RESUMEN
Hydroxyurea (hydroxycarbamide) is an effective treatment for sickle cell anaemia (SCA), but clinical responses depend primarily upon the degree of fetal haemoglobin (HbF) induction and the heterogeneity of HbF expression across erythrocytes. The number and characteristics of HbF-containing cells (F-cells) are not assessed by traditional HbF measurements. Conventional hydroxyurea dosing (e.g. fixed doses or low starting doses with stepwise escalation) produces a moderate heterocellular HbF induction, but haemolysis and clinical complications continue. Robust, pancellular HbF induction is needed to minimise or fully inhibit polymerisation of sickle haemoglobin. We treated children with hydroxyurea using an individualised, pharmacokinetics-guided regimen starting at predicted maximum tolerated dose (MTD). We observed sustained HbF induction (mean >30%) for up to 6 years, which was not dependent on genetic determinants of HbF expression. Nearly 70% of patients had ≥80% F-cells (near-pancellular), and almost half had ≥90% F-cells (pancellular). The mean HbF/F-cell content was ~12 pg. Earlier age of initiation and better medication adherence were associated with high F-cell responses. In summary, early initiation of hydroxyurea using pharmacokinetics-guided starting doses at predicted MTD can achieve sustained near-pancellular or pancellular HbF expression and should be considered an achievable goal for children with SCA treated with hydroxyurea at optimal doses. Clinical trial registration number: NCT02286154 (clinicaltrials.gov).
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Hemoglobina Fetal/análisis , Hidroxiurea/uso terapéutico , Adolescente , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/farmacocinética , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/farmacocinética , Masculino , Medicina de PrecisiónAsunto(s)
Anemia de Células Falciformes , Antidrepanocíticos , Eritrocitos/metabolismo , Hemoglobina Falciforme/metabolismo , Hidroxiurea , Adolescente , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/farmacocinética , Biomarcadores/sangre , Niño , Preescolar , Femenino , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/farmacocinética , Lactante , MasculinoRESUMEN
BACKGROUND: Without early initiation of disease-modifying therapy, the acute and chronic complications of sickle cell anemia (SCA) begin early in childhood and progress throughout life. Hydroxyurea is a safe and effective medication that reduces or prevents most SCA-related complications. Despite recommendations to prescribe hydroxyurea for all children with SCA as young as 9 months, utilization remains low. PROCEDURE: We completed a retrospective review of hydroxyurea-prescribing practices and associated clinical outcomes at our institution over a 10-year period before and after the 2014 National Heart, Lung, and Blood Institute (NHLBI) recommendations to use hydroxyurea for all children with SCA. RESULTS: Hydroxyurea use more than doubled within our pediatric SCA population from 43% in 2010 to 95% in 2019. The age of hydroxyurea initiation was significantly younger during 2014-2019 compared to 2010-2013 (median 2 years vs. 6 years, p ≤ .001). With this change in clinical practice, nearly all (69/71 = 97%) children born after 2013 received disease-modifying therapy by the end of 2019, primarily hydroxyurea (93%). Concurrently, the number of SCA-related admissions significantly decreased from 67/100 patient-years in 2010 to 39/100 patient-years in 2019 (p < .001). CONCLUSION: The early and universal prescription of hydroxyurea for children with SCA is the standard of care. Here, we demonstrate that a careful and deliberate commitment to follow this guideline in clinical practice is feasible and results in measurable improvements in clinical outcomes. Our approach and improved outcomes can serve as a model for other programs to expand their hydroxyurea use for more children with SCA.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Hidroxiurea/uso terapéutico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adolescente , Antidrepanocíticos/efectos adversos , Antidrepanocíticos/farmacocinética , Transporte Biológico , Niño , Preescolar , Humanos , Hidroxiurea/efectos adversos , Hidroxiurea/farmacocinética , Lactante , Recién Nacido , Masculino , Estudios Retrospectivos , Adulto JovenRESUMEN
Neurologic complications are common in patients with sickle cell anemia (SCA), but conventional tools such as MRI and transcranial Doppler ultrasonography (TCD) do not fully assess cerebrovascular pathology. Cerebral tissue oximetry measures mixed oxygen saturation in the frontal lobes (SCT O2 ) and provides early prognostic information about tissue at risk of ischemic injury. Untreated patients with SCA have significantly lower SCT O2 than healthy controls that declines with age. Hydroxyurea is effective in preventing many SCA-related complications, but the degree to which it preserves normal neurophysiology is unclear. We analyzed participants enrolled in the Therapeutic Response Evaluation and Adherence Trial (TREAT, NCT02286154), which enrolled participants initiating hydroxyurea using individualized dosing (new cohort) and those previously taking hydroxyurea (old cohort) and was designed to monitor the long-term benefits of hydroxyurea. Cerebral oximetry was performed at baseline and annually. For the new cohort (median starting age = 12 months, n = 55), mean baseline SCT O2 was normal before starting hydroxyurea (mean 65%, 95% CI 58-72%) and significantly increased after 2 years (mean 72%, 95% CI 65-79%, p < .001). The SCT O2 for patients receiving long-term hydroxyurea (median age = 9.6 years) was normal at study entry (mean 66%, 95% CI 58-74%) and remained stable across 2 years. Both cohorts had significantly higher SCT O2 than published data from predominantly untreated SCA patients. Cerebral oximetry is a non-invasive method to assess cerebrovascular pathology that complements conventional imaging. Our results indicate that hydroxyurea suggests protection against neurophysiologic changes seen in untreated SCA.
