSO4 ) significantly improves respiratory function and reduces hospitalization rate in children with moderate to severe asthma exacerbations. Current dosing regimens involve a short infusion of 25-75 mg/kg over 20 min (maximum 2-2.5 g/dose), though no studies have directly compared dosages for relative efficacy. Several studies suggest utilizing a peak plasma concentration of magnesium higher than 4 mg/dL as a surrogate of efficacy. This review summarizes the literature regarding the use of IV MgSO4 for the treatment of pediatric acute asthma. CONCLUSIONS: We suggest that optimized dosing regimens could be developed using a linked pharmacokinetic-pharmacodynamic modeling and simulation approach. We propose the factors that should be considered in future clinical trial design in order to better understand the use of IV MgSO4 in pediatric acute asthma. Pediatr Pulmonol. 2016;51:1414-1421. © 2016 Wiley Periodicals, Inc.


Assuntos
Antiasmáticos/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Sulfato de Magnésio/uso terapêutico , Doença Aguda , Administração por Inalação , Administração Intravenosa , Adolescente , Corticosteroides/uso terapêutico , Albuterol/uso terapêutico , Asma/tratamento farmacológico , Criança , Pré-Escolar , Quimioterapia Combinada , Serviço Hospitalar de Emergência , Hospitalização , Humanos , Lactente , Ipratrópio/uso terapêutico
16.
Expert Opin Drug Metab Toxicol ; 11(12): 1861-78, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26535960

RESUMO

INTRODUCTION: Neonatal patients, because of the inability of their immune system to properly respond to microbial challenge, are highly susceptible to viral infections. Immunoglobulins, monoclonal antibody and antiviral drugs are used for prophylaxis and treatment of viral diseases in neonates. Neonates and, especially, preterm infants differ in drug absorption, distribution, metabolism and excretion from adults and older children. AREAS COVERED: This review will evaluate deficiencies of neonatal immune responses to microbial challenge that predispose newborns to viral infections, clinical manifestations and the treatment of viral diseases in neonates. We focus on published studies describing antiviral drug pharmacokinetics in neonates and make recommendations on the dosing of these drugs, allowing achievement of maximal clinical benefits in neonates. EXPERT OPINION: While some efforts were undertaken to study pharmacokinetics and pharmacodynamics of antiviral drugs, much more needs to be done. Current data indicate that the pharmacokinetics of antiviral drugs may vary significantly depending on gestational age, maturation processes of drug-metabolizing enzymes and renal clearance. Specifics of pharmacokinetics of antiviral drugs need to be taken into consideration when they are prescribed to neonates and infants.


Assuntos
Antivirais/farmacocinética , Sistema Imunitário/fisiologia , Viroses/tratamento farmacológico , Adulto , Fatores Etários , Animais , Antivirais/administração & dosagem , Criança , Suscetibilidade a Doenças/imunologia , Relação Dose-Resposta a Droga , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Viroses/epidemiologia , Viroses/imunologia
17.
Antimicrob Agents Chemother ; 59(12): 7671-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26416874

RESUMO

Sofosbuvir (SOF) is a highly efficacious and well-tolerated uridine nucleotide analog that inhibits the hepatitis C virus (HCV) NS5B polymerase enzyme. SOF is administered as a prodrug, which undergoes intracellular phosphorylation by host enzymes to a monophosphate, diphosphate, and finally a pharmacologically active triphosphate. In order to fully understand the clinical pharmacology of SOF, there is a great need to determine the intracellular phosphate concentrations of the drug. We describe the validation and utilization of a method to characterize SOF's disposition into various in vivo cell types, including hepatocytes, peripheral blood mononuclear cells (PBMC), and red blood cells (RBC). Standard bioanalytical validation criteria were applied to lysed cellular matrices, with a validated linear range of 50 to 50,000 fmol/sample for each phosphate moiety. The assay was utilized to collect the first data demonstrating concentrations of phosphorylated anabolites formed in PBMC, hepatocytes, and RBC in vivo during SOF therapy. Median concentrations in PBMC were 220 (range, 51.5 to 846), 70.2 (range, 25.8 to 275), and 859 (range, 54.5 to 6,756) fmol/10(6) cells in the monophosphate, diphosphate, and triphosphate fractions, respectively. In contrast, RBC triphosphate concentrations were much lower than those of PBMC, as the median concentration was 2.91 (range, 1.14 to 10.4) fmol/10(6) cells. The PBMC triphosphate half-life was estimated at 26 h using noncompartmental approaches, while nonlinear mixed-effect modeling was used to estimate a 69 h half-life for this moiety in RBC. The validated method and the data it generates provide novel insight into the cellular disposition of SOF and its phosphorylated anabolites in vivo.


Assuntos
Antivirais/análise , Sofosbuvir/análise , Antivirais/farmacocinética , Cromatografia Líquida de Alta Pressão , Eritrócitos/química , Meia-Vida , Hepatite C/sangue , Hepatite C/metabolismo , Hepatócitos/química , Humanos , Monócitos/química , Dinâmica não Linear , Fosfatos/análise , Fosforilação , Controle de Qualidade , Reprodutibilidade dos Testes , Sofosbuvir/farmacocinética , Espectrometria de Massas em Tandem
18.
Antimicrob Agents Chemother ; 59(10): 6653-6, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26259790

RESUMO

We present a 31-year-old female who had undergone an allogeneic bone marrow transplantation and who was started on intravenous posaconazole for pulmonary mycosis while undergoing continuous venovenous hemofiltration (CVVH). We performed steady-state pharmacokinetic evaluations for both posaconazole and sulfobutylether-ß-cyclodextrin (SBECD). SBECD was effectively removed by CVVH, with observed exposure similar to that for patients with moderate renal impairment. Intravenous posaconazole at standard doses may be utilized in critically ill patients undergoing CVVH without significant risk of SBECD accumulation.


