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Bioensayo/métodos , Compuestos Heterocíclicos de 4 o más Anillos/administración & dosificación , Síndromes Neoplásicos Hereditarios/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Piel/efectos de los fármacos , Administración Cutánea , Adulto , Biopsia , Receptor con Dominio Discoidina 2/antagonistas & inhibidores , Receptor con Dominio Discoidina 2/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Humanos , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/metabolismo , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/patología , Prueba de Estudio Conceptual , Receptor trkB/antagonistas & inhibidores , Receptor trkB/metabolismo , Piel/patología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
AIMS: Carboplatin dosage is calculated by using the estimated glomerular filtration rate (GFR) to achieve a target plasma area under the plasma concentration-time curve (AUC). The aims of the present study were to investigate factors that influence the pharmacokinetics of carboplatin in children with high-risk neuroblastoma, and whether target exposures for carboplatin were achieved using current treatment protocols. METHODS: Data on children receiving high-dose carboplatin, etoposide and melphalan for neuroblastoma were obtained from two study sites [European International Society for Paediatric Oncology (SIOP) Neuroblastoma study, Children's Hospital at Westmead; n = 51]. A population pharmacokinetic model was built for carboplatin to evaluate various dosing formulas. The pharmacokinetics of etoposide and melphalan was also investigated. The final model was used to simulate whether target carboplatin AUC (16.4 mg ml-1 ·min) would be achieved using the paediatric Newell formula, modified Calvert formula and weight-based dosing. RESULTS: Allometric weight was the only significant, independent covariate for the pharmacokinetic parameters of carboplatin, etoposide and melphalan. The paediatric Newell formula and modified Calvert formula were suitable for achieving the target AUC of carboplatin for children with a GFR <100 ml min-1 1.73 m-2 but not for those with a GFR ≥100 ml min-1 1.73 m-2 . A weight-based dosing regimen of 50 mg kg-1 achieved the target AUC more consistently than the other formulas, regardless of renal function. CONCLUSIONS: GFR did not appear to influence the pharmacokinetics of carboplatin after adjusting pharmacokinetic parameters for weight. This model-based approach validates the use of weight-based dosing as an appropriate alternative for carboplatin in children with either mild renal impairment or normal renal function.
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Antineoplásicos/farmacocinética , Carboplatino/farmacocinética , Etopósido/farmacocinética , Riñón/fisiopatología , Melfalán/farmacocinética , Neuroblastoma/tratamiento farmacológico , Factores de Edad , Antineoplásicos/administración & dosificación , Área Bajo la Curva , Peso Corporal , Carboplatino/administración & dosificación , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Cálculo de Dosificación de Drogas , Etopósido/administración & dosificación , Femenino , Tasa de Filtración Glomerular/fisiología , Humanos , Lactante , Masculino , Melfalán/administración & dosificación , Modelos BiológicosRESUMEN
Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.
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Aurora Quinasas/antagonistas & inhibidores , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacocinética , Leucemia/tratamiento farmacológico , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacocinética , Urea/análogos & derivados , Enfermedad Aguda , Adolescente , Bencimidazoles/efectos adversos , Niño , Preescolar , Femenino , Humanos , Lactante , Leucemia/enzimología , Masculino , Dosis Máxima Tolerada , Inhibidores de Proteínas Quinasas/efectos adversos , Urea/administración & dosificación , Urea/efectos adversos , Urea/farmacocinéticaRESUMEN
INTRODUCTION: Busulfan is widely used in a neuroblastoma setting, with several studies reporting marked inter-patient variability in busulfan pharmacokinetics and pharmacodynamics. The current study reports on the pharmacokinetics of oral versus intravenous (IV) busulfan in high-risk neuroblastoma patients treated on the European HR-NBL-1/SIOPEN study. METHODS: Busulfan was administered four times daily for 4 days to children aged 0.7-13.1 years, either orally (1.45-1.55 mg/kg) or by the IV route (0.8-1.2mg/kg according to body weight strata). Blood samples were obtained prior to administration, 2, 4, and 6h after the start of administration on dose 1. Busulfan analysis was carried out by gas chromatography-mass spectrometry and data analysed using a NONMEM population pharmacokinetic approach. RESULTS: Busulfan plasma concentrations obtained from 38 patients receiving IV busulfan and 25 patients receiving oral busulfan, were fitted simultaneously using a one-compartment pharmacokinetic model. Lower variability in drug exposure was observed following IV administration, with a mean busulfan area under the plasma concentration versus time curve (AUC) of 1146 ± 187 µM.min (range 838-1622), as compared to 953 ± 290 µM.min (range 434-1427) following oral busulfan. A total of 87% of children treated with IV busulfan achieved AUC values within the target of 900-1500 µM.min versus 56% of patients following oral busulfan. Busulfan AUC values were significantly higher in HR-NBL-1/SIOPEN trial patients who experienced hepatic toxicity or veno-occlusive disease (VOD) (1177 ± 189 µM.min versus 913 ± 256 µM.min; p=0.0086). Further stratification based on route of administration suggested that the incidence of hepatic toxicity was related to both high busulfan AUC and oral drug administration. CONCLUSION: The reduced pharmacokinetic variability and improved control of busulfan AUC observed following IV administration support its utility within the ongoing HR-NBL-1/SIOPEN trial.