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Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Circulación Cerebrovascular/efectos de los fármacos , Hidroxiurea/uso terapéutico , Oximetría/métodos , Adolescente , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/fisiopatología , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/farmacocinética , Antidrepanocíticos/farmacología , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Intervención Médica Temprana , Femenino , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/farmacocinética , Hidroxiurea/farmacología , Lactante , Masculino , Oximetría/instrumentación , Oxígeno/sangre , Oxihemoglobinas/análisis , Medicina de Precisión , Estudios Prospectivos , Adulto JovenRESUMEN
Reactivation of fetal hemoglobin (HbF) expression by therapeutic agents has been suggested as an alternative treatment to modulate anemia and the related symptoms of severe ß-thalassemia and sickle cell disease (SCD). Hydroxyurea (HU) is the first US FDA-approved HbF inducer for treating SCD. However, approximately 25% of the patients with SCD do not respond to HU. A previous study identified TN1 (1) as a small-molecule HbF inducer. However, this study found that the poor potency and oral bioavailability of compound 1 limits the development of this inducer for clinical use. To develop drug-like compounds, further structure-activity relationship studies on the purine-based structure of 1 were conducted. Herein, we report our discovery of a more potent inducer, compound 13a, that can efficiently induce γ-globin gene expression at non-cytotoxic concentrations. The molecular mechanism of 13a, for the regulation HbF expression, was also investigated. In addition, we demonstrated that oral administration of 13a can ameliorate anemia and the related symptoms in SCD mice. The results of this study suggest that 13a can be further developed as a novel agent for treating hemoglobinopathies, such as ß-thalassemia and SCD.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/síntesis química , Hemoglobina Fetal/metabolismo , Purinas/síntesis química , Talasemia beta/tratamiento farmacológico , Administración Oral , Animales , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/farmacocinética , Permeabilidad de la Membrana Celular , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Desarrollo de Medicamentos , Células Eritroides , Hemoglobina Fetal/genética , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones , Purinas/administración & dosificación , Purinas/farmacocinética , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-ActividadRESUMEN
AIMS: Voxelotor (previously GBT440) is a haemoglobin (Hb) modulator that increases Hb-oxygen affinity, thereby reducing Hb polymerization and sickling of red blood cells (RBCs), being developed as a once-daily oral drug to treat sickle cell disease (SCD). This first-in-human study evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of voxelotor in healthy volunteers and SCD patients. METHODS: A total of 40 healthy volunteers (100, 400, 1000, 2000 or 2800 mg) and 8 SCD patients (1000 mg) were randomly assigned to a single dose of voxelotor once daily (n = 6 per group) or placebo (n = 2 per group). Twenty-four healthy volunteers received multiple doses of voxelotor once daily for 15 days (300, 600 or 900 mg, n = 6 per group) or placebo (n = 2 per group). RESULTS: Voxelotor was well tolerated and exhibited a linear pharmacokinetic profile and a half-life ranging from 61 ± 7 h to 85 ± 7 h. High partitioning into the RBC compartment provides evidence of highly specific binding to Hb. Voxelotor exhibited a concentration-dependent left-shift of oxygen equilibrium curves. Percent Hb modification following 900 mg voxelotor for 15 days was 38 ± 9%. Terminal half-life of voxelotor in SCD patients (50 ± 3 h) was shorter than in healthy volunteers. Evaluation of erythropoietin, exercise testing, and haematologic parameters were consistent with normal oxygen delivery during both rest and exercise. CONCLUSION: This first-in-human study demonstrates voxelotor was well tolerated in SCD patients and healthy volunteers and established proof of mechanism on increasing Hb-oxygen affinity.