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1.
Artigo em Inglês | MEDLINE | ID: mdl-32730191

RESUMO

INTRODUCTION: Three major classes of natural products (NPs) for medicinal purposes or improving wellbeing are generally available in the US: conventional drugs of herbal origin, botanical drugs, and dietary supplements (DSs). Consumer consumption of DSs is growing annually, with >50% of adults in the US taking dietary supplements. The US FDA regulates conventional and botanical drugs for safety and efficacy; however, DSs are minimally regulated. AREAS COVERED: This article will: i) highlight the importance of NP as a significant source of prescription drugs; ii) discuss differences in the regulation of conventional drugs of NP product, botanical drugs, and DSs; iii) discuss the safety and efficacy of DSs and iv) make recommendations for improvement of safety for minimally regulated NPs. The authors conducted a comprehensive literature search in two electronic databases, relevant NP and U.S. government websites for articles and regulatory documents published between January 1994 and April 2020. EXPERT OPINION: Toxicities associated with the use of NPs, including vitamins and DSs, are mainly due to excessive use and interactions with conventional drug(s) and may represent challenges for clinicians. Conventional and botanical-based prescription drugs are rarely associated with unknown toxicities. However, DSs are minimally regulated and can produce severe adverse effects. We believe that clinical pharmacologists can have a role in developing criteria for DS safety analysis. There is also the potential for a standardized NP stewardship program(s) and the development of NP policies and practices nationally and globally.

2.
Clin Pharmacol Ther ; 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32696977

RESUMO

The estimated glomerular filtration rate (eGFR) equations based on serum creatinine (SCR) have been used for pediatric dose adjustment in drug labeling. This study evaluated the performance of those equations in estimating individual clearance of drugs that are predominantly eliminated by glomerular filtration, using clinical data from the renally-eliminated drugs gadobutrol, gadoterate, amikacin, and vancomycin. The eGFR was compared with the observed drug clearance (CL) in 352 pediatric patients from birth to 12 years of age. Multiple eGFR equations overestimated the drug clearance on average, including the original and bedside Schwartz equations, which showed an average eGFR/CL ratio between 1 and 3. Further analysis with bedside Schwartz equation showed a higher eGFR/CL ratio in the subjects with a lower SCR or CL. Supraphysiological eGFR as high as 380 mL/min/1.73m2 was obtained using bedside Schwartz equation for some of the subjects, most of whom are children less than two years of age with SCR < 0.2 mg/dL. Excluding the subjects with supraphysiological eGFR from the analysis did not change the overall trend of overestimation. In conclusion, Schwartz equations led to an overestimation of drug clearance for the drugs evaluated. When greater precision is required in predicting eGFR for pediatric patients, such as in drug dosing, revised k constants for the Schwartz equation or new methods of GFR estimation may be necessary.

3.
Br J Clin Pharmacol ; 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32497307

RESUMO

AIMS: The aim of this study was to evaluate the population pharmacokinetics (PopPK) of olanzapine in children and devise a model-informed paediatric dosing scheme. METHODS: The PopPK of olanzapine was characterized using opportunistically collected plasma samples from children receiving olanzapine per standard of care for any indication. A nonlinear mixed effect modelling approach was employed for model development using the software NONMEM (v7.4). Simulations from the developed PopPK model were used to devise a paediatric dosing scheme that targeted comparable plasma exposures to adolescents and adults. RESULTS: Forty-five participants contributed 83 plasma samples towards the analysis. The median (range) postnatal age and body weight of participants were 3.8 years (0.2-19.2) and 14.1 kg (4.2-111.7), respectively. The analysis was restricted to pharmacokinetic (PK) samples collected following enteral administration (oral and feeding tube). A one-compartment model with linear elimination provided an appropriate fit to the data. The final model included the covariates body weight and postmenstrual age (PMA) on apparent olanzapine clearance (CL/F). Typical CL/F and apparent volume of distribution (scaled to 70 kg) were 16.8 L/h (21% RSE) and 663 L (13% RSE), respectively. Developed dosing schemes used weight-normalized doses for children ≤6 months postnatal age or <15 kg and fixed doses for children ≥15 kg. CONCLUSION: We developed a paediatric PopPK model for enterally-administered olanzapine. To our knowledge, this analysis is the first study to characterize the PK of olanzapine in participants ranging from infants to adolescents. Body weight and PMA were identified as influential covariates for characterizing developmental changes in olanzapine apparent clearance.

