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1.
Leukemia ; 14(10): 1736-42, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11021748

RESUMO

The purpose of this study was to assess the feasibility and efficacy of a treatment regimen for pediatric acute myelogenous leukemia (AML) that uses four rotating drug pairs and adjusts dosages of etoposide and cytarabine to target specific plasma concentrations. Thirty-one girls and 27 boys (median age, 9.7 years) with de novo AML were treated on the protocol. Six cycles of chemotherapy were planned. Cycles 1 to 4 comprised the drug combinations cytarabine plus etoposide, cytarabine plus daunomycin, etoposide plus amsacrine, and etoposide plus azacitidine, respectively. For cycles 5 and 6, the first two combinations were repeated. Dosages were adjusted to achieve plasma concentrations of 1.0 microM +/- 0.1 microM cytarabine and 30 microM +/- 0.3 microM etoposide. Forty-four patients (76%) entered complete remission. Of those, 24 have had relapses; 23 remain alive in first or subsequent remission. The 5-year event-free survival (EFS) estimate was 31.0% +/- 5.9%; the 5-year survival estimate was 41.4% +/- 6.3%. Six patients (10%) died of the toxic effects of therapy. Severe neutropenia occurred in all cycles. Long-term complications of therapy included hepatitis C, cardiac insufficiency, and hearing loss. Adjustment of cytarabine and etoposide dosage was feasible for achieving targeted plasma drug concentrations; however, the potential clinical efficacy of this approach was offset by substantial acute and long-term toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Pré-Escolar , Citarabina/administração & dosagem , Citarabina/farmacocinética , Relação Dose-Resposta a Droga , Etoposídeo/administração & dosagem , Etoposídeo/farmacocinética , Feminino , Humanos , Lactente , Masculino , Resultado do Tratamento
2.
N Engl J Med ; 338(8): 499-505, 1998 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-9468466

RESUMO

BACKGROUND: The rate of clearance of antileukemic agents differs by a factor of 3 to 10 among children with acute lymphoblastic leukemia. We hypothesized that the outcome of treatment would be improved if doses were individualized to prevent low systemic exposure to the drugs in patients with fast drug clearance. METHODS: We stratified and randomly assigned 182 children with newly diagnosed acute lymphoblastic leukemia to postremission regimens that included high-dose methotrexate and teniposide plus cytarabine. The doses of these drugs were based on body-surface area (in the conventional-therapy group) or the rates of clearance of the three medications in each patient (in the individualized-treatment group). In the individualized-treatment group, doses were increased in patients with rapid clearance and decreased in patients with very slow clearance. RESULTS: Patients who received individualized doses had significantly fewer courses of treatment with systemic exposures below the target range than did patients who received conventional doses (P<0.001 for each medication). Among the patients with B-lineage leukemia, those who received individualized therapy had a significantly better outcome than those given conventional therapy (P=0.02); the mean (+/-SE) rates of continuous complete remission at five years were 76+/-6 percent and 66+/-7 percent, respectively. There was no significant difference between treatments for patients with T-lineage leukemia (P=0.54). In a proportional-hazards model, the time-dependent systemic exposure to methotrexate, but not to teniposide or cytarabine, was significantly related to the risk of early relapse in children with B-lineage leukemia. CONCLUSIONS: Adjusting the dose of methotrexate to account for the patient's ability to clear the drug can improve the outcome in children with B-lineage acute lymphoblastic leukemia.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Criança , Pré-Escolar , Citarabina/administração & dosagem , Citarabina/farmacocinética , Feminino , Humanos , Lactente , Leucemia de Células B/tratamento farmacológico , Masculino , Taxa de Depuração Metabólica , Metotrexato/administração & dosagem , Metotrexato/farmacocinética , Planejamento de Assistência ao Paciente , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Indução de Remissão , Análise de Sobrevida , Teniposídeo/administração & dosagem , Teniposídeo/farmacocinética
3.
J Pharmacol Exp Ther ; 284(1): 89-94, 1998 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9435165

RESUMO

Topotecan is primarily eliminated by the kidneys, with 60 to 70% of the dose recovered as topotecan total in the urine. To elucidate the mechanisms of topotecan renal clearance, we evaluated the effect of probenecid on topotecan renal and systemic disposition in mice. Topotecan lactone or hydroxy acid (1.25 mg/kg i.v.) was administered alone or in combination with probenecid (600 or 1,200 mg/kg) given by oral gavage 30 min before and 3 hr after topotecan. Serial blood samples (three mice per time point) and urine samples (five mice per treatment arm) were collected during a 6-hr period. Compared with topotecan alone, coadministration of topotecan lactone or hydroxy acid with probenecid (600 mg/kg) decreased topotecan lactone, total, and hydroxy acid systemic clearance, and total renal clearance. The predominant effect of probenecid was to increase hydroxy acid area under the plasma concentration time curve after administration of topotecan lactone (238.8 vs. 109.9 ng.hr/ml alone, P < .05), or hydroxy acid (1297.2 vs. 355.0 ng.hr/ml alone, P < .05). By inhibiting renal tubular secretion, probenecid decreased renal and systemic clearance which led to an increase in topotecan systemic exposure. These data suggest that probenecid primarily inhibited secretion of the anionic hydroxy acid form, and by direct or indirect mechanisms increased topotecan lactone systemic exposure. Topotecan elimination through renal tubular secretion may have clinical relevance for the use of topotecan in patients with altered renal function.


