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1.
Artigo em Inglês | MEDLINE | ID: mdl-32647364

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32546826

RESUMO

Currently it is difficult to prospectively estimate human toxicokinetics (particularly for novel chemicals) in a high-throughput manner. The R software package httk has been developed, in part, to address this deficiency, and the aim of this investigation was to develop a generalized inhalation model for httk. The structure of the inhalation model was developed from two previously published physiologically based models from Jongeneelen and Berge (Ann Occup Hyg 55:841-864, 2011) and Clewell et al. (Toxicol Sci 63:160-172, 2001), while calculated physicochemical data was obtained from EPA's CompTox Chemicals Dashboard. In total, 142 exposure scenarios across 41 volatile organic chemicals were modeled and compared to published data. The slope of the regression line of best fit between log-transformed simulated and observed blood and exhaled breath concentrations was 0.46 with an r2 = 0.45 and a root mean square error (RMSE) of direct comparison between the log-transformed simulated and observed values of 1.11. Approximately 5.1% (n = 108) of the data points analyzed were >2 orders of magnitude different than expected. The volatile organic chemicals examined in this investigation represent small, generally lipophilic molecules. Ultimately this paper details a generalized inhalation component that integrates with the httk physiologically based toxicokinetic model to provide high-throughput estimates of inhalation chemical exposures.

4.
Clin Pharmacokinet ; 57(10): 1325-1336, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29654492

RESUMO

INTRODUCTION: Acetaminophen (paracetamol, APAP) is widely used as an analgesic and antipyretic drug in children and neonates. A number of enzymes contribute to the metabolism of acetaminophen, and genetic factors might be important to explain variability in acetaminophen metabolism among individuals. METHODS: The current investigation utilized a previously published parent-metabolite population pharmacokinetic model describing acetaminophen glucuronidation, sulfation, and oxidation to examine the potential role of genetic variability on the relevant metabolic pathways. Neonates were administered 30-min intravenous infusions of acetaminophen 15 mg/kg every 12 h (< 28 weeks' gestational age [GA]) or every 8 h (≥ 28 weeks GA) for 48 h. A total of 18 sequence variations (SVs) in UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and cytochrome P450 (CYP) genes from 33 neonates (aged 1-26 days) were examined in a stepwise manner for an effect on the metabolic formation clearance of acetaminophen by glucuronidation (UGT), sulfation (SULT), and oxidation (CYP). The stepwise covariate modeling procedure was performed using NONMEM® version 7.3. RESULTS: Incorporation of genotype as a covariate for one SV located in the UGT1A9 gene promoter region (rs3832043, - 118 > insT, T9 > T10) significantly improved model fit (likelihood ratio test, p < 0.001) and reduced between-subject variability in glucuronide formation clearance. Individuals with the UGT1A9 T10 polymorphism, indicating insertion of an additional thymidine nucleotide, had a 42% reduction in clearance to APAP-glucuronide as compared to their wild-type counterparts. CONCLUSION: This study shows a pharmacogenetic effect of an SV in the UGT1A9 promoter region on the metabolism of acetaminophen in neonates.


Assuntos
Acetaminofen/farmacocinética , Glucuronídeos/metabolismo , Glucuronosiltransferase/genética , Modelos Biológicos , Polimorfismo Genético , Feminino , Humanos , Recém-Nascido , Masculino , Regiões Promotoras Genéticas , Estudos Prospectivos
5.
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.

6.
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
7.
Expert Opin Drug Metab Toxicol ; 13(9): 925-934, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28772091

RESUMO

INTRODUCTION: When in flight, pilots of high performance aircraft experience conditions unique to their profession. Training flights, performed as often as several times a week, can expose these pilots to altitudes in excess of 15 km (~50,000 ft, with a cabin pressurized to an altitude of ~20,000 ft), and the maneuvers performed in flight can exacerbate the G-forces felt by the pilot. While the pilots specifically train to withstand these extreme conditions, the physiologic stress could very likely lead to differences in the disposition of chemicals in the body, and consequently, dangerously high exposures. Unfortunately, very little is known about how the conditions experienced by fighter pilots affects chemical disposition. Areas covered: The purpose of this review is to present information about the effects of high altitude, G-forces, and other conditions experienced by fighter pilots on chemical disposition. Using this information, the expected changes in chemical exposure will be discussed, using isopropyl alcohol as an example. Expert opinion: There is a severe lack of information concerning the effects of the fighter pilot environment on the pharmacokinetics and pharmacodynamics of chemicals. Given the possibility of exposure prior to or during flight, it is important that these potential effects be investigated further.