5.
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.

6.
Front Pharmacol ; 11: 227, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32218731

RESUMO

We have identified distinct histamine pharmacodynamic response phenotypes in children with allergic disease utilizing histamine iontophoresis with laser Doppler (HILD). These response phenotypes may be relevant in guiding therapeutic decision making for agents targeting the allergic response pathways. However, the reliability of these response phenotypes has not been assessed. Therefore, we performed HILD in children with allergic rhinitis and/or asthma on two to three separate occasions. HILD response-time data were analyzed in NONMEM using a linked effect PKPD model. Examination of observed vs. classified response phenotypes predicted response plots and the sum of residuals. The intraclass correlation coefficient (ICC) was used to determine the reliability of phenotype classification. Eighty-two percent of children exhibited a reliable histamine response phenotype [intraclass correlation coefficient 0.77 (95% CI 0.44-0.93]. These preliminary results suggest moderate reliability of HILD response phenotype in children. Further exploration is needed to determine contributions to phenotype variability.

7.
Paediatr Drugs ; 22(3): 279-293, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32140997

RESUMO

Supplemental arginine has shown promise as a safe therapeutic option to improve endogenous nitric oxide (NO) regulation in cardiovascular diseases associated with endothelial dysfunction. In clinical studies in adults, L-arginine, an endogenous amino acid, was reported to improve cardiovascular function in hypertension, pulmonary hypertension, preeclampsia, angina, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome. L-citrulline, a natural precursor of L-arginine, is more bioavailable than L-arginine because it avoids hepatic first-pass metabolism and has a longer circulation time. Although not yet well-studied, arginine/citrulline has immense therapeutic potential in some life-threatening diseases in children. However, the optimal clinical development of arginine or citrulline in children requires more information about pharmacokinetics and exposure-response relationships at appropriate ages and under relevant disease states. This article summarizes the preclinical and clinical studies of arginine/citrulline in both adults and children, including currently available pharmacokinetic information. The pharmacology of arginine/citrulline is confounded by several patient-specific factors such as variations in baseline arginine/citrulline due to developmental ages and disease states. Currently available pharmacokinetic studies are insufficient to inform the optimal design of clinical studies, especially in children. Successful bench-to-bedside clinical translation of arginine supplementation awaits information from well-designed pharmacokinetic/pharmacodynamic studies, along with pharmacometric approaches.


Assuntos
Arginina/uso terapêutico , Citrulina/uso terapêutico , Farmacologia Clínica/métodos , Adolescente , Adulto , Arginina/farmacologia , Criança , Citrulina/farmacologia , Feminino , Humanos , Masculino , Adulto Jovem
8.
Front Pharmacol ; 10: 1191, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31680968