Assuntos
Antineoplásicos/farmacocinética , Túbulos Renais/efeitos dos fármacos , Probenecid/farmacologia , Fármacos Renais/farmacologia , Topotecan/farmacocinética , Animais , Feminino , Túbulos Renais/metabolismo , Camundongos , Camundongos Endogâmicos CBA
4.
J Pediatr Hematol Oncol ; 19(5): 438-42, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9329466

RESUMO

PURPOSE: The outcome for children with advanced-stage rhabdomyosarcoma remains poor with contemporary treatment regimens. Evaluation of new drugs is important to improve clinical outcome. Because methotrexate has shown promising activity in the treatment of patients with recurrent rhabdomyosarcoma, we conducted a phase II trial in untreated children with advanced-stage disease to evaluate the efficacy and safety of this agent. PATIENTS AND METHODS: Fifteen patients received 1 to 4 courses of high-dose methotrexate (HDMTX, 12 g/m2). Patients then received standard multiagent chemotherapy (vincristine, dactinomycin, cyclophosphamide, ifosfamide, mesna) with cytokine support and local radiotherapy. Patients who responded to HDMTX received four additional courses of this drug during continuation therapy. RESULTS: Twelve patients were evaluable for response after 2 or more courses of HDMTX; 4 achieved a partial response (33.3%). After administration of standard chemotherapy and radiation, the estimated 2-year progression-free survival for all patients was 56% (SD 15%). The drug was well-tolerated and the most common side effects included mucositis, transient elevation of transaminases, and neutropenia. The four patients who received additional courses of HDMTX during continuation therapy had limited toxicity which included mucositis, anemia, and thrombocytopenia. CONCLUSIONS: About one-third of children with previously untreated advanced-stage rhabdomyosarcoma responded to HDMTX. Its different mechanism of action and non-overlapping toxicity with other agents make HDMTX an attractive candidate for incorporation into front-line treatment regimens for rhabdomyosarcoma.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Metotrexato/uso terapêutico , Rabdomiossarcoma/tratamento farmacológico , Adolescente , Antimetabólitos Antineoplásicos/efeitos adversos , Criança , Pré-Escolar , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Estadiamento de Neoplasias , Radiografia , Rabdomiossarcoma/diagnóstico por imagem , Rabdomiossarcoma/mortalidade , Rabdomiossarcoma/patologia , Medição de Risco , Taxa de Sobrevida
5.
Cancer Chemother Pharmacol ; 40(3): 259-65, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-9219511

RESUMO

The present study was conducted to quantitate the disposition of irinotecan lactone and its active metabolite SN-38 lactone in mice following oral and intravenous administration, and to evaluate the systemic exposure of irinotecan lactone and SN-38 lactone associated with antitumor doses of irinotecan lactone in mice bearing human tumor xenografts. Nontumor-bearing mice were given a single oral or intravenous irinotecan dose (5, 10, 40, or 75 mg/kg), and serial plasma samples were subsequently obtained. Irinotecan and SN-38 lactone plasma concentrations were measured using an isocratic HPLC assay with fluorescence detection. The disposition of intravenous irinotecan lactone was modeled using a two-compartment pharmacokinetic model, and the disposition of oral irinotecan and SN-38 lactone was modeled with noncompartmental methods. Irinotecan lactone showed biphasic plasma disposition following intravenous dosing with a terminal half-life ranging between 1.1 to 3 h. Irinotecan lactone disposition was linear at lower doses (5 and 10 mg/kg), but at 40 mg/kg irinotecan lactone clearance decreased and a nonlinear increase in irinotecan lactone AUC was observed. The steady-state volume of distribution ranged from 19.1 to 48.1 l/m2. After oral dosing, peak irinotecan and SN-38 lactone concentrations occurred within 1 h, and the irinotecan lactone bioavailability was 0.12 at 10 mg/kg and 0.21 at 40 mg/kg. The percent unbound SN-38 lactone in murine plasma at 1000 ng/ml was 3.4 +/- 0.67%, whereas at 100 ng/ml the percent unbound was 1.18 +/- 0.14%. Irinotecan and SN-38 lactone AUCs in micebearing human neuroblastoma xenografts were greater than in nontumor-bearing animals. Systemic exposure to unbound SN-38 lactone in nontumor-bearing animals after a single oral irinotecan dose of 40, 10, and 5 mg/kg was 28.3, 8.6, and 2.9 ng h/ml, respectively. Data from the present study provide important information for the design of phase I studies of oral irinotecan.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Administração Oral , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Área Sob a Curva , Proteínas Sanguíneas/metabolismo , Camptotecina/administração & dosagem , Camptotecina/farmacocinética , Feminino , Injeções Intravenosas , Irinotecano , Camundongos , Camundongos Endogâmicos CBA , Transplante de Neoplasias , Neuroblastoma , Ligação Proteica
6.
Clin Pharmacol Ther ; 59(5): 529-40, 1996 May.
Artigo em Inglês | MEDLINE | ID: mdl-8646824