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Busulfano/administración & dosificación , Busulfano/farmacocinética , Agonistas Mieloablativos/administración & dosificación , Agonistas Mieloablativos/farmacocinética , Neuroblastoma/tratamiento farmacológico , Administración Oral , Adolescente , Área Bajo la Curva , Busulfano/efectos adversos , Busulfano/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Niño , Preescolar , Esquema de Medicación , Europa (Continente) , Cromatografía de Gases y Espectrometría de Masas , Humanos , Lactante , Inyecciones Intravenosas , Tasa de Depuración Metabólica , Modelos Biológicos , Agonistas Mieloablativos/efectos adversos , Agonistas Mieloablativos/sangre , Neuroblastoma/sangre , Medición de Riesgo , Factores de RiesgoRESUMEN
BACKGROUND AND PURPOSE: Fenretinide (4-HPR) is a retinoic acid analogue, currently used in clinical trials in oncology. Metabolism of 4-HPR is of particular interest due to production of the active metabolite 4'-oxo 4-HPR and the clinical challenge of obtaining consistent 4-HPR plasma concentrations in patients. Here, we assessed the enzymes involved in various 4-HPR metabolic pathways. EXPERIMENTAL APPROACH: Enzymes involved in 4-HPR metabolism were characterized using human liver microsomes (HLM), supersomes over-expressing individual human cytochrome P450s (CYPs), uridine 5'-diphospho-glucoronosyl transferases (UGTs) and CYP2C8 variants expressed in Escherichia coli. Samples were analysed by high-performance liquid chromatography and liquid chromatography/mass spectrometry assays and kinetic parameters for metabolite formation determined. Incubations were also carried out with inhibitors of CYPs and methylation enzymes. KEY RESULTS: HLM were found to predominantly produce 4'-oxo 4-HPR, with an additional polar metabolite, 4'-hydroxy 4-HPR (4'-OH 4-HPR), produced by individual CYPs. CYPs 2C8, 3A4 and 3A5 were found to metabolize 4-HPR, with metabolite formation prevented by inhibitors of CYP3A4 and CYP2C8. Differences in metabolism to 4'-OH 4-HPR were observed with 2C8 variants, CYP2C8*4 exhibited a significantly lower V(max) value compared with *1. Conversely, a significantly higher V(max) value for CYP2C8*4 versus *1 was observed in terms of 4'-oxo formation. In terms of 4-HPR glucuronidation, UGTs 1A1, 1A3 and 1A6 produced the 4-HPR glucuronide metabolite. CONCLUSIONS AND IMPLICATIONS: The enzymes involved in 4-HPR metabolism have been characterized. The CYP2C8 isoform was found to have a significant effect on oxidative metabolism and may be of clinical relevance.
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Sistema Enzimático del Citocromo P-450/metabolismo , Fenretinida/metabolismo , Glucuronosiltransferasa/metabolismo , Microsomas Hepáticos/metabolismo , Hidrocarburo de Aril Hidroxilasas/antagonistas & inhibidores , Hidrocarburo de Aril Hidroxilasas/genética , Hidrocarburo de Aril Hidroxilasas/metabolismo , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A , Sistema Enzimático del Citocromo P-450/genética , Inhibidores Enzimáticos/farmacología , Fenretinida/análogos & derivados , Glucurónidos/metabolismo , Glucuronosiltransferasa/genética , Humanos , Mucosa Intestinal/metabolismo , Intestinos/efectos de los fármacos , Cinética , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Proteínas Mutantes/metabolismo , Proteínas Recombinantes/metabolismo , Tretinoina/análogos & derivados , Tretinoina/metabolismoRESUMEN
INTRODUCTION: Carboplatin dosing based on renal function and therapeutic monitoring have been previously shown to be beneficial in the treatment of children with cancer. However, the applicability of such approaches to the treatment of premature or newborn infants, where kidney function may change markedly with advancing gestational and postnatal age, is unknown. Diagnosis of retinoblastoma in a preterm infant provided a rare opportunity to carry out adaptive carboplatin dosing in a patient with immature renal function. CASE REPORT: A preterm female infant born at a gestational age of 32 weeks was diagnosed with bilateral retinoblastoma at 35 weeks. Carboplatin treatment with real-time pharmacokinetic monitoring was initiated on day 26 of life at an initial dose of 6.6 mg/kg. Plasma samples were obtained at specified time points and carboplatin levels quantified by atomic absorption spectrometry. Additional doses of carboplatin were determined by pharmacokinetic monitoring based on the achievement of carboplatin AUC values of 5.2-7.8 mg/ml min on three courses of treatment. Increased carboplatin doses administered on successive courses of treatment reflected a greater than twofold increase in drug clearance, from 3.4-7.1 ml/min over a 7-week period. Pharmacokinetically-guided carboplatin dosing led to the attainment of AUCs within 10% of target values on each course of treatment. The patient completed five courses of carboplatin with both tumours defined as inactive after this treatment period. CONCLUSIONS: Data obtained from studying this patient suggests that adaptive carboplatin monitoring represents a feasible and beneficial clinical approach in preterm infants or neonates.