RESUMO

Neonatal sepsis causes significant mortality and morbidity worldwide. Diagnosis is usually confirmed via blood culture results. Blood culture sepsis confirmation can take days and suffer from contamination and false negatives. Empiric therapy with antibiotics is common. This study aims to retrospectively describe and compare treatments of blood culture-confirmed and unconfirmed, but suspected, sepsis within the University of Utah Hospital system. Electronic health records were obtained from 1,248 neonates from January 1, 2006, to December 31, 2017. Sepsis was categorized into early-onset (≤3 days of birth, EOS) and late-onset (>3 and ≤28 days of birth, LOS) and categorized as culture-confirmed sepsis if a pathogen was cultured from the blood and unconfirmed if all blood cultures were negative with no potentially contaminated blood cultures. Of 1,010 neonates in the EOS cohort, 23 (2.3%) were culture-confirmed, most with Escherichia coli (42%). Treatment for unconfirmed EOS lasted an average of 6.1 days with primarily gentamicin and ampicillin while confirmed patients were treated for an average of 12.3 days with increased administration of cefotaxime. Of 311 neonates in the LOS cohort, 62 (20%) were culture-confirmed, most culturing coagulase negative staphylococci (46%). Treatment courses for unconfirmed LOS lasted an average of 7.8 days while confirmed patients were treated for an average of 11.4 days, these patients were primarily treated with vancomycin and gentamicin. The use of cefotaxime for unconfirmed EOS and LOS increased throughout the study period. Cefotaxime administration was associated with an increase in neonatal mortality, even when potential confounding factors were added to the logistic regression model (adjusted odds ratio 2.8, 95%CI [1.21, 6.88], p = 0.02). These results may not be generalized to all hospitals and the use of cefotaxime may be a surrogate for other factors. Given the low rate of blood culture positive diagnosis and the high exposure rate of empiric antibiotics, this patient population might benefit from improved diagnostics with reevaluation of antibiotic use guidelines.

9.
Cancers (Basel) ; 11(11)2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31652904

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) remains a devastating human malignancy with poor prognosis and low survival rates. Several cellular mechanisms have been linked with pancreatic carcinogenesis and also implicated in inducing tumor resistance to known therapeutic regimens. Of various factors, immune evasion mechanisms play critical roles in tumor progression and impeding the efficacy of cancer therapies including PDAC. Among immunosuppressive cell types, myeloid-derived suppressor cells (MDSCs) have been extensively studied and demonstrated to not only support PDAC development but also hamper the anti-tumor immune responses elicited by therapeutic agents. Notably, recent efforts have been directed in devising novel approaches to target MDSCs to limit their effects. Multiple strategies including immune-based approaches have been explored either alone or in combination with therapeutic agents to target MDSCs in preclinical and clinical settings of PDAC. The current review highlights the roles and mechanisms of MDSCs as well as the implications of this immunomodulatory cell type as a potential target to improve the efficacy of therapeutic regimens for PDAC.

10.
Cell Transplant ; 28(12): 1624-1631, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31619057

RESUMO

The efficacy of melphalan (MEL) 140 mg/m2 pre-transplant conditioning versus MEL 200 mg/m2 for the elderly is still debated. We hypothesized that single-agent intravenous busulfan (BU) would show significant anti-myeloma efficacy and be better tolerated by elderly patients. A prospective 3+3 dose escalation study enrolled symptomatic multiple myeloma (MM) patients 65 years or older with SWOG performance 0-2 for treatment with intravenous BU pre-transplant at different administration levels. The primary objective was to determine the maximum tolerated dose (MTD) of BU that could be safely given over the least number of days. All patients, except one, received maintenance treatment post-transplant, mostly for 2 years. We enrolled 13 patients, mean age of 73 years (range 68-80). Pharmacokinetic analysis showed no greater than 2% accumulation in the 13 patients, confirming a lack of accumulation in the multi-dose regimen. No deaths occurred in the peri-transplant period. Grade 3/4 adverse effects were hematological, no dose-limiting toxicity was observed and MTD was not reached. Three patients developed grade 3 mucositis but none developed veno-occlusive disease. Ten (77%) patients achieved a complete remission (CR) post-transplant with a remarkably long average time to best response of 6.7 months (range: 6-14 m), and two attained a partial response. Median overall survival was 84 months (95% CI, 21-104) and the median progression-free survival was 60 months (95% CI, 9-93). Our results suggest that IV BU could be an alternative conditioning regimen to MEL 140 in elderly patients with MM, and supports future randomized trials.