RESUMO

The plasma disposition of three model substrates (lorazepam, indocyanine green, and antipyrine) and the formation clearance of antipyrine metabolites (3-hydroxymethylantipyrine, norantipyrine, and 4-hydroxyantipyrine) were evaluated in 15 subjects with mild cystic fibrosis and in 15 healthy control subjects. Plasma clearance was significantly greater in patients with cystic fibrosis for both lorazepam (1.7 +/- 0.4 versus 1.2 +/- 0.5 ml/min/kg) and indocyanine green (14.2 +/- 6.1 versus 9.1 +/- 3.0 ml/min/kg). In contrast, the clearance of antipyrine was not significantly different (1.0 +/- 0.7 versus 0.8 +/- 0.3 ml/min/kg), but the formation clearance for 3-hydroxymethylantipyrine was significantly greater in patients with cystic fibrosis. Lorazepam and antipyrine apparent steady-state volume of distribution were not different between groups. These results suggest that clearance of drugs that undergo conjugation (e.g., lorazepam) or biliary excretion (e.g., indocyanine green) is increased in patients with mild cystic fibrosis. In contrast, the increased formation clearance of only one antipyrine metabolite suggests that alterations in clearance of drugs metabolized by cytochrome P450 enzymes are substrate specific and isoform specific in patients with cystic fibrosis.


Assuntos
Ansiolíticos/farmacocinética , Anti-Inflamatórios não Esteroides/farmacocinética , Corantes/farmacocinética , Fibrose Cística/metabolismo , Fígado/metabolismo , Adolescente , Adulto , Ansiolíticos/sangue , Ansiolíticos/urina , Anti-Inflamatórios não Esteroides/sangue , Anti-Inflamatórios não Esteroides/urina , Antipirina/sangue , Antipirina/farmacocinética , Antipirina/urina , Bile/metabolismo , Criança , Cromatografia Líquida de Alta Pressão , Fibrose Cística/sangue , Fibrose Cística/urina , Sistema Enzimático do Citocromo P-450/metabolismo , Feminino , Humanos , Verde de Indocianina/metabolismo , Verde de Indocianina/farmacocinética , Infusões Intravenosas , Lorazepam/sangue , Lorazepam/farmacocinética , Lorazepam/urina , Masculino , Análise de Regressão , Relação Estrutura-Atividade
7.
Cancer Chemother Pharmacol ; 37(3): 195-202, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8529278

RESUMO

The purpose of this study was to describe the cerebrospinal fluid (CSF) penetration of topotecan in humans, to generate a pharmacokinetic model to simultaneously describe topotecan lactone and total concentrations in the plasma and CSF, and to characterize the CSF and plasma pharmacokinetics of topotecan administered as a continuous infusion (CI). Plasma and CSF samples were collected from 17 patients receiving 5.5 or 7.5 mg/m2 per day as a 24-h CI (5 patients, 7 courses), or 0.5 to 1.25 mg/m2 per day as a 72-h CI (12 patients, 12 courses). CSF samples were obtained from either a ventricular reservoir (VR) or a lumbar puncture (LP). Topotecan lactone and total (lactone plus hydroxy acid) concentrations were determined by HPLC and fluorescence detection. Using MAP-Bayesian modelling, a three-compartment model was fitted simultaneously to topotecan lactone and total concentrations in the plasma and CSF. The penetration of topotecan into the CSF was determined from the ratio of the CSF to the plasma area under the concentration-time curve. The median CSF ventricular lactone concentrations, obtained prior to the end of infusion (EOI), were 0.86, 1.4, 0.73, 5.3, and 4.6 ng/ml for patients receiving 0.5, 1.0, 1.25, 5.5, and 7.5 mg/m2 per day, respectively. EOI CSF lumbar lactone concentrations measured in three patients were 0.44, 1.1, and 1.7 ng/ml for topotecan doses of 1.0, 5.5, and 7.5 mg/m2 per day, respectively. In two patients receiving 1.25 mg/m2 per day, EOI CSF concentrations were obtained simultaneously from a VR and LP; the lumbar lactone concentrations were 30% and 49% lower than the ventricular concentrations. During a 24-h and a 72-h CI, the median CSF penetration of topotecan lactone was 0.29 (range 0.10 to 0.59) and 0.42 (range 0.11 to 0.86), respectively. A three-compartment model adequately described topotecan lactone and total concentrations in the plasma and CSF. Topotecan was therefore found to significantly penetrate into the CSF in humans. The pharmacokinetic model presented may be useful in the design of clinical studies of topotecan to treat CNS tumors.