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/farmacocinética , Benzaldehídos/farmacocinética , Pirazinas/farmacocinética , Pirazoles/farmacocinética , Adolescente , Adulto , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/diagnóstico , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/efectos adversos , Benzaldehídos/administración & dosificación , Benzaldehídos/efectos adversos , Biomarcadores/sangre , Método Doble Ciego , Eritrocitos/efectos de los fármacos , Eritrocitos/metabolismo , Femenino , Humanos , Londres , Masculino , Persona de Mediana Edad , Modelos Biológicos , Oxihemoglobinas/metabolismo , Pirazinas/administración & dosificación , Pirazinas/efectos adversos , Pirazoles/administración & dosificación , Pirazoles/efectos adversos , San Francisco , Resultado del Tratamiento , Adulto JovenRESUMEN
AIMS: The purposes of this work were to: (1) compare pharmacokinetic (PK) parameters for hydroxycarbamide in children receiving their first dose (HCnew ) vs. those receiving chronic therapy (HCchronic ), (2) assess the external validity of a published PK dosing strategy, and (3) explore the accuracy of dosing strategies based on a limited number of HC measurements. METHODS: Utilizing data from two prospective, multicenter trials of hydroxycarbamide (Pharmacokinetics of Liquid Hydroxyurea in Pediatric Patients with Sickle Cell Anemia; NCT01506544 and Single-Dose (SD) and Steady-State (SS) Pharmacokinetics of Hydroxyurea in Children and Adolescents with Sickle Cell Disease), plasma drug concentration vs. time profiles were evaluated with a model independent approach in the HCnew and HCchronic groups. Various predictive scenarios were analysed to evaluate whether systemic exposure with hydroxycarbamide could be accurately predicted. RESULTS: Absorption of hydroxycarbamide was rapid, variable and dose independent. Dose-normalized peak plasma concentrations and drug exposure (AUC) were higher, and weight-normalized apparent oral clearance was lower in the HCnew group. We assessed a PK-guided dosing strategy along with other predictive scenarios and found that inclusion of plasma samples only slightly improved the accuracy of AUC predictions when compared to a population-based method. CONCLUSIONS: Children naïve to hydroxycarbamide exhibit a different PK profile compared to children receiving chronic therapy. Accuracy of population-based dosing is sufficient to target AUCs in individual patients. Further clearance/bioavailability studies are needed to address the factors responsible for variability in the disposition of hydroxycarbamide.
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Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/farmacocinética , Hidroxiurea/farmacocinética , Modelos Biológicos , Adolescente , Anemia de Células Falciformes/sangre , Antidrepanocíticos/administración & dosificación , Área Bajo la Curva , Disponibilidad Biológica , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Hidroxiurea/administración & dosificación , Masculino , Estudios ProspectivosRESUMEN
Hydroxyurea is a potent disease-modifying therapeutic agent with efficacy for the treatment of sickle cell anemia. When administered at once-daily oral doses that lead to mild marrow suppression, hydroxyurea leads to substantial and sustained fetal hemoglobin induction, which effectively inhibits erythrocyte sickling. When escalated to maximum tolerated dose, hydroxyurea has proven laboratory and clinical effects for both children and adults with sickle cell anemia. However, there is substantial inter-patient variability with regard to the optimal dosing regimen, as well as differences in treatment-related toxicities and responses that may be explained by hydroxyurea pharmacokinetics and pharmacogenetics. Addressing the safety and efficacy of hydroxyurea treatment requires quantitative and accurate drug analysis, and various laboratory techniques have been established. We review the historical and current analytical techniques for measuring hydroxyurea concentrations accurately, and discuss clinical settings where quantitative analysis can increase understanding and safety of this important therapeutic agent, and ultimately improve patient outcomes.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/farmacocinética , Monitoreo de Drogas/métodos , Hidroxiurea/farmacocinética , Animales , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/uso terapéutico , Cromatografía Líquida de Alta Presión/métodos , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/uso terapéutico , Espectrometría de Masas/métodosRESUMEN
