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Eur J Cancer ; 38(8): 1081-9, 2002 May.
Artículo en Inglés | MEDLINE | ID: mdl-12008196


Despite the success of adjuvant cyclophosphamide, methotrexate (MTX), 5-fluouracil (5-FU) (CMF) treatment for early stage breast cancer, more than 35% of patients die within 5 years of diagnosis. Optimisation of the dose of each component drug may improve survival and reduce toxicity. In this study, the pharmacokinetics of intravenous (i.v.) cyclophosphamide (600 mg/m(2)), MTX (40 mg/m(2)) and 5-FU (600 mg/m(2)) were determined in 46 women, with data on two consecutive courses available for 41 patients. A population analysis using NONMEM was performed to investigate the effect of patient covariates on pharmacokinetics (PK), and to estimate the relative magnitude of interindividual and interoccasion variability. Patient weight had a significant influence on the clearance of cyclophosphamide and on the volume of central compartment for MTX, whose clearance was dependent on renal function. For all three drugs, interoccasion variability was of the same order (20-40%) as that between individuals, suggesting a limited potential for dose-optimisation of this regimen.

Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Neoplasias de la Mama/metabolismo , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Cromatografía Líquida de Alta Presión/métodos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/sangre , Ciclofosfamida/farmacocinética , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/sangre , Fluorouracilo/farmacocinética , Humanos , Infusiones Intravenosas , Metotrexato/administración & dosificación , Metotrexato/sangre , Metotrexato/farmacocinética , Persona de Mediana Edad
Invest New Drugs ; 14(3): 325-35, 1996.
Artículo en Inglés | MEDLINE | ID: mdl-8958188


Lometrexol is an antifolate which inhibits glycinamide ribonucleotide formyltransferase (GARFT), an enzyme essential for de novo purine synthesis. Extensive experimental and limited clinical data have shown that lometrexol has activity against tumours which are refractory to other drugs, notably methotrexate. However, the initial clinical development of lometrexol was curtailed because of severe and cumulative antiproliferative toxicities. Preclinical murine studies demonstrated that the toxicity of lometrexol can be prevented by low dose folic acid administration, i.e. for 7 days prior to and 7 days following a single bolus dose. This observation prompted a Phase I clinical study of lometrexol given with folic acid supplementation which has confirmed that the toxicity of lometrexol can be markedly reduced by folic acid supplementation. Thrombocytopenia and mucositis were the major toxicities. There was no clear relationship between clinical toxicity and the extent of plasma folate elevation. Associated studies demonstrated that lometrexol plasma pharmacokinetics were not altered by folic acid administration indicating that supplementation is unlikely to reduce toxicity by enhancing lometrexol plasma clearance. The work described in this report has identified for the first time a clinically acceptable schedule for the administration of a GARFT inhibitor. This information will facilitate the future evaluation of this class of compounds in cancer therapy.

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Transferasas de Hidroximetilo y Formilo , Aciltransferasas/antagonistas & inhibidores , Administración Oral , Adulto , Anciano , Antídotos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Enfermedades de la Médula Ósea/inducido químicamente , Enfermedades de la Médula Ósea/metabolismo , Relación Dosis-Respuesta a Droga , Drogas en Investigación/administración & dosificación , Drogas en Investigación/efectos adversos , Drogas en Investigación/farmacocinética , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/farmacocinética , Femenino , Ácido Fólico/administración & dosificación , Ácido Fólico/sangre , Antagonistas del Ácido Fólico/administración & dosificación , Antagonistas del Ácido Fólico/efectos adversos , Antagonistas del Ácido Fólico/farmacocinética , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/metabolismo , Humanos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Fosforribosilglicinamida-Formiltransferasa , Tetrahidrofolatos/administración & dosificación , Tetrahidrofolatos/efectos adversos , Tetrahidrofolatos/farmacocinética
Clin Cancer Res ; 1(12): 1479-86, 1995 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-9815947


(6R)-5,10-Dideaza-5,6,7,8-tetrahydrofolic acid (lometrexol) is an antipurine antifolate which selectively inhibits glycinamide ribonucleotide formyltransferase. Lometrexol pharmacokinetics were evaluated in 17 patients (32 courses) as part of a Phase I study in which folic acid supplementation was used to improve tolerance to the drug, its clinical utility being previously limited by severe cumulative toxicity. Lometrexol was administered as an i.v. bolus every 4 weeks at a starting dose of 12 mg/m2, with subsequent interpatient dose escalation to 16, 30, and 45 mg/m2. p.o. folic acid (5 mg/day) was given for 7 days before and 7 days after lometrexol administration. The disposition of total lometrexol in plasma was best described by a biexponential model for data acquired up to 12 h after drug administration, although triexponential plasma pharmacokinetics were often found to give a more adequate description when data were available at later time intervals (24 h and greater). Mean plasma half-lives (+ SD) for model-dependent analysis were t1/2alpha 19 +/- 7 min, t1/2beta 256 +/- 96 min, and t1/2gamma (where measurable) 1170 +/- 435 min. Lometrexol area under plasma concentration versus time curve was proportional to the dose administered. Moderate plasma protein binding of lometrexol was evident (78 +/- 3%) with an inverse linear relationship between fraction of unbound lometrexol and the concentration of serum albumin. The volume of distribution of lometrexol at steady state was between 4.7 and 15.8 l/m2. Renal elimination of lometrexol, studied in 19 patients (21 courses), was considerable, accounting for 56 +/- 17% of the total dose administered within 6 h of treatment, and 85 +/- 16% within 24 h of treatment. These recoveries of unchanged lometrexol indicate that the drug does not appear to undergo appreciable systemic metabolism at the range of concentrations studied. Lometrexol pharmacokinetics were also examined in seven patients who received 45 or 60 mg/m2 lometrexol as part of a separate study of the drug given with folinic acid rescue 5-7 days after treatment. No marked differences were evident in lometrexol plasma half-lives, plasma clearance, or the extent of plasma protein binding, indicating that there is not a pronounced pharmacokinetic interaction between lometrexol and folic acid.