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Antineoplásicos/farmacocinética , Carboplatino/farmacocinética , Neoplasias de la Retina/metabolismo , Retinoblastoma/metabolismo , Antineoplásicos/administración & dosificación , Área Bajo la Curva , Carboplatino/administración & dosificación , Relación Dosis-Respuesta a Droga , Monitoreo de Drogas , Femenino , Edad Gestacional , Humanos , Recién Nacido , Recien Nacido Prematuro , Pruebas de Función Renal , Tasa de Depuración Metabólica , Neoplasias de la Retina/tratamiento farmacológico , Neoplasias de la Retina/patología , Retinoblastoma/tratamiento farmacológico , Retinoblastoma/patología , Distribución Tisular , Resultado del TratamientoRESUMEN
Renal function-based carboplatin dosing is used routinely in paediatric oncology clinical practice. It is important that accurate assessments of renal function are carried out consistently across clinical centres, a view supported by recently published British Nuclear Medicine Society (BNMS) guidelines for measuring glomerular filtration rate (GFR). These guidelines recommend the use of a radioisotope method for GFR determination, with between two and five blood samples taken starting 2 h after radioisotope injection and application of the Brochner-Mortensen (BM) correction factor. To study the likely impact of these guidelines, we have investigated current practices of measuring GFR in all 21 Children's Cancer and Leukaemia Group (CCLG) paediatric oncology centres in the United Kingdom. This information was used to evaluate the potential impact on renal function-based carboplatin dosing using raw 51Cr-EDTA clearance data from 337 GFR tests carried out in children with cancer. A questionnaire survey revealed that between two and four samples were taken after isotope administration, with BM and Chantler corrections used in 38% (8/21) and 28% (6/21) of centres, respectively. A change from Chantler to BM correction, based on the BNMS guidelines, would result in a > 10% decrease in carboplatin dose in at least 15% of patients and a > 25% decrease in 2% of patients. A greater proportion of patients would have an alteration in carboplatin dose when centres not using any correction factor implement the BM correction. The increase in estimated 51Cr-EDTA half-life observed by omitting the I h sample decreases carboplatin dose by > 10% in 23-52% of patients and by > 25% in 3% of patients. This study highlights current variations in renal function measurement between clinical centres and the potential impact on carboplatin dosing. A standard methodology for estimating GFR should be followed to achieve uniform dosing in children with cancer.
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Antineoplásicos/administración & dosificación , Carboplatino/administración & dosificación , Tasa de Filtración Glomerular , Riñón/fisiología , Neoplasias/tratamiento farmacológico , Renografía por Radioisótopo/normas , Adolescente , Adulto , Antineoplásicos/farmacocinética , Área Bajo la Curva , Carboplatino/farmacocinética , Niño , Preescolar , Relación Dosis-Respuesta a Droga , Ácido Edético/farmacocinética , Humanos , Lactante , Neoplasias/metabolismo , Compuestos Organometálicos/farmacocinética , Renografía por Radioisótopo/estadística & datos numéricos , Estudios Retrospectivos , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Isomerisation to all-trans-retinoic acid (ATRA) is widely accepted as the key mechanism underlying the favourable clinical properties of 13-cis-retinoic acid (13cisRA). As intracellular metabolism of ATRA by CYP26 may result in clinical resistance to 13cisRA, an increase in efficacy may be achieved through modulation of this metabolic pathway. We have evaluated the effect of the CYP26 inhibitor R116010 on retinoid metabolism in neuroblastoma cell lines and a xenograft model. In neuroblastoma cells, which showed a high level of CYP26 induction in response to ATRA, R116010 selectively inhibited ATRA metabolism. In addition, siRNA-mediated knockdown of CYP26 selectively increased ATRA levels and the expression of retinoid-responsive marker genes was potentiated by R116010. Treatment of mice bearing SH-SY5Y xenografts with 13cisRA (100 mg kg(-1)) revealed substantial levels (16%) of intratumoral ATRA after 6 h, despite plasma ATRA levels representing only 1% total retinoids under these conditions. Co-administration of R116010 with 13cisRA in this mouse model resulted in significant increases in plasma ATRA and 13cisRA concentrations. Furthermore, R116010 induced significant decreases in levels of 4-oxo metabolites in hepatic tissue after co-administration with either ATRA or 13cisRA. These data suggest considerable potential for CYP26 inhibitors in the future treatment of neuroblastoma with 13cisRA.