Hydroxyurea is the primary pharmacotherapy to prevent complications of sickle cell anemia (SCA). Accumulated clinical experience across multiple age ranges has suggested that the use of an individualized maximum tolerated dose (MTD) will achieve optimal benefit of hydroxyurea treatment. However, the current empirical and trial-and-error approach for dose escalation often results in a lengthy titration process and is not strictly implemented in many clinics. Opportunities exist for pharmacokinetics model-based precision dosing of hydroxyurea to quickly achieve individual MTD. This review intends to introduce the use of a quantitative modeling approach including a Bayesian adaptive control strategy for the precision dosing of hydroxyurea. The rationale and practical considerations for the implementation of this approach are discussed. Future research directions with a focus on integrating specific safety and other clinical outcome endpoints into dose selection decision making are also discussed.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/uso terapéutico , Hidroxiurea/uso terapéutico , Animales , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/efectos adversos , Antidrepanocíticos/farmacocinética , Teorema de Bayes , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/efectos adversos , Hidroxiurea/farmacocinética , Dosis Máxima Tolerada , Modelos BiológicosRESUMEN
A major driver of the pathophysiology of sickle cell disease (SCD) is polymerization of deoxygenated haemoglobin S (HbS), which leads to sickling and destruction of red blood cells (RBCs) and end-organ damage. Pharmacologically increasing the proportion of oxygenated HbS in RBCs may inhibit polymerization, prevent sickling and provide long term disease modification. We report that GBT440, a small molecule which binds to the N-terminal α chain of Hb, increases HbS affinity for oxygen, delays in vitro HbS polymerization and prevents sickling of RBCs. Moreover, in a murine model of SCD, GBT440 extends the half-life of RBCs, reduces reticulocyte counts and prevents ex vivo RBC sickling. Importantly, oral dosing of GBT440 in animals demonstrates suitability for once daily dosing in humans and a highly selective partitioning into RBCs, which is a key therapeutic safety attribute. Thus, GBT440 has the potential for clinical use as a disease-modifying agent in sickle cell patients.
Asunto(s)
Anemia de Células Falciformes/metabolismo , Antidrepanocíticos/farmacología , Supervivencia Celular/efectos de los fármacos , Eritrocitos Anormales/efectos de los fármacos , Eritrocitos Anormales/metabolismo , Hemoglobina Falciforme/metabolismo , Oxígeno/metabolismo , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/tratamiento farmacológico , Animales , Antidrepanocíticos/química , Antidrepanocíticos/farmacocinética , Análisis de los Gases de la Sangre , Modelos Animales de Enfermedad , Hemoglobina Falciforme/química , Humanos , Ratones , Agregación Patológica de Proteínas/tratamiento farmacológico , Agregación Patológica de Proteínas/metabolismo , Unión ProteicaRESUMEN
Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSßspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability of a liquid vs capsule formulation. This multicenter; prospective; open-label trial enrolled 39 children with SCA who provided 682 plasma samples for PK analysis following administration of HU. Noncompartmental and population PK models are described. We report that liquid and capsule formulations of HU are bioequivalent; weight-based dosing schemes provide consistent drug exposure; and age-based dosing schemes are unnecessary. These data support the use of liquid HU in children unable to swallow capsules and in those whose weight precludes the use of fixed capsule formulations. Taken with existing safety and efficacy literature; these findings should encourage the use of HU across the spectrum of age and weight in children with SCA; and they should facilitate the expanded use of HU as recommended in the National Heart; Lung; and Blood Institute guidelines for individuals with SCA.