11.
Int Immunopharmacol ; 76: 105868, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31487613

RESUMO

The use of immunoglobulins is gradually increasing. Intravenous immunoglobulins (IVIG) are used as replacement therapy for primary and secondary immune deficiencies, and as an anti-inflammatory and immunomodulatory medication for the treatment of neurologic, dermatologic, and rheumatologic diseases. The objective of this study was to analyze trends in the IVIG use in pediatric patients hospitalized to 47 US-based children's hospitals from 2007 to 2014. IVIG was used for the treatment of >2300 primary diagnoses in 53,648 unique patients. The number of IVIG admissions increased by 30.2% during the study period, while the mean rate of IVIG admissions/100,000 admissions increased only 5.8%. Most patients receiving IVIG were children and adolescents. IVIG was frequently used off-label or for the treatment of FDA-approved indications in children under two years of age and BMT patients <20 years of age. Primary immune deficiencies represented only 1.2% of all IVIG admissions. Pediatric patients with mucocutaneous lymph node syndrome (Kawasaki disease, KD) and idiopathic thrombocytopenic purpura (ITP) were two primary consumers of the IVIG. Another top-ranked indications were acute infectious polyneuritis (Guillain-Barré syndrome, GBS) and prophylaxis of infections in patients receiving antineoplastic chemotherapy. IVIG usage is a dynamic process guided by emerging evidence and FDA approval for new indications. IVIG was mostly prescribed for treatment of diseases with pathologic immune responses to foreign of self-antigens. These indications usually, require higher amounts of IVIG per admission. More studies are needed to understand whether IVIG treatments of off-label indications are effective and cost-efficient.


Assuntos
Uso de Medicamentos/tendências , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Síndrome de Guillain-Barré/tratamento farmacológico , Hospitais Pediátricos , Humanos , Síndrome do Coração Esquerdo Hipoplásico/tratamento farmacológico , Lactente , Recém-Nascido , Controle de Infecções , Masculino , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Uso Off-Label/estatística & dados numéricos , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Estudos Retrospectivos , Estados Unidos
13.
AAPS J ; 21(4): 68, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31140019

RESUMO

Body weight is the primary covariate in pharmacokinetics of many drugs and dramatically changes during the first weeks of life of neonates. The objective of this study is to determine if missing body weights in preterm and term neonates affect estimates of model parameters and which methods can be used to improve performance of a population pharmacokinetic model of paracetamol. Data for our analysis were obtained from previously published studies on the pharmacokinetics of intravenous paracetamol in neonates. We adopted a population model of body weight change in neonates to implement three previously introduced methods of handling missing covariates based on data imputation, likelihood function modification, and full random effects modeling. All models were implemented in NONMEM 7.4, and population parameters were estimated using the FOCE method. Our major finding was that missing body weights minimally affect population estimates of pharmacokinetic parameters but do affect the covariate relationship parameters, particularly the one describing dependence of clearance on body weight. None of the tested methods changed estimates of between-subject variability nor impacted the predictive performance of the model. Our analysis shows that a modeling approach towards handling missing covariates allows borrowing information gathered in various studies as long as they target the same population. This approach is particularly useful for handling time-dependent missing covariates.


Assuntos
Acetaminofen/farmacocinética , Analgésicos não Entorpecentes/farmacocinética , Peso Corporal , Modelos Biológicos , Acetaminofen/administração & dosagem , Acetaminofen/sangue , Analgésicos não Entorpecentes/administração & dosagem , Analgésicos não Entorpecentes/sangue , Cálculos da Dosagem de Medicamento , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Injeções Intravenosas , Funções Verossimilhança , Dinâmica não Linear , Fatores de Tempo
14.
Semin Arthritis Rheum ; 49(2): 251-259, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30987856

RESUMO

Glucocorticoids are potent anti-inflammatory and immunosuppressant medications and remain the mainstay of systemic lupus erythematosus (SLE) therapy. The potency of a specific glucocorticoid, i.e., the dose of glucocorticoid that is required to produce a specific effect, is dependent on its pharmacokinetic (PK) and pharmacodynamic (PD) properties. In this review, we summarize the PK/PD properties of commonly used glucocorticoids in an attempt to better delineate their role in the management of children with childhood-onset SLE (cSLE). We also address glucocorticoid side effects as these play a major role when deciding on the dose, frequency, and duration of use. A better understanding of the pharmacology of glucocorticoids appears useful to achieve improved outcomes in the management of cSLE.