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Benzotiazoles/farmacología , Inhibidores Enzimáticos del Citocromo P-450 , Imidazoles/farmacología , Neuroblastoma/metabolismo , Tretinoina/metabolismo , Animales , Línea Celular Tumoral , Sistema Enzimático del Citocromo P-450 , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Isoenzimas/metabolismo , Ratones , Ratones Desnudos , Neuroblastoma/patología , ARN Interferente Pequeño/farmacología , Ácido Retinoico 4-Hidroxilasa , Trasplante Heterólogo , Tretinoina/farmacocinéticaRESUMEN
A pharmacokinetic-pharmacodynamic study was carried out to investigate the feasibility and potential importance of therapeutic monitoring following high-dose carboplatin treatment in children. High-dose carboplatin was administered over 3 or 5 days, with the initial dose based on renal function, to achieve target area under the plasma concentration-time curve (AUC) values of 21 or 20 mg ml(-1).min, respectively. Dose adjustment was carried out based on observed individual daily AUC values, to obtain the defined target exposures. Platinum-DNA adduct levels were determined in peripheral blood leucocytes and toxicity data were obtained. Twenty-eight children were studied. Based on observed AUC values, carboplatin dose adjustment was performed in 75% (21 out of 28) patients. Therapeutic monitoring resulted in the achievement of carboplatin exposures within 80-126% of target AUC values, as compared to estimated exposures of 65-213% of target values without dose adjustment. The carboplatin AUC predicted with no dose modification was positively correlated with pretreatment glomerular filtration rate (GFR) values. Higher GFR values were observed in those patients who would have experienced AUC values >25% above the target AUC than those patients attaining AUC values >25% below the target AUC, following renal function-based dosing. Platinum-DNA adduct levels correlated with observed AUC values on day 1 of carboplatin and increased over a 5-day course of treatment. Real-time monitoring of carboplatin pharmacokinetics with adaptive dosing is both feasible and necessary for the attainment of consistent AUC values in children receiving high-dose carboplatin treatment. Pharmacodynamic data suggest a strong correlation between carboplatin pharmacokinetics and the drug-target interaction.
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Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Carboplatino/administración & dosificación , Carboplatino/farmacocinética , Aductos de ADN/sangre , Neoplasias/tratamiento farmacológico , Adolescente , Adulto , Área Bajo la Curva , Niño , Preescolar , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Femenino , Tasa de Filtración Glomerular , Humanos , Lactante , MasculinoRESUMEN
The administration of 13-cis-retinoic acid (13-cisRA), following myeloablative therapy improves 3-year event-free survival rates in children with high-risk neuroblastoma. This study aimed to determine the degree of inter-patient pharmacokinetic variation and extent of metabolism in children treated with 13-cisRA. 13-cis-retinoic acid (80 mg m(-2) b.d.) was administered orally and plasma concentrations of parent drug and metabolites determined on days 1 and 14 of courses 2, 4 and 6 of treatment. Twenty-eight children were studied. The pharmacokinetics of 13-cisRA were best described by a modified one-compartment, zero-order absorption model combined with lag time. Mean population pharmacokinetic parameters included an apparent clearance of 15.9 l h(-1), apparent volume of distribution of 85 l and absorption lag time of 40 min with a large inter-individual variability associated with all parameters (coefficients of variation greater than 50%). Day 1 peak 13-cisRA levels and exposure (AUC) were correlated with method of administration (P<0.02), with 2.44- and 1.95-fold higher parameter values respectively, when 13-cisRA capsules were swallowed as opposed to being opened and the contents mixed with food before administration. Extensive accumulation of 4-oxo-13-cisRA occurred during each course of treatment with plasma concentrations (mean+/-s.d. 4.67+/-3.17 microM) higher than those of 13-cisRA (2.83+/-1.44 microM) in 16 out of 23 patients on day 14 of course 2. Extensive metabolism to 4-oxo-13-cisRA may influence pharmacological activity of 13-cisRA.