Assuntos
Antineoplásicos/farmacocinética , Neoplasias Encefálicas/metabolismo , Camptotecina/análogos & derivados , Adolescente , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/líquido cefalorraquidiano , Teorema de Bayes , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/líquido cefalorraquidiano , Neoplasias Encefálicas/tratamento farmacológico , Camptotecina/administração & dosagem , Camptotecina/sangue , Camptotecina/líquido cefalorraquidiano , Camptotecina/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Infusões Intravenosas , Masculino , Estatísticas não Paramétricas , Topotecan
8.
Invest New Drugs ; 14(1): 37-47, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8880392

RESUMO

Topotecan, irinotecan, and 9-aminocamptothecin (9-AC) are analogs of the plant alkaloid 20(S)-camptothecin (CMT), the prototypical DNA topoisomerase I interactive agent. These agents interact with the topoisomerase I-DNA complex and prevent resealing topoisomerase I-mediated DNA single-strand breaks. This eventual leads to double-strand DNA breaks and apoptosis or cell death. Topotecan, irinotecan, and 9-AC have shown significant activity in mice bearing pediatric solid tumor xenografts; the greatest antitumor responses were found with protracted continuous schedules. Preclinical data also suggest that maintenance of an exposure-duration threshold (EDT) may be required to achieve optimal cytotoxicity. Pediatric Phase I trials have evaluated the toxicity and safety to camptothecin analogs in children with relapsed solid tumors and relapsed acute leukemia. The primary dose-limiting toxicity (DLT) for the CMT analogs in children has been myelosuppression, except for mucositis observed with the 120-hr continuous topotecan infusion schedule. Pharmacodynamic relationships with these analogs have been reported between systemic exposure, and myelosuppression and mucositis. Although not a primary objective of the early Phase I studies, antitumor responses have been reported. In this review, the pharmacokinetic and pharmacodynamics of the CMT analogs studied in children are summarized, and future studies of these agents are discussed.


Assuntos
Antineoplásicos/uso terapêutico , Dano ao DNA/efeitos dos fármacos , DNA Topoisomerases Tipo I/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/farmacologia , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Criança , Humanos , Camundongos , Neoplasias/enzimologia , Topotecan
9.
Drug Metab Dispos ; 23(10): 1110-6, 1995 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-8654200

RESUMO

Many drugs eliminated by the liver exhibit age-related differences in systemic clearance, necessitating different dosage requirements in children and adults. However, the physiological basis for these age-related changes is not well defined, including the importance of liver size in determining systemic clearance. Therefore, magnetic resonance imaging was used to determine liver volume in pediatric and adolescent patients, in whom systemic clearance of three model substrates [lorazepam (0.03 mg/kg), antipyrine (10 mg/kg), and indocyanine green (ICG; 0.5 mg/kg)] was also determined. In 16 children (ages 3.3-18.8 years; 8 boys), liver volume ranged from 469 to 1640 ml (median 937), and was significantly related to age, body weight, and body surface area (BSA). Younger children had larger liver normalized to body weight (ml/kg), but there was no difference when liver volume was normalized to BSA (ml/m2). Unnormalized lorazepam and ICG clearances (ml/min) were significantly related to absolute liver volume (r2 = 50.2% and 31.4%, respectively), whereas unnormalized antipyrine clearance was not. Lorazepam, ICG, and antipyrine clearance normalized to BSA did not exhibit age-related changes, nor did lorazepam or ICG clearance normalized to body weight decreased significantly with increasing age (r2 = 36.9%, p=0.012), as did antipyrine clearance relative to liver volume. Thus, age-related changes in drug clearance and the importance of liver volume may differ based on the principal hepatic mechanisms involved in drug elimination.