Asunto(s)
Anemia de Células Falciformes/sangre , Hidroxiurea/química , Hidroxiurea/farmacocinética , Adolescente , Antidrepanocíticos/sangre , Antidrepanocíticos/farmacocinética , Cápsulas , Niño , Preescolar , Femenino , Humanos , Hidroxiurea/sangre , Masculino , Estudios Prospectivos , Soluciones , Equivalencia TerapéuticaRESUMEN
AIMS: Hydroxyurea has emerged as the primary disease-modifying therapy for patients with sickle cell anaemia (SCA). The laboratory and clinical benefits of hydroxyurea are optimal at maximum tolerated dose (MTD), but the current empirical dose escalation process often takes up to 12 months. The purpose of this study was to develop a pharmacokinetic-guided dosing strategy to reduce the time required to reach hydroxyurea MTD in children with SCA. METHODS: Pharmacokinetic (PK) data from the HUSTLE trial (NCT00305175) were used to develop a population PK model using non-linear mixed effects modelling (nonmem 7.2). A D-optimal sampling strategy was developed to estimate individual PK and hydroxyurea exposure (area under the concentration-time curve (AUC)). The initial AUC target was derived from HUSTLE clinical data and defined as the mean AUC at MTD. RESULTS: PK profiles were best described by a one compartment with Michaelis-Menten elimination and a transit absorption model. Body weight and cystatin C were identified as significant predictors of hydroxyurea clearance. The following clinically feasible sampling times are included in a new prospective protocol: pre-dose (baseline), 15-20 min, 50-60 min and 3 h after an initial 20 mg kg(-1) oral dose. The mean target AUC(0,∞) for initial dose titration was 115 mg l(-1) h. CONCLUSION: We developed a PK model-based individualized dosing strategy for the prospective Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154). This approach has the potential to optimize the dose titration of hydroxyurea therapy for children with SCA, such that the clinical benefits at MTD are achieved more quickly.
Asunto(s)
Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/farmacocinética , Hidroxiurea/farmacocinética , Modelación Específica para el Paciente , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/uso terapéutico , Área Bajo la Curva , Niño , Ensayos Clínicos como Asunto , Simulación por Computador , Relación Dosis-Respuesta a Droga , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/uso terapéutico , Tasa de Depuración Metabólica , Medicina de Precisión , Factores de TiempoRESUMEN
BACKGROUND: Hydroxyurea is used in the treatment of various malignancies and sickle cell disease. There are limited studies on the pharmacokinetics of hydroxyurea, particularly in pediatric patients. An accurate, precise, and sensitive method is needed to support such studies and to monitor therapeutic adherence. We describe a novel gas chromatography-mass spectrometry (GC-MS) method for the determination of hydroxyurea concentration in plasma using stable labeled hydroxyurea C N2 as an internal standard. METHODS: The method involved an organic extraction followed by the preparation of trimethylsilyl (TMS) derivatives of hydroxyurea for GC-MS selected ion-monitoring analysis. The following mass-to-charge (m/z) ratio ions for silated hydroxyurea and hydroxyurea C N2 were monitored: hydroxyurea-quantitative ion 277, qualifier ions 292 and 249; hydroxyurea C N2-quantitative ion 280, qualifier ion 295. This method was evaluated for reportable range, accuracy, within-run and between-run imprecisions, and limits of quantification. RESULTS: The reportable range for the method was 0.1-100 mcg/mL. All results were accurate within an allowable error of 15%. Within-run and between-run imprecisions were <15%. Samples were stable for at least 4 hours at room temperature, 2 months at -20°C, and 6 months at -70°C, and after 3 freeze/thaw cycles. Extraction efficiency for 1-, 5-, 10-, and 50-mcg/mL samples averaged 2.2%, 1.8%, 1.6%, and 1.4%, respectively. CONCLUSIONS: The isotope-dilution GC-MS method for analysis of hydroxyurea described here is accurate, sensitive, precise, and robust. Its characteristics make the method suitable for supporting pharmacokinetic studies and/or clinical therapeutic monitoring.
Asunto(s)
Monitoreo de Drogas/métodos , Cromatografía de Gases y Espectrometría de Masas/métodos , Hidroxiurea/sangre , Hidroxiurea/farmacocinética , Técnicas de Dilución del Indicador , Adolescente , Antidrepanocíticos/sangre , Antidrepanocíticos/farmacocinética , Isótopos de Carbono/sangre , Niño , Humanos , Isótopos de Nitrógeno/sangreRESUMEN
The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R(2) = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure.