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Isotretinoína/farmacocinética , Neuroblastoma/tratamiento farmacológico , Absorción , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Isotretinoína/efectos adversos , Isotretinoína/uso terapéutico , Masculino , Oxidación-ReducciónRESUMEN
BACKGROUND: The objective of this study was to determine the minimum volume of blood that should be discarded from a range of different types of central venous catheter (CVC), such that the subsequent blood sample was not diluted or contaminated by the residual intra-luminal fluid. PROCEDURE: Seventy children aged 1-19 years with central venous access inserted as part of their standard clinical treatment were recruited to this prospective study. Statistical comparison of the extent of variation in biochemical and haematological parameters observed between two blood samples taken following routine 5 ml discard blood volumes, as compared to the extent of variation between samples drawn following a 5 ml discard volume and <5 ml volumes, was carried out. RESULTS: Data indicate that the measurement error in a clinical sample obtained following a 3 ml discard volume is no different to the measurement error obtained when using a standard 5 ml discard volume. Comparable results were obtained from patients with various different types of CVC or portacath access. CONCLUSIONS: The withdrawal of a 3 ml discard volume is sufficient to ensure that the subsequent blood sample is not diluted or contaminated by residual intra-luminal fluid. This may have a significant clinical impact in paediatric oncology, where patients frequently require blood transfusions due to the haematological toxicities associated with chemotherapy. It is hoped that these results will impact on hospital policies concerning specified discard volumes taken from CVCs prior to the withdrawal of blood samples for research purposes and routine clinical analysis.
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Recolección de Muestras de Sangre/métodos , Cateterismo Venoso Central/métodos , Neoplasias/sangre , Adolescente , Adulto , Análisis Químico de la Sangre/métodos , Recolección de Muestras de Sangre/instrumentación , Cateterismo Venoso Central/instrumentación , Niño , Preescolar , Estudios de Seguimiento , Humanos , Lactante , Estudios ProspectivosRESUMEN
Recent data indicate that isomerisation to all-trans retinoic acid (ATRA) is the key mechanism underlying the favourable clinical properties of 13-cis retinoic acid (13cisRA) in the treatment of neuroblastoma. Retinoic acid (RA) metabolism is thought to contribute to resistance, and strategies to modulate this may increase the clinical efficacy of 13cisRA. The aim of this study was to test the hypothesis that retinoids, such as acitretin, which bind preferentially to cellular retinoic acid binding proteins (CRABPs), or specific inhibitors of the RA hydroxylase CYP26, such as R116010, can increase the intracellular availability of ATRA. Incubation of SH-SY5Y cells with acitretin (50 microM) or R116010 (1 or 10 microM) in combination with either 10 microM ATRA or 13cisRA induced a selective increase in intracellular levels of ATRA, while 13cisRA levels were unaffected. CRABP was induced in SH-SY5Y cells in response to RA. In contrast, acitretin had no significant effect on intracellular retinoid concentrations in those neuroblastoma cell lines that showed little or no induction of CRABP after RA treatment. Both ATRA and 13cisRA dramatically induced the expression of CYP26A1 in SH-SY5Y cells, and treatment with R116010, but not acitretin, potentiated the RA-induced expression of a reporter gene and CYP26A1. The response of neuroblastoma cells to R116010 was consistent with inhibition of CYP26, indicating that inhibition of RA metabolism may further optimise retinoid treatment in neuroblastoma.
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Antineoplásicos/metabolismo , Isotretinoína/metabolismo , Retinoblastoma/tratamiento farmacológico , Retinoblastoma/metabolismo , Tretinoina/metabolismo , Acitretina/farmacología , Antineoplásicos/farmacología , Benzotiazoles , Western Blotting , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Sistema Enzimático del Citocromo P-450/metabolismo , Humanos , Imidazoles/farmacología , Isotretinoína/farmacología , Ácido Retinoico 4-Hidroxilasa , Proteínas de Unión al Retinol/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tiazoles/farmacología , Tretinoina/farmacologíaRESUMEN
Estimation of glomerular filtration rate (GFR) using the clearance of chromium 51 EDTA ((51)Cr-EDTA) (or other radiolabelled isotopes) is reliable, but invasive and not always practicable. Mathematical models have been devised for estimating GFR using readily obtainable patient characteristics. Unfortunately, these models were developed using various patient populations and may not provide the optimal prediction of GFR in children with cancer. The current study uses population pharmacokinetics to determine the relationship between (51)Cr-EDTA clearance, and patient covariates in 50 paediatric cancer patients. These models were validated using a separate group of 43 children and were compared with previously published models of renal function. Body size was the major determinant of (51)Cr-EDTA clearance and inclusion of weight or surface area reduced the residual variability between individuals (coefficient of variation) from 61 to 32%. Serum creatinine was the only other parameter that significantly improved the model. Mean percentage error values of -5.0 and -1.1% were observed for models including weight alone or weight and creatinine, respectively, with precision estimates of 21.7 and 20.0%. These simple additive models provide a more rationale approach than the use of complex formulae, involving additional parameters, to predict renal function.