Assuntos
Fígado/metabolismo , Adolescente , Fatores Etários , Antipirina/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Verde de Indocianina/farmacocinética , Lorazepam/farmacocinética , Masculino , Taxa de Depuração Metabólica
10.
Environ Health Perspect ; 102 Suppl 11: 111-7, 1994 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-7737035

RESUMO

Pharmacokinetic studies have made many significant contributions to rational therapeutics in children. Pharmacokinetic data have helped distinguish between differences in drug disposition and drug sensitivity in children as compared to adults and led to the establishment of age-specific dosage guidelines. Factors influencing the observed differences between drug disposition in children and adults are reviewed. Specific examples utilizing anticancer drugs are presented. The use of model substrates to study hepatic drug metabolism and renal excretion in children is described and some results are discussed. The significance of genetic polymorphic drug metabolism is presented and the use of model substrates to determine individual metabolic phenotypes is described. The use of pharmacokinetic data to define the maximum-tolerated systemic exposure rather than the maximum-tolerated dosage of anticancer drugs in children is presented.


Assuntos
Desenvolvimento Infantil/fisiologia , Farmacocinética , Adolescente , Fatores Etários , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Composição Corporal , Superfície Corporal , Criança , Pré-Escolar , Humanos , Modelos Biológicos , Farmacogenética , Fenótipo , Polimorfismo Genético
11.
J Pediatr ; 125(4): 642-9, 1994 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7931891

RESUMO

We studied the pharmacokinetics of vincristine in children with acute lymphocytic leukemia by means of a specific high-performance liquid chromatographic assay with ultraviolet and electrochemical detection and a limited sampling strategy. Our objectives were to characterize the disposition of vincristine in pediatric patients, to determine clinical, demographic, or biochemical variables related to variability in vincristine pharmacokinetic parameters, and to assess the relationship between pharmacokinetic parameters and vincristine neurotoxicity. Plasma samples were collected at 5 and 30 minutes, and 1, 3, and 24 hours after a rapid intravenous injection during 3 minutes. Vincristine-induced neurotoxicity was retrospectively evaluated by chart review. Pharmacokinetic studies were completed for 64 doses in 54 children between 2 months and 18 years of age (median, 4.3 years), including 2-month-old monozygous twin girls. Vincristine clearance, estimated by Bayesian methods, was highly variable, with a mean (SD) clearance of 19.9 (14.9) ml/min per kilogram or 482 (342) ml/min per square meter. Mean clearance for all subjects was faster than in published studies of adults, which may be related in part to the greater specificity of the assay used in our study, as well as to age-related differences in drug disposition. Vincristine-associated neurotoxicity was frequent but mild and was not predicted by vincristine systemic exposure; however, neurotoxicity may have been underestimated. Clearance in one patient who received concomitant treatment with pentobarbital exceeded the 75th percentile for all patients, and four of five patients receiving concomitant histamine2 antagonists had clearances below the 25th percentile for all subjects, suggesting that drugs that induce or inhibit hepatic cytochrome P-450 enzymes may affect vincristine disposition. Further studies are needed to identify the factors responsible for interpatient variability in vincristine disposition and to develop improved dosing guidelines.


Assuntos
Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Vincristina/farmacocinética , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Taxa de Depuração Metabólica , Sistema Nervoso/efeitos dos fármacos , Vincristina/toxicidade
12.
J Clin Oncol ; 12(9): 1946-54, 1994 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-8083716

RESUMO

PURPOSE: Topotecan pharmacokinetics and pharmacodynamics were studied following a 72-hour continuous infusion in 20 children with cancer (median age, 8 years; range, 3.5 to 18). METHODS: Serial plasma and urine samples were collected during the infusion and for up to 6 hours following the end of infusion. Topotecan (lactone) and total (lactone plus hydroxy acid) concentrations were determined by a sensitive and specific high-performance liquid chromatography (HPLC) assay with fluorescence detection. Using maximum a posteriori-Bayesian modeling, lactone and total plasma concentrations were described separately by a two-compartment model. Hematologic toxicity was expressed as the percent decrease in absolute neutrophil count (ANC) and platelet count. The relation between systemic exposure (SE) and hematologic toxicity was modeled using a sigmoid maximum-effect model. RESULTS: Systemic clearance rates for lactone and total topotecan were (mean +/- SD) 18.5 +/- 7.0 and 6.5 +/- 2.4 L/h/m2, respectively. Urinary recovery of total topotecan was (mean +/- SD) 67.5% +/- 25.2% (n = 12 patients). SE (area under the concentration-time curve from zero to infinity [AUC] or steady-state plasma concentration [Cpss]) to either topotecan lactone or total topotecan was significantly correlated to hematologic toxicity (P < .05). Overall, patients with a higher SE to topotecan experienced greater hematologic toxicity. CONCLUSION: These data demonstrate a relation between systemic exposure to topotecan and clinical effect (myelosuppression). Moreover, these data provide the basis for development of individualized topotecan administration schedules.