15.
Pediatr Blood Cancer ; 66(5): e27629, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30719841

RESUMO

INTRODUCTION: Patients with germline TP53 pathogenic variants (Li-Fraumeni syndrome [LFS]) are at extremely high lifetime risk of developing cancer. Recent data suggest that tumor surveillance for patients with LFS may improve survival through early cancer detection. The objective of this study was to assess the cost-effectiveness of a cancer surveillance strategy for patients with LFS compared with those whose tumors present clinically. METHODS: A Markov decision analytic model was developed from a third-party payer perspective to estimate cost-effectiveness of routine cancer surveillance over a patient's lifetime. The model consisted of four possible health states: no cancer, cancer, post-cancer survivorship, and death. Model outcomes were costs (2015 United States Dollars [USD]), effectiveness (life years [LY] gained), and incremental cost-effectiveness ratio (ICER; change in cost/LY gained). One-way sensitivity analyses and probabilistic sensitivity analyses examined parameter uncertainty. RESULTS: The model showed a mean cost of $46 496 and $117 102 and yielded 23 and 27 LY for the nonsurveillance and surveillance strategies, respectively. The ICER for early cancer surveillance versus no surveillance was $17 125 per additional LY gained. At the commonly accepted willingness to pay threshold of $100 000/life-year gained, surveillance had a 98% probability of being the most cost-effective strategy for early cancer detection in this high-risk population. CONCLUSIONS: Presymptomatic cancer surveillance is cost-effective for patients with germline pathogenic variants in TP53. Lack of insurance coverage or reimbursement in this population may have significant consequences and leads to undetected cancers presenting in later stages of disease with worse clinical outcomes.


Assuntos
Análise Custo-Benefício , Detecção Precoce de Câncer/economia , Síndrome de Li-Fraumeni/diagnóstico , Síndrome de Li-Fraumeni/economia , Cadeias de Markov , Anos de Vida Ajustados por Qualidade de Vida , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Síndrome de Li-Fraumeni/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estados Unidos/epidemiologia , Adulto Jovem
16.
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
17.
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
18.
J Burn Care Res ; 40(1): 91-96, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30371861

RESUMO

Pain management is critical for burn care. Unfortunately, interindividual variation in pharmacokinetics (PK) due to burn hypermetabolism and genetic polymorphisms can lead to treatment failures in this at-risk population. Analgesics may be affected by genetic polymorphisms affecting cytochrome P450 (CYP) drug metabolizing enzymes. Fentanyl is a common opiate primarily metabolized by CYP3A4 subtypes. Recent studies demonstrate CYP2D6 variants, affecting fentanyl PK. Functional CYP polymorphisms can significantly alter opiate levels resulting in inadequate analgesia or life-threatening toxicity. The goal of our study was to evaluate fentanyl PK and assess associations with CYP polymorphisms. We obtained samples from the previously banked blood of 13 patients (eight males and five females) with >20% TBSA burns. Mean (SD) patient age was 41.7 (14.5) years, and mean burn size was 25.8 (15.3) %TBSA. Plasma fentanyl was quantified, and CYP genotyping was performed. Pharmacokinetic analysis was performed using Monolix software (Lixsoft, France) with a two-compartment population model best-representing fentanyl profiles. Three CYP slow-metabolizing genotypes were identified, which included CYP2D6*9, CYP2D6*29, and CYP3A4*1B. All three patients with variant polymorphisms had increased serum fentanyl concentrations due to impaired clearance. This pilot study supports the need for further research in this topic, and CYP genotyping of individual patients prior to receiving opiate analgesics to inform precision-guided decisions, improve therapeutic efficacy, and, most importantly, increase patient well-being and safety.