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Quelantes/farmacocinética , Ácido Edético/farmacocinética , Tasa de Filtración Glomerular , Modelos Teóricos , Adolescente , Adulto , Niño , Preescolar , Radioisótopos de Cromo , Femenino , Humanos , Lactante , Masculino , Neoplasias/complicaciones , Neoplasias/tratamiento farmacológico , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
Our understanding of the clinical and cellular pharmacology of drugs commonly used in the treatment of childhood cancer have increased greatly over the past two decades. However, with the exception of childhood acute lymphoblastic leukaemia (ALL), our current knowledge of factors such as inter-patient pharmacokinetic variability and cellular determinants of chemosensitivity has not been utilized in the design of integrated clinical studies. Recent pre-clinical and clinical evaluation of the topoisomerase I inhibitors topotecan and irinotecan has highlighted the potential importance of pharmacological factors in their effectiveness as cytotoxics. In this review, the clinical and cellular pharmacology of vincristine, actinomycin D, doxorubicin, cyclophosphamide, ifosfamide, cisplatin, carboplatin and etoposide will be discussed in relation to the major paediatric solid tumours. For each disease type, knowledge of the clinical and cellular pharmacology of a candidate drug will be related to pharmacodynamic responses such as response, toxicity and prognosis. For diseases such as Wilms' tumour, osteogenic sarcoma and Ewing's tumour, histological response to initial induction chemotherapy is of prognostic significance, and the depth of response is increasingly recognised as an important determinant of prognosis for high-risk neuroblastoma. For several of these tumour types, the dose-intensity of chemotherapy may be an important variable in determining prognosis. However the relationship between pharmacokinetic variability, cellular pharmacology and the major determinants of chemosensitivity to those drugs employed in first line therapy is unknown. The study of these relationships, by means of up front window studies in children who present with high-risk disease, may be as important as the introduction of new agents. Indeed, the optimisation of current therapies may be required to allow a fully informed selection of those children for whom novel therapies are truly needed. Funding and international collaboration at the clinical and scientific level would be required to achieve these aims.
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Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Neoplasias Óseas/tratamiento farmacológico , Niño , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Neoplasias Renales/tratamiento farmacológico , Neuroblastoma/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Rabdomiosarcoma/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Sarcoma de Ewing/tratamiento farmacológico , Inhibidores de Topoisomerasa I , Tumor de Wilms/tratamiento farmacológicoRESUMEN
The formation of platinum (Pt)-DNA adducts is thought to be crucial to the antitumor activity of cisplatin, and relationships between adduct formation in peripheral blood leukocytes (PBLs) and response to cisplatin therapy have been reported. The current study directly tests, for the first time, whether pharmacokinetic or other factors predominantly determine the drug-target interaction of cisplatin in a pediatric patient population. Cisplatin pharmacokinetics and Pt-DNA adduct formation in PBLs were determined in 10 children in parallel with measurement of adduct levels after incubation of pretreatment blood samples with cisplatin in vitro. Total and unbound plasma Pt concentrations were determined by atomic absorption spectrophotometry and adduct measurements performed by competitive ELISA. Pt-DNA adduct levels determined after cisplatin treatment showed considerable interindividual variation (peak levels at 24 h ranged from 0.15 to 1.31 nmol/g DNA) and correlated strongly with adduct levels determined after incubation of pretreatment whole blood with cisplatin (r = 0.92; P = 0.0002). No significant correlation was observed between in vivo adduct formation and either unbound or total cisplatin plasma concentrations (r = 0.14 and 0.18, respectively). A correlation was also observed between the degree of myelosuppression, as determined by WBC nadirs measured over a 14-day period after cisplatin treatment, and the extent of adduct formation, with greater WBC toxicity observed in patients with higher levels of Pt-DNA adducts (P = 0.010). These preliminary results provide evidence that interpatient variation in formation of Pt-DNA adducts in PBLs of children is determined by host-specific factors other than cisplatin pharmacokinetics. These results imply that analysis of adducts in PBLs after incubation of pretreatment blood samples with cisplatin may be used to predict in vivo adduct levels, leukopenia, and, potentially, response to cisplatin therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Cisplatino/uso terapéutico , Aductos de ADN/efectos de los fármacos , Leucocitos/efectos de los fármacos , Adolescente , Adulto , Antineoplásicos/farmacocinética , Área Bajo la Curva , Niño , Preescolar , Cisplatino/farmacocinética , ADN/sangre , ADN/química , ADN/efectos de los fármacos , Aductos de ADN/sangre , Femenino , Humanos , Lactante , Recuento de Leucocitos , Leucocitos/química , Masculino , Neuroblastoma/tratamiento farmacológico , Osteosarcoma/tratamiento farmacológico , Platino (Metal)/químicaRESUMEN
Pre-clinical studies indicate that cisplatin encapsulated in STEALTH((R))liposomes (SPI-77) retains anti-tumour activity, but has a much reduced toxicity, compared to native cisplatin. A phase I study was conducted to determine the toxicity and pharmacokinetics of SPI-77 administered to children with advanced cancer not amenable to other treatment. Paediatric patients were treated at doses ranging from 40 to 320 mg m(-2)by intravenous infusion every 4 weeks. Blood samples taken during, and up to 3 weeks after, administration and plasma and ultrafiltrate were prepared immediately. Urine was collected, when possible, for 3 days after administration. SPI-77 administration was well tolerated with the major toxicity being an infusion reaction which responded to modification of the initial infusion rate of SPI-77. Limited haematological toxicity and no nephrotoxicity were observed. No responses to treatment were seen during the course of this phase I study. Measurement of total plasma platinum showed that cisplatin was retained in the circulation with a half life of up to 134 h, with maximum plasma concentrations approximately 100-fold higher than those reported following comparable doses of cisplatin. Comparison of plasma and whole blood indicated that cisplatin was retained in the liposomes and there was no free platinum measurable in the ultrafiltrate. Urine recovery was less than 4% of the dose administered over 72 h. Results from this phase I study indicate that high doses of liposomal cisplatin can safely be given to patients, but further studies are required to address the issue of reformulation of liposomally bound cisplatin.