Assuntos
Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Adolescente , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/farmacocinética , Criança , Pré-Escolar , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Infusões Intravenosas/métodos , Lactonas/farmacocinética , Contagem de Leucócitos/efeitos dos fármacos , Masculino , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neutrófilos , Contagem de Plaquetas/efeitos dos fármacos , Topotecan
13.
J Clin Oncol ; 12(8): 1667-72, 1994 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8040679

RESUMO

PURPOSE: Following high-dose methotrexate (HD-MTX) treatment, delayed MTX elimination is an important problem because it necessitates increased leucovorin rescue and additional hospitalization for hydration and urinary alkalinization. Our purpose was to identify factors associated with high-risk MTX plasma concentrations (defined by plasma concentration > or = 1.0 mumol/L at 42 hours from the start of MTX) and with toxicity. PATIENTS AND METHODS: Variables associated with MTX concentrations and toxicity were assessed in 134 children treated with one to five courses of HD-MTX (900 to 3,700 mg/m2 intravenously [i.v.] over 24 hours for a total of 481 courses) for acute lymphoblastic leukemia (ALL). RESULTS: High-risk MTX concentrations, toxicity (usually mild mucositis), and delay in resuming continuation chemotherapy occurred in 106 (22%), 123 (26%), and 66 (14%) of 481 courses, respectively. Using a mixed effects model for repeated measures, high-risk MTX concentrations were significantly associated with a higher MTX area-under-the-concentration-time curve (AUC), low urine pH, emesis, low MTX clearance, low urine output relative to intake, use of antiemetics during the MTX infusion, and concurrent intrathecal therapy (all p values < .01). Clinical toxicities and delay in resumption of continuation chemotherapy due to myelosuppression were more common in those with high 42-hour MTX concentrations, despite increased leucovorin rescue for all patients with high-risk MTX concentrations. However, with individualized rescue, no patient developed life-threatening toxicity. A more aggressive hydration and alkalinization regimen for subsequent courses reduced the frequency of high-risk MTX concentrations to 7% of courses (13 of 183) (P = .0001), and the frequency of toxicity decreased to 11% of courses (P = .0074). CONCLUSION: This study identified several clinical variables that influence MTX disposition that, when modified, can reduce the frequency of high-risk MTX concentrations and toxicity.


Assuntos
Metotrexato/efeitos adversos , Metotrexato/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangue , Criança , Pré-Escolar , Feminino , Hidratação , Humanos , Concentração de Íons de Hidrogênio , Infusões Intravenosas , Leucovorina/administração & dosagem , Masculino , Metotrexato/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Fatores de Risco , Urina , Vômito/sangue
14.
Blood ; 84(4): 1237-42, 1994 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-7914104

RESUMO

The majority of children with acute myeloid leukemia (AML) who are treated exclusively with chemotherapy die of progressive disease. Improvement in outcome will likely require new active drugs capable of eradicating resistant blast cells early in the clinical course. We therefore assessed the cytoreductive potential of 2-chlorodeoxyadenosine (2-CdA), a halogenated purine analogue, in 22 consecutive children with newly diagnosed AML. The drug was administered as a single 120-hour continuous infusion (8.9 mg/m2 of body surface area per day) before the introduction of standard remission induction therapy. Six patients (27%) had complete hematologic remissions by a median of 21 days after treatment with the nucleoside (range, 14 to 33 days). Seven others had partial responses, yielding a total response rate of 59%. The drug also eliminated leukemic cells from cerebrospinal fluid in 4 of the 6 patients tested. Concentrations of 2-CdA in cerebrospinal fluid on day 5 after the initiation of treatment ranged from 12.4% to 38.0% (mean, 22.7%) of the steady-state plasma concentrations. Severe but reversible myelosuppression and thrombocytopenia developed in all patients. Analysis of factors that may have influenced the complete remission rate suggested a better outcome in patients with myeloblastic leukemia (M0-M2 subtypes in the revised French-American-British classification system). These results demonstrate clinically significant activity by 2-CdA against previously untreated AML in children, including leukemic blast cells in the central nervous system. Its use in combination chemotherapy may improve the outlook for patients with this often fatal hematologic cancer.


Assuntos
Cladribina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Crise Blástica/tratamento farmacológico , Crise Blástica/genética , Criança , Pré-Escolar , Cladribina/administração & dosagem , Cladribina/toxicidade , Feminino , Humanos , Lactente , Infusões Intravenosas , Cariotipagem , Leucemia Mieloide Aguda/classificação , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino
15.
Cancer Res ; 54(5): 1235-9, 1994 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-7906999