Assuntos
Altitude , Doenças Profissionais/fisiopatologia , Pilotos , 2-Propanol/envenenamento , Aeronaves , Animais , Gravitação , Humanos , Exposição Ocupacional/efeitos adversos , Estresse Fisiológico/fisiologia
8.
Congenit Heart Dis ; 11(6): 693-699, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27257953

RESUMO

OBJECTIVE: Malnutrition and poor weight gain, common in neonates following repair of complex congenital heart disease (CHD), are associated with increased morbidity and mortality. Oxandrolone, an anabolic steroid, improves weight gain in older children at high-risk for growth failure. We sought to determine feasibility, safety, and efficacy of oxandrolone therapy in neonates following surgery for complex CHD. DESIGN: Neonates with RACHS-1 score >3 were eligible to receive open-label oxandrolone for 28 days in this prospective pilot trial. There were 3 cohorts of 5 subjects receiving oxandrolone therapy under 3 specified dosage and preparation protocols: 0.1 mg/kg/day aqueous solution, 0.2 mg/kg/day aqueous solution, and 0.1 mg/kg/day preparation in medium chain triglyceride (MCT) oil. Age- and diagnosis-matched neonates who underwent surgery, but received no oxandrolone, served as a control cohort. Anthropometric measurements, physical examination for virilization, safety labs, and adverse events were monitored. RESULTS: Of 25 eligible patients, 15 consented (60%, 13/15 with Norwood procedure). There was no evidence of virilization, no changes in safety labs, and no serious adverse events related to oxandrolone among subjects receiving therapy. No subject met criteria for termination of study drug. There was a significant difference in change in weight-for-age z-score among the four cohorts, with subjects receiving 0.1 mg/kg/day in MCT oil having the lowest decline during the study period (-1.8 ± 0.5 for controls, -1.7 ± 0.4 for 0.1 mg/kg/day aqueous, -1.0 ± 0.4 for 0.2 mg/kg/day aqueous, and -0.6 ± 0.7 for 0.1 mg/kg/day MCT oil, P = .012). CONCLUSIONS: Oxandrolone therapy at the doses studied appears safe in neonates after surgery for complex CHD. The decline in weight-for-age z-score was lowest in those receiving the MCT oil preparation suggesting better bioavailability of this preparation and a potential growth benefit with oxandrolone therapy. Further investigation is needed to define optimal dosing and assess efficacy.


Assuntos
Anabolizantes/uso terapêutico , Androgênios/uso terapêutico , Procedimentos Cirúrgicos Cardíacos , Desenvolvimento Infantil/efeitos dos fármacos , Cardiopatias Congênitas/cirurgia , Oxandrolona/uso terapêutico , Ganho de Peso/efeitos dos fármacos , Anabolizantes/efeitos adversos , Androgênios/efeitos adversos , Antropometria , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Composição de Medicamentos , Estudos de Viabilidade , Feminino , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/fisiopatologia , Humanos , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Masculino , Estado Nutricional , Oxandrolona/efeitos adversos , Projetos Piloto , Estudos Prospectivos , Fatores de Tempo , Resultado do Tratamento , Utah
9.
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
10.
Clin Pharmacokinet ; 55(2): 185-96, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26245673

RESUMO

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.


Assuntos
Sistemas de Liberação de Medicamentos , Vias de Administração de Medicamentos , Humanos , Recém-Nascido , Preparações Farmacêuticas/administração & dosagem
11.
Arch Dis Child Fetal Neonatal Ed ; 101(3): F236-43, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26400103

RESUMO

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 ≥1.5 mg/dL persisting for ≥48 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.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antibacterianos/efeitos adversos , Vancomicina/efeitos adversos , Lesão Renal Aguda/epidemiologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/efeitos adversos , Bacteriemia/epidemiologia , Estudos de Coortes , Creatinina/sangue , Quimioterapia Combinada , Permeabilidade do Canal Arterial/epidemiologia , Feminino , Gentamicinas/administração & dosagem , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Masculino , Pontuação de Propensão , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Estados Unidos/epidemiologia
12.
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
13.
J Anal Toxicol ; 39(7): 526-31, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26017381

RESUMO

A high-performance liquid chromatography-tandem mass spectrometry (LC-MS-MS) method for the determination of oxandrolone concentration in human plasma (0.5 mL) was developed and validated according to the 2001 FDA Bioanalytical Guidelines. Oxandrolone is an anabolic steroid used to promote weight gain for cachectic patients with severe burn injuries, HIV/AIDS, hepatitis C and other wasting syndromes. The assay procedure involved a liquid-liquid extraction of oxandrolone and methyltestosterone (the internal standard, IS) from plasma with n-butyl chloride. The organic layer was clarified by centrifugation and evaporated to dryness under a stream of air. The residue was reconstituted in a solution containing 25% methanol and 75% Milli-Q water, and injected onto a Luna C18 reversed-phase HPLC column (30 mm × 2.0 mm, 2 µm). Separation of oxandrolone and methyltestosterone was achieved with a mobile phase starting composition of 55% methanol and 45% ammonium formate buffer at a flow rate of 0.1 mL/min. The total run time was 21 min per sample. Selected reaction monitoring mode was used for quantifying oxandrolone (m/z 307 → 271) and the IS, methyltestosterone (m/z 301 → 149). To the authors' knowledge, this is the first LC-MS-MS method validated for oxandrolone quantification in human plasma. This method can be used in future pharmacokinetic studies involving oxandrolone.


Assuntos
Anabolizantes/sangue , Cromatografia Líquida de Alta Pressão , Oxandrolona/sangue , Espectrometria de Massas em Tandem , Calibragem , Cromatografia Líquida de Alta Pressão/normas , Estabilidade de Medicamentos , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Padrões de Referência , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/normas
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