Asunto(s)
Antineoplásicos/farmacocinética , Cisplatino/farmacocinética , Neoplasias/tratamiento farmacológico , Podofilino/análogos & derivados , Podofilino/farmacocinética , Adolescente , Antineoplásicos/efectos adversos , Área Bajo la Curva , Niño , Preescolar , Colesterol/sangre , Cisplatino/efectos adversos , Cisplatino/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Lactante , Lípidos/sangre , Lipoproteínas HDL/sangre , Lipoproteínas HDL/efectos de los fármacos , Lipoproteínas LDL/sangre , Lipoproteínas LDL/efectos de los fármacos , Liposomas , Masculino , Neoplasias/metabolismo , Podofilino/efectos adversos , Podofilino/sangre , Podofilotoxina/análogos & derivados , Factores de Tiempo , Triglicéridos/sangreRESUMEN
Didanosine (2',3'-dideoxyinosine; ddI) requires intracellular metabolism to its active triphosphate, 2',3'-dideoxyadenosine 5'-triphosphate (ddATP), to inhibit the replication of human immunodeficiency virus (HIV). We have investigated the metabolism of ddI to ddATP in the presence and absence of a range of compounds. In addition, we determined the levels of the endogenous competitor of ddATP, 2'-deoxyadenosine 5'-triphosphate (dATP), and calculated ddATP/dATP ratios. None of the nucleoside analogs studied had any effect on ddI phosphorylation at 1 and 10 microM concentrations. At 100 microM concentrations, ddC reduced total ddA phosphates (82% of control total ddA phosphates; p < 0.001). ZDV significantly decreased the levels of dATP, whereas ddC significantly increased dATP pools (e.g., at 100 microM ZDV, 82% of control dATP levels; p < 0.001). Hence, the ddATP/dATP ratio was increased in the presence of ZDV, but was decreased in the presence of ddC. Neither d4T nor 3TC affected the ddATP/dATP ratio. Deoxyinosine (dI) significantly reduced ddA phosphate production at 100 microM concentrations, with ddATP reduced to undetectable levels (p < 0.001). Hydroxyurea (HU) did not affect the activation of ddI, but significantly reduced dATP pools at 100 microM concentrations (67% of control dATP levels; p < 0.001), enhancing the ddATP/dATP ratio. ddA phosphate production was significantly reduced by pentoxyfylline (PXF) at 10 and 100 microM concentrations. dATP levels were unaffected, but the ddATP/dATP ratio was reduced. Finally, 8-aminoguanosine (8-AMG) had no effect on either ddI activation or dATP pools. These studies demonstrate the importance of determining both the active TP and the competing endogenous TP, as changes to the resulting ratio could alter the efficacy of the nucleoside analog in question.
Asunto(s)
Fármacos Anti-VIH/metabolismo , Didanosina/metabolismo , Interacciones Farmacológicas , Fármacos Anti-VIH/farmacología , Nucleótidos de Desoxiadenina/metabolismo , Didanosina/farmacología , Didesoxinucleótidos , Guanosina/análogos & derivados , Guanosina/farmacología , Humanos , Hidroxiurea/farmacología , Inosina/análogos & derivados , Inosina/farmacología , Líquido Intracelular , Lamivudine/farmacología , Pentoxifilina/farmacología , Estavudina/farmacología , Células U937 , Zidovudina/farmacologíaRESUMEN
We have used a ribonuclease protection assay to investigate RNase H cleavage of HIV-1 mRNA mediated by phosphorothioate antisense oligonucleotides complementary to the gag region of the HIV-1 genome in vitro. Cell lysate experiments in H9 and U937 cells chronically infected with HIV-1 IIIB showed RNase H cleavage of unspliced gag message but no cleavage of spliced message which did not contain the target gag region. RNase H cleavage products were detected at oligonucleotide concentrations as low as 0.01 microM and the RNase H activity was seen to be concentration dependent. Similar experiments with 1-, 3- and 5-mismatch oligonucleotides demonstrated sequence specificity at low concentrations, with cleavage of gag mRNA correlating with the predicted activities of the parent and mismatch oligonucleotides based on their hybridization melting temperatures. Experiments in living cells suggested that RNase H-specific antisense activity was largely determined by the amount of oligonucleotide taken up by the different cell lines studied. RNase H cleavage products were detected in antisense oligonucleotide treated MT-4 cells acutely infected with HIV-1 IIIB, but not in infected H9 cells treated with oligonucleotide under the same conditions. The data presented demonstrate potent and specific RNase H cleavage of HIV-1 mRNA mediated by an antisense oligonucleotide targeted to HIV-1 gag mRNA, and are in agreement with previous reports that the major obstacle to demonstrating antisense activity in living cells remains the lack of penetration of these agents into the desired cellular compartment.