RESUMO

Cladribine is a synthetic purine nucleoside with demonstrated activity in hairy cell leukemia and acute myeloid leukemia. We have studied the pharmacokinetics of this drug in 25 pediatric patients with acute leukemia treated with cladribine as a single agent, 8.9 mg/m2/24 h, for 5 days by continuous i.v. infusion. Twelve patients were in relapse, and acute myeloid leukemia was newly diagnosed in 13 patients. Plasma, urine, and cerebrospinal fluid cladribine concentrations were determined by a radioimmunoassay with a limit of detection of 1 nM. An open two-compartment model was fit to the plasma concentration data. The mean (SD) clearance was 39.4 (12.4) liters/h/m2 and ranged from 14.4-55.4 liters/h/m2. When clearance was normalized to body weight (liters/h/kg) it was negatively correlated with age, with older patients having slower clearances per unit of body weight. However, when clearance was normalized to body surface area, no significant correlation with age was observed. The mean (SD) steady-state plasma concentration (predicted 120-h concentration) was 37.7 (17.3) nM and ranged from 23.2-84.5 nM. The terminal phase half-life in 22 patients ranged from 14.3-25.8 h, with a mean (SD) of 19.7 (3.4) h. The volume of distribution at steady state was highly variable, with a mean (SD) of 356.6 (225.2) liters/m2. None of these parameters was significantly different between patients in relapse and patients with newly diagnosed disease. Renal clearance was determined in 7 patients and ranged from 34.6-643.6 ml/min/m2, with a mean (SD) of 317.9 (208.7) ml/min/m2. Renal clearance as a percentage of total systemic clearance ranged from 11.0-85.1%, with a mean of 51.0%. In 11 patients, the mean (SD) cerebrospinal fluid concentration was 6.1 (3.97) nM, a mean of 18.2% of the steady-state plasma concentration. The CSF:plasma concentration ratio was significantly higher on day 5 (22.7% in 7 patients) than on day 4 (7.6% in 3 patients; P = 0.03). Additional studies are needed to further define the metabolic fate of cladribine. In this paper we provide the first comprehensive description of the pharmacokinetics of this drug in children and provide data which suggest that cladribine may be useful in the treatment of patients with meningeal leukemia or malignancies of the central nervous system.


Assuntos
Cladribina/farmacocinética , Leucemia Mieloide/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Doença Aguda , Adolescente , Adulto , Bilirrubina/análise , Criança , Pré-Escolar , Cladribina/líquido cefalorraquidiano , Cladribina/uso terapêutico , Creatinina/sangue , Esquema de Medicação , Feminino , Meia-Vida , Humanos , Lactente , Infusões Intravenosas , Rim/metabolismo , Leucemia Mieloide/líquido cefalorraquidiano , Leucemia Mieloide/tratamento farmacológico , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquidiano , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Valor Preditivo dos Testes
16.
J Pharmacokinet Biopharm ; 21(6): 639-51, 1993 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-8138891

RESUMO

Flavone acetic acid (FAA) is an antineoplastic agent that has undergone extensive study in Phase I trials. Concentration-dependent plasma protein binding has been demonstrated in vitro at concentrations of total drug that are achieved in vivo. Moreover, dose-dependent total systemic clearance has been described when FAA has been administered as a short iv infusion. When administered as a prolonged 24-hr infusion, total FAA (bound plus unbound) plasma pharmacokinetics are well described with a first-order two-compartment model. However, measurement of unbound FAA intra- and post-intravenous infusion in eight patients revealed a twofold increase in fraction of FAA unbound in plasma intrainfusion. We attempted to fit pharmacokinetic structural models of varying complexity to the unbound concentrations alone and simultaneously to the unbound and bound FAA plasma concentrations. The data were adequately described only by a model that incorporated simultaneous saturable plasma protein binding and a Michaelis-Menten process for elimination. A comparison among models is presented, as well as pharmacokinetic parameter estimates for FAA in children. These clinical data are consistent with predictions of the clearance model in which both saturable protein binding (resulting in a dynamically increasing unbound fraction) and saturable elimination (resulting in gradually decreasing unbound intrinsic clearance) are operative.


Assuntos
Antineoplásicos/farmacocinética , Flavonoides/farmacocinética , Neoplasias/metabolismo , Antineoplásicos/sangue , Criança , Flavonoides/sangue , Humanos , Cinética , Neoplasias/sangue , Neoplasias/tratamento farmacológico , Neoplasias Experimentais/sangue , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Ligação Proteica
17.
Semin Oncol ; 20(1): 18-29, 1993 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8475406

RESUMO

Pharmacokinetic variability in children with cancer is substantial and confounds drawing conclusions regarding optimal therapy based only on dose-response relationships. Careful pharmacokinetic studies performed during drug development in conjunction with an assessment of patient characteristics, such as age, renal and hepatic function, and concomitant therapy, is essential for defining those factors that may alter drug disposition. By integrating pharmacokinetic studies with measures of efficacy and toxicity, a pharmacodynamic framework can be established for guiding therapy to minimize differences in systemic exposure among subpopulations of patients (eg, impaired renal function and neonates). In selected instances when pharmacokinetic variability cannot be predicted by patient covariates, the potential for individualizing dosages based on patient-specific pharmacokinetic parameters is now a clinically feasible option. The need for and benefits of incorporating such strategies into routine therapy represents an exciting area for further clinical research.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Adulto , Transplante de Medula Óssea , Criança , Pré-Escolar , Humanos , Leucemia/tratamento farmacológico , Neoplasias/tratamento farmacológico , Proteínas Recombinantes
18.
Am J Hosp Pharm ; 49(9 Suppl 1): S9-14, 1992 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-1530005