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Anemia de Células Falciformes/metabolismo , Antidrepanocíticos/farmacocinética , Hidroxiurea/farmacocinética , Modelos Biológicos , Administración Oral , Adolescente , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/orina , Antidrepanocíticos/sangre , Antidrepanocíticos/orina , Área Bajo la Curva , Niño , Preescolar , Femenino , Humanos , Hidroxiurea/sangre , Hidroxiurea/orina , MasculinoRESUMEN
Hydroxyurea is currently the only FDA-approved drug that ameliorates the pathophysiology of sickle cell anemia. Unfortunately, substantial interpatient variability in the pharmacokinetics (PK) of hydroxyurea may result in variation of the drug's efficacy. However, little is known about mechanisms that modulate hydroxyurea PK. Recent in vitro studies identifying hydroxyurea as a substrate for organic anion transporting polypeptide (OATP1B) transporters prompted the current investigation assessing the role of OATP1B transporters in modulating hydroxyurea PK. Using wild-type and Oatp1b knockout (Oatp1b(-/-)) mice, hydroxyurea PK was analyzed in vivo by measuring [(14)C]hydroxyurea distribution in plasma, kidney, liver, urine, or the exhaled (14)CO2 metabolite. Plasma levels were significantly reduced by 20% in Oatp1b(-/-) mice compared with wild-type (area under the curve of 38.64 or 48.45 µg·h(-1)·ml(-1), respectively) after oral administration, whereas no difference was observed between groups following intravenous administration. Accumulation in the kidney was significantly decreased by twofold in Oatp1b(-/-) mice (356.9 vs. 748.1 pmol/g), which correlated with a significant decrease in urinary excretion. Hydroxyurea accumulation in the liver was also decreased (136.6 vs. 107.3 pmol/g in wild-type or Oatp1b(-/-) mice, respectively) correlating with a decrease in exhaled (14)CO2. These findings illustrate that deficiency of Oatp1b transporters alters the absorption, distribution, and elimination of hydroxyurea thus providing the first in vivo evidence that cell membrane transporters may play a significant role in modulating hydroxyurea PK. Future studies to investigate other transporters and their role in hydroxyurea disposition are warranted for understanding the sources of variation in hydroxyurea's PK.
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Antidrepanocíticos/farmacocinética , Hidroxiurea/farmacocinética , Transportadores de Anión Orgánico Sodio-Independiente/metabolismo , Animales , Área Bajo la Curva , Femenino , Regulación de la Expresión Génica/fisiología , Transportador 1 de Anión Orgánico Específico del Hígado , Ratones , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Transportadores de Anión Orgánico Sodio-Independiente/genética , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) confirmed safety and efficacy of hydroxyurea therapy for infants with sickle cell anemia. Treatment was associated with reduction in rates of pain, acute chest syndrome, hospitalizations, and blood transfusions; improved hematologic values; and, perhaps, preservation of organ function. During the study, a 2-year-old ingested at one time an entire 35-day supply of hydroxyurea (612 mg/kg body weight). Despite a serum level of 7,756 µM 4 hours post-ingestion, the only toxicity was transient mild myelosuppression. With wider usage of hydroxyurea anticipated, conservative management of future overdoses seems reasonable (ClinicalTrials.gov NCT00006400).
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Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos , Hidroxiurea , Anemia de Células Falciformes/sangre , Anemia de Células Falciformes/fisiopatología , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/efectos adversos , Antidrepanocíticos/farmacocinética , Preescolar , Sobredosis de Droga , Femenino , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/efectos adversos , Hidroxiurea/farmacocinética , LactanteRESUMEN
Efaproxiral (2-[4-[[(3,5-dimethylanilino)carbonyl]methyl]phenoxyl]-2-methylpropionic acid, formerly referred to as RSR13) is prohibited in sports according to the World Anti-Doping Agency (WADA). The drug as well as structurally related compounds and a stable isotope-labeled derivative have been synthesized to elucidate the fragmentation pathway of efaproxiral, using electrospray ionization (ESI) and tandem mass spectrometry by employing a novel linear ion trap--orbitrap hybrid mass spectrometer--in positive and negative ionization modes. The elimination of 2-methyl acrylic acid (-86 u) has been identified as a major fragmentation process in both charge states. Negative ionization and collision-induced dissociation (CID) caused an additional release of carbon dioxide (-44 u), and positive ionization the loss of formic acid (-46 u). Efaproxiral was incorporated into an existing screening procedure for doping controls using solid-phase extraction (SPE) followed by liquid chromatography-tandem mass spectrometry, enabling a limit of detection of 2.5 ng/ml and interday precisions ranging from 7.9 to 13.0%.