Asunto(s)
Productos del Gen gag/genética , Infecciones por VIH/genética , VIH-1/fisiología , Oligonucleótidos Antisentido/genética , ARN Mensajero/genética , Infecciones por VIH/terapia , Humanos , Oligonucleótidos Antisentido/uso terapéutico , ARN Viral/genética , Ribonucleasa H/genética , Análisis de Secuencia , Células U937 , Replicación Viral/efectos de los fármacos , Replicación Viral/genéticaRESUMEN
We have studied the effects of the gag antisense phosphorothioate oligonucleotide GEM 91 and mismatch antisense controls on the antiviral activities of ddC and other nucleoside analogs in HIV-infected MT-4 cells using a cytoprotection based assay. Under standard assay conditions, i.e. simultaneous incubation of drugs, HIV-1 IIIB and MT-4 cells, both GEM 91 and mismatch controls interacted synergistically with ddC resulting in an approximate 40-fold decrease in the IC50 value of ddC; this suggests a potent but sequence non-specific effect of GEM 91. Under post-adsorption assay conditions, i.e. pre-incubation of virus and cells and removal of excess HIV before drug addition, GEM 91 exhibited synergism with ddC, with an approximate 5-fold decrease in ddC IC50 value. This favorable interaction was not seen with any of the mismatch oligonucleotides, suggesting the involvement of a sequence-specific mechanism of action. Similar results were seen with the thymidine analogs AZT and d4T in combination with GEM 91. These data suggest a potential role for GEM 91 and future sequence-specific antisense drugs in combination with nucleoside analogs for the treatment of HIV infection. It is essential that potential interactions between new and existing classes of anti-HIV drugs are studied extensively as antiretroviral drug combinations become increasingly more complex.
Asunto(s)
Fármacos Anti-VIH/farmacología , Didesoxinucleósidos/farmacología , Productos del Gen gag/genética , VIH-1/efectos de los fármacos , Oligonucleótidos Antisentido/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Tionucleótidos/farmacología , Adsorción , Línea Celular , Sinergismo Farmacológico , Humanos , Oligonucleótidos Antisentido/toxicidad , Tionucleótidos/toxicidadRESUMEN
Lamivudine (2'-deoxy-3'-thiacytidine; 3TC) is a dideoxynucleoside analogue that inhibits the replication of human immunodeficiency virus (HIV). We are currently investigating the intracellular metabolism of 3TC to its active triphosphate (3TCTP) in peripheral blood mononuclear cells (PBMC) and a monocytic cell line (U937). Optimal phosphorylation of 3TC was achieved after incubation for 24 hr, with 3TC diphosphate (3TCDP) the predominant metabolite formed, in both cell types investigated. Further studies in PBMCs followed preincubation with the mitogen phytohaemagglutinin (PHA) for 72 hr. This enabled greater detection of phosphates, compared to resting cells. A 3TC concentration of 1 microM was chosen for future interaction studies, allowing good detection of 3TC and phosphates on radiochromatograms whilst being similar to the plasma level found in clinical studies (i.e. 3 microM). With a shift in treatment to combination therapy, it is essential that potential interactions between nucleoside analogues are investigated at the phosphorylation level, as this could affect antiviral activity. Both deoxycytidine (dC) and 2',3'-dideoxycytidine (ddC) significantly inhibited 3TC phosphorylation (e.g. at dC 100 microM, no 3TCTP was detected in PBMCs; P < 0.001, whereas 66% of control 3TCTP production was observed in U937 cells; P < 0.01). Zidovudine (ZDV) caused a small but significant reduction of 3TC phosphate production in both PBMCs and U937 cells. However, this may be due to toxicity or an effect on endogenous dCTP pools. Neither 2',3'-dideoxyinosine (ddI) or 2',3'-didehydro-2',3'-dideoxythymidine (d4T) significantly inhibited 3TC phosphorylation. These results suggest it would be better to coadminister two nucleoside analogues with different activation pathways.