RESUMO

The clinical importance of individual pharmacokinetic and pharmacodynamic differences among enantiomers is discussed. A number of mechanisms in the body can be stereoselective, among them first-pass metabolism, metabolic clearance, renal clearance, and protein and tissue binding. Differences in first-pass metabolism may cause differences in the ratio of plasma concentrations of enantiomers when a drug is given by the intravenous route compared with the oral route. Stereoisomers of a drug may be metabolized by two different enzyme systems, resulting in different rates of metabolic clearance; age and sex may also affect the rates of enzymatic metabolism of stereoisomers. Substantial differences in the protein binding of two enantiomers may result in a difference in their glomerular filtration rates. Two enantiomers may bind differently to protein or to other tissue receptor sites, resulting in differences in drug effects or distribution. There are no simple answers to questions regarding the pharmacokinetics of racemic drug mixtures and single enantiomers. The properties of enantiomers in each drug will have to be evaluated for their pharmacokinetic disposition and their therapeutic index.


Assuntos
Conformação Molecular , Preparações Farmacêuticas/metabolismo , Farmacocinética , Farmacologia , Animais , Humanos
19.
Br J Cancer Suppl ; 18: S23-9, 1992 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-1503923

RESUMO

Maturation of physiologic process which govern the disposition of pharmacologic agents can yield significant changes in absorption, distribution, metabolism, and elimination of drugs in neonates, infants and children. However, there are very little data concerning the disposition of anticancer drugs in young children. Pharmacokinetic data for six anticancer agents were compared in infants less than 1 year of age and children greater than 1 year of age treated at St Jude Children's Research Hospital. No pharmacokinetic data were available for infants less than 2 months of age. Median methotrexate clearance tended to be lower in four infants (0.26-0.99 years) vs 108 children (1-19 years): 80 vs 103 ml min-1 m-2, respectively (P = 0.01). There was no difference in the median 42 h methotrexate concentration. Teniposide systemic clearance and terminal half-life and cytarabine systemic clearance were not different between the two groups. There was no significant difference in etoposide systemic clearance when normalised to body surface area (ml min-1 m-2), however a significantly lower systemic clearance relative to body weight (ml min-1 kg-1) was observed in two infants, 0.5 to 1 year of age, vs 23 children, 3-18 years of age. Doxorubicin systemic clearance was not significantly different between the two groups when systemic clearance was expressed in ml min-1 kg-1. However, there was a trend toward a lower rate of systemic clearance in ml min-1 m-2 in infants.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológico , Fatores Etários , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Proteínas Sanguíneas/metabolismo , Criança , Pré-Escolar , Doxorrubicina/farmacocinética , Etoposídeo/farmacocinética , Humanos , Lactente , Recém-Nascido , Fígado/efeitos dos fármacos , Fígado/patologia , Mercaptopurina/farmacocinética , Metotrexato/farmacocinética , Neoplasias/sangue , Sistema Nervoso/efeitos dos fármacos , Sistema Nervoso/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Teniposídeo/farmacocinética
20.
Leukemia ; 5(11): 999-1003, 1991 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1961043

RESUMO

Plasma methotrexate (MTX) concentrations were measured following intrathecal (IT) MTX treatment in four patients with acute lymphocytic leukemia and acute renal dysfunction. All four patients had raised serum MTX concentrations to potentially cytotoxic concentrations for a prolonged period of time, (96-120 h). In contrast, serum MTX concentrations after the same dosage of IT treatment ranged from undetectable to 0.11 microM by 15-24 h in seven control patients with normal renal function, and were undetectable by 48 h in all controls. The terminal MTX T1/2 was 19-44 h in the patients with renal dysfunction. Decreased renal clearance or a rapid efflux of MTX from cerebrospinal fluid, or both, could account for the high and sustained concentrations. Plasma MTX concentrations after IT treatment were normal in two patients treated after their renal function returned to normal. Patients with renal dysfunction should be carefully monitored for plasma MTX concentrations and may require leucovorin to prevent systemic side-effects after IT MTX treatment.


Assuntos
Nefropatias/complicações , Metotrexato/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Feminino , Meia-Vida , Humanos , Injeções Espinhais , Nefropatias/metabolismo , Nefropatias/prevenção & controle , Masculino , Metotrexato/administração & dosagem , Metotrexato/sangue , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações
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