Assuntos
Analgésicos Opioides/farmacocinética , Queimaduras/tratamento farmacológico , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Fentanila/farmacocinética , Polimorfismo Genético , Adulto , Feminino , Genótipo , Humanos , Masculino , Projetos Piloto
19.
J Clin Pharmacol ; 59(2): 198-205, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30371946

RESUMO

The prevalence of pulmonary methicillin-resistant Staphylococcus aureus infections in patients with cystic fibrosis (CF) has increased over the last 2 decades. Two concentrations-a postdistributive and a trough-are currently used to estimate the area under the curve (AUC) of vancomycin, an antibiotic routinely used to treat these infections, to achieve the target AUC/minimum inhibitory concentration of ≥400 mg·h/L in ensuring optimal dosing of this drug. This study evaluated precision and bias in estimating vancomycin AUCs obtained either from a population pharmacokinetic (PK) model by using a single trough concentration or from standard PK equation-based 2-point monitoring approach. AUCs were either obtained from a single trough concentration-fitted model or derived from a model fitted by 2 concentration points. Children ≥2 years of age with CF received intravenous vancomycin at 2 centers from June 2012 to December 2014. A population PK model was developed in Pmetrics to quantify the between-subject variability in vancomycin PK parameters, define the sources of PK variability, and leverage information from the population to improve individual AUC estimates. Twenty-three children with CF received 27 courses of vancomycin. The median age was 12.3 (interquartile range [IQR] 8.5-16.6) years. From the individual vancomycin PK parameter estimates from the population PK model, median AUC was 622 (IQR 529-680) mg·h/L. Values were not significantly different from the AUC calculated using the standard PK equation-based approach (median 616 [IQR 540-663] mg·h/L) (P = .89). A standard PK equation-based approach using 2 concentrations and a population PK model-based approach using a single trough concentration yielded unbiased and precise AUC estimates. Findings suggest that options exist to implement AUC-based pediatric vancomycin dosing in patients with CF. The findings of this study reveal that several excellent options exist for centers to implement AUC-based pediatric vancomycin dosing for patients with CF.

20.
Ther Drug Monit ; 41(1): 44-52, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30299427

RESUMO

BACKGROUND: Amikacin is widely used to treat severe Gram-negative bacterial infections. Its peak concentration in plasma is associated with treatment efficacy. Amikacin pharmacokinetics (PK) is influenced by disease conditions, in addition to other patient characteristics. In this retrospective study, we evaluated the impact of clinical characteristics and disease condition on amikacin PK in children with burn injuries and those with cancer. METHODS: Amikacin PK data from 66 children with burn injuries and 112 children with cancer were analyzed. A population PK model was developed using the nonlinear mixed-effects modeling approach. Models were developed using NONMEM 7.3 (ICON Development Solutions, LLC, Ellicott City, MD). Data processing and visualization was performed using R packages. RESULTS: The amikacin PK data were best described by a 2-compartment model. The parameters were estimated with mean values (95% confidence intervals) as follows: central volume of distribution (V1), 5.70 L (4.64-6.76 L); central clearance, 2.12 L/h (1.79-2.46 L/h); peripheral volume of distribution (V2), 4.79 L (2.36-7.22 L); and distribution clearance (Q), 0.71 L/h (0.25-1.16 L/h). The final model identified the disease condition as a significant covariate and indicated 55% (28%-82%) higher central clearance and 17% (1%-34%) higher V1 in burn patients compared with cancer patients. Volume of distribution was significantly influenced by age and body weight. Clearance was significantly influenced by age, body weight, and creatinine clearance. Using the final PK model, we developed a workflow for selecting optimal dosing strategies for 3 representative pediatric patient profiles. CONCLUSIONS: Disease condition was significant in influencing amikacin PK in children. To reach the same target concentrations (64 mg/L peak concentration) with a daily-dose plan, burn patients need higher doses than cancer patients. Future investigations are needed to explore the impact of other diseases on amikacin disposition in children, and to prospectively validate the proposed dosing strategy.


Assuntos
Amicacina/farmacocinética , Antibacterianos/farmacocinética , Queimaduras/metabolismo , Neoplasias/metabolismo , Adolescente , Amicacina/uso terapêutico , Queimaduras/sangue , Criança , Pré-Escolar , Feminino , Infecções por Bactérias Gram-Negativas/sangue , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/metabolismo , Humanos , Lactente , Masculino , Neoplasias/sangue , Estudos Retrospectivos
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