Assuntos
Estado Terminal/terapia , Ciclodextrinas/sangue , Triazóis/sangue , beta-Ciclodextrinas/sangue , Administração Intravenosa , Adulto , Ciclodextrinas/administração & dosagem , Feminino , Hemofiltração , Humanos , Triazóis/administração & dosagem , beta-Ciclodextrinas/administração & dosagem
19.
J Antimicrob Chemother ; 70(8): 2322-9, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25971261

RESUMO

OBJECTIVES: Ribavirin concentrations may impact hepatitis C virus (HCV) treatment outcome. We modelled ribavirin serum and intracellular ribavirin monophosphate (RBV-MP) and ribavirin triphosphate (RBV-TP) pharmacokinetics in red blood cells (RBC) using samples collected during the NIAID SPARE trial to explore associations with treatment outcome and the development of anaemia. PATIENTS AND METHODS: Individuals infected with HCV genotype 1 (GT1) received 400 mg of sofosbuvir and either low-dose or weight-based ribavirin as part of the NIAID SPARE trial. Concentrations were modelled using NONMEM and associated with treatment outcomes using unpaired t-tests or Pearson's rho correlations. RESULTS: Average day 14 RBV-MP concentrations were higher in subjects with haemoglobin nadir <10 g/dL relative to patients with haemoglobin nadir ≥10 g/dL (6.54 versus 4.48 pmol/10(6) cells; P = 0.02). Additionally, day 14 RBV-MP average concentrations trended towards being higher in subjects that achieved sustained virological response (SVR) as compared with patients who relapsed (4.97 versus 4.09 pmol/10(6) cells; P = 0.07). Receiver operating characteristic curves suggested day 14 RBV-MP concentration thresholds of 4.4 pmol/10(6) cells for SVR (P = 0.06) and 6.1 pmol/10(6) cells for haemoglobin nadir <10 versus ≥10 g/dL (P = 0.02), with sensitivity and specificity ≥60%. Dosing simulations showed that 800 mg of ribavirin once daily produced day 14 RBV-MP concentrations within the 4.4-6.1 pmol/10(6) cells range. CONCLUSIONS: RBV-MP concentrations in RBC at day 14 were related to anaemia and SVR. A therapeutic range was identified for RBV-MP in persons with HCV GT1 disease receiving 24 weeks of sofosbuvir plus ribavirin, suggesting a potential pharmacological basis for individualized ribavirin dosing in IFN-free regimens.


Assuntos
Antivirais/administração & dosagem , Antivirais/farmacocinética , Eritrócitos/química , Ribavirina/administração & dosagem , Ribavirina/farmacocinética , Soro/química , Sofosbuvir/administração & dosagem , Adulto , Idoso , Anemia/induzido quimicamente , Antivirais/efeitos adversos , Feminino , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepacivirus/isolamento & purificação , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Ribavirina/efeitos adversos , Resultado do Tratamento , Carga Viral
20.
Crit Care ; 19: 32, 2015 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-25645660

RESUMO

INTRODUCTION: Intravenous (IV) voriconazole is not recommended in patients with creatinine clearance <50 ml/min to avoid potentially toxic accumulation of sulfobutylether-ß-cyclodextrin (SBECD). The purpose of this study was to evaluate the pharmacokinetics of SBECD, voriconazole, and voriconazole N-oxide in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to determine if CRRT removes SBECD sufficiently to allow for the use of IV voriconazole without significant risk of SBECD accumulation. METHODS: This prospective, open-label pharmacokinetic study enrolled patients >18 years old receiving IV voriconazole for a known or suspected invasive fungal infection while undergoing CRRT. Serial blood and effluent samples were collected on days 1, 3, 5, 7, and every 3 to 5 days thereafter. SBECD, voriconazole, and voriconazole N-oxide plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic, pharmacodynamic, and pharmacogenetic analyses were conducted. RESULTS: Ten patients (mean ± standard deviation (SD)) 53 ± 11 years old, 50% male, 81 ± 14 kg, with Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores of 31.5 ± 3.8 were evaluated. All patients underwent continuous venovenous hemofiltration (CVVH) with a median predilution replacement fluid rate of 36 (interquartile range (IQR) 32 to 37) ml/kg/hr and total ultrafiltration rate of 38 (IQR 34 to 39) ml/kg/hr. Mean ± SD voriconazole and SBECD dosages administered were 8.1 ± 2.1 mg/kg/day and 129 ± 33 mg/kg/day, respectively. Voriconazole plasma trough concentrations were >1 mg/L in all patients with CVVH accounting for only 15% of the total body clearance. CVVH accounted for 86% of the total body clearance of SBECD with the majority of the dose being recovered in the effluent. Minimal increases in dose normalized SBECD area under the concentration-time curve from 0 to 12 hours (AUC0-12) (4,484 ± 4,368 to 4,553 ± 2,880 mg*hr/L; P = 0.97) were observed after study day 1. CONCLUSIONS: CVVH effectively removed SBECD at a rate similar to the ultrafiltration rate. Voriconazole clearance by CVVH was not clinically significant. Standard dosages of IV voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01101386 . Registered 6 April 2010.


Assuntos
Antifúngicos/farmacocinética , Falência Renal Crônica/tratamento farmacológico , Terapia de Substituição Renal , Terapêutica/métodos , Voriconazol/farmacocinética , beta-Ciclodextrinas/farmacocinética , Adulto , Estado Terminal , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Terapêutica/efeitos adversos , beta-Ciclodextrinas/toxicidade
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