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Compuestos de Anilina/orina , Antidrepanocíticos/orina , Cromatografía Liquida/métodos , Doping en los Deportes , Propionatos/orina , Espectrometría de Masa por Ionización de Electrospray/métodos , Compuestos de Anilina/química , Compuestos de Anilina/farmacocinética , Antidrepanocíticos/química , Antidrepanocíticos/farmacocinética , Cromatografía Liquida/normas , Humanos , Propionatos/química , Propionatos/farmacocinética , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Espectrometría de Masa por Ionización de Electrospray/normasRESUMEN
The pharmacokinetic profile of hydroxyurea (HU) was investigated by measuring the rate of drug disappearance from the plasma in wild-type and transgenic (Tg) sickle cell mice. The absorption and elimination processes of HU exhibited first-order kinetics after intraperitoneal administration of HU at 10, 50, 100 or 200 mg/kg body weight (BW). The dosage had a marked effect on the pharmacokinetics of HU in the Tg sickle cell mice. Although the area under the plasma concentration curve (AUC) increased in direct proportion with the HU dose in the wild-type mice, the AUC increased to a much greater extent at higher doses in the Tg sickle cell mice. In the Tg sickle cell mice, there was a considerable increase in the mean residence time (MRT) and a significant reduction in the apparent clearance (CL/F) at HU dose > or =100 mg/kg BW, when compared to the lower doses. At an HU dose of 200 mg/kg BW, the CL/F in the Tg sickle cell mice was reduced by about 50% of the value obtained at a dose of 10 mg/kg BW. This phenomenon was not noticeable in the wild-type mice. The MRT value in the wild-type mice at all doses was relatively constant. The steady-state distribution volume of HU in both the wild-type and Tg sickle cell mice was relatively constant at all doses of the drug. The AUC, CL/F, MRT, and terminal half-life values at any given HU dose showed significant differences between the wild-type and Tg sickle cell mice. Following intraperitoneal administration of HU at a dose of 10, 50, 100, or 200 mg/kg BW, the mean percentage of HU excreted in the urine of the wild-type and Tg sickle cell mice over 120 min was 84 +/- 6.4% and 50 +/- 8.2%, respectively, indicating a significant difference in the amount of HU excreted in urine in the two kinds of mice. The results obtained in this study may be useful in establishing an optimal dose of HU in the treatment and management of patients with sickle cell disease and other hemoglobinopathies.
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Anemia de Células Falciformes/metabolismo , Antidrepanocíticos/farmacocinética , Hidroxiurea/farmacocinética , Anemia de Células Falciformes/tratamiento farmacológico , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
PURPOSE: To determine the safety, pharmacokinetics, and pharmacodynamic effect of 2-[4-(3, 5-dimethylanilino)carbonyl]methyl]phenoxy]-2-methylproprionic++ + acid (RSR13) 100 mg/kg/d with radiation therapy (RT) for glioblastoma multiforme (GBM). RSR13, a synthetic allosteric modifier of hemoglobin (HgB), is a novel radioenhancing agent that noncovalently binds to HgB, thereby reducing oxygen binding affinity and increasing tissue oxygen release to hypoxic tissues. PATIENTS AND METHODS: In this multi-institutional, dose frequency-seeking trial, 19 adult patients with newly diagnosed GBM received RSR13 100 mg/kg every other day or daily along with cranial RT (60 Gy/30 fractions). RSR13 was given over 1 hour by central venous access with 4 L/min of O(2 )by nasal cannula, followed by RT within 30 minutes. Pharmacokinetic (PK) and pharmacodynamic (PD) determinations were performed. The PD end point was shift in P50, the oxygen half-saturation pressure of HgB. RESULTS: Grade 3 dose-limiting toxicity occurred in none of the patients with every-other-day dosing and in two of the 10 patients with daily dosing. Grade 2 or greater toxicity occurred in three out of nine and six out of 10, respectively. PK and PD data demonstrate that a substantial PD effect was reliably achieved, that PD effect was related to RBC RSR13 concentration, and that there was no significant drug accumulation even with daily dosing. The mean shift in P50 was 9.24 +/- 2.6 mmHg (a 34% increase from baseline), which indicates a substantial increase in tendency toward oxygen unloading. CONCLUSION: Daily RSR13 (100 mg/kg) during cranial RT is well tolerated and achieves the desired PD end point. A phase II trial of daily RSR13 for newly diagnosed malignant glioma is currently accruing patients within the New Approaches to Brain Tumor Therapy Central Nervous System Consortium to determine survival outcome.