Antimetabolitos Antineoplásicos/farmacocinética , Ácido Fólico/administración & dosificación , Tetrahidrofolatos/farmacocinética , Adulto , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/sangre , Antimetabolitos Antineoplásicos/orina , Área Bajo la Curva , Proteínas Sanguíneas/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/sangre , Neoplasias/orina , Tetrahidrofolatos/administración & dosificación , Tetrahidrofolatos/sangre , Tetrahidrofolatos/orina
Cancer Res ; 53(20): 4881-9, 1993 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-8402676


Pharmacokinetic studies of etoposide administered at 100-200 mg/m2 to 33 children are described. Twenty-seven studies were performed in children aged < 10 years. Repeat studies were performed in 11 patients. Median pharmacokinetic parameters were as follows: plasma clearance, 26 ml/min/m2; volume of distribution, 4.9 liters/m2; area under the etoposide plasma concentration-time curve (AUC), 3.9 mg/ml x min per 100 mg/m2. Interindividual variability in pharmacokinetic parameters was large (coefficient of variation (CV) = 30, 28, and 27%, respectively) in comparison with intraindividual variability (CV = 12, 14, and 12%, respectively). Variability in AUC was much greater in those patients treated with 150-200 mg/m2 etoposide than with 100 mg/m2 (CV, 35 versus 13%) and was related to variability in renal function and prior exposure to cisplatin. Data from the first 20 studies were used to develop pharmacokinetic monitoring equations which were validated in a further 13 patients. The most accurate equation relies upon the elimination constant of 51Cr-EDTA and a single blood specimen taken at the end of the etoposide infusion. [formula: see text] where K = 51Cr-EDTA elimination rate constant. This equation showed no significant bias, and the predictive error was small with respect to AUC calculated according to a two-compartment model. Predictive error did not increase with increasing AUC, whereas a marked increase in predictive error was seen for dosing according to body surface area. Dosing according to body surface area alone led to marked over- or underexposure to etoposide in 8 patients. Pharmacokinetic monitoring using the equation described would have identified these patients and permitted dose modification. This approach provides an accurate means of monitoring etoposide AUC for administration times of 1-4 h without the need for detailed pharmacokinetic sampling. It will allow a significant reduction in the variability of exposure seen with surface area-based dosing.

Etopósido/farmacocinética , Etopósido/uso terapéutico , Neoplasias/tratamiento farmacológico , Adolescente , Neoplasias Encefálicas/tratamiento farmacológico , Niño , Preescolar , Etopósido/sangre , Femenino , Humanos , Lactante , Masculino , Tasa de Depuración Metabólica , Neoplasias/sangre , Neuroblastoma/tratamiento farmacológico , Glándula Pineal , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Sarcoma/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Teratoma/tratamiento farmacológico
J Clin Oncol ; 4(8): 1245-52, 1986 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-3734849


CB3717 is a quinazoline antifolate whose cytotoxic activity is mediated by inhibition of thymidylate synthase (TS). A phase I clinical trial commenced in September 1981 and 99 patients have received 296 treatments. Doses were dissolved in 0.15 mol/L NaHCO3 (pH 9.0) at a concentration of 4 mg/mL infused over one hour or in a total volume of 1 L infused over 12 hours. Doses were repeated every 3 weeks. The starting dose of 140 mg/m2 was escalated to 600 mg/m2. Renal toxicity, detected by a decrease in the 51Cr EDTA clearance, was dose-related and occurred in seven of ten patients receiving greater than 450 mg/m2. Reversible hepatic toxicity often associated with malaise occurred in 223 of 288 assessable courses (77%). Fifty-nine courses (20%) were associated with increases in alanine transaminase (ALT) levels to greater than 2.5 times the upper limit of the normal laboratory range. Increases in alkaline phosphatase levels also occurred, but were less marked. The severity and prevalence of these elevations were unaffected by the duration of the infusion. A self-limiting rash appeared in 12 patients and a radiation recall reaction was seen in two. Leukopenia developed in 17 patients (WBC less than 3 X 10(9)/L), and thrombocytopenia occurred in six patients (platelets less than 100 X 10(9)/L). The mean leucocyte nadir occurred on day 10 and was followed by recovery at 11 to 19 days. Neither the incidence nor the severity of any of these latter toxicities was dose related. The maximum tolerated dose was in the region of 600 mg/m2 with renal toxicity being dose limiting, although the inter-patient variation did not allow a precise definition. Seventy-six patients were evaluable for response. Responses occurred at doses greater than or equal to 200 mg/m2 and were ovary, one complete response (CR), one partial response (PR), seven minor responses (MR) in 30 cases; breast, two PRs and one MR in eight cases; adenocarcinoma of the lung, one MR in 5 cases; mesothelioma, one PR in five cases; and colon, two MRs in four cases. CB3717 has activity in heavily pretreated patients. The recommended phase II dose for good-risk patients is 400 mg/m2 using the one-hour infusion schedule of administration.

Antineoplásicos/uso terapéutico , Antagonistas del Ácido Fólico/uso terapéutico , Ácido Fólico/análogos & derivados , Neoplasias/tratamiento farmacológico , Quinazolinas/uso terapéutico , Timidilato Sintasa/antagonistas & inhibidores , Acetilglucosaminidasa/orina , Fosfatasa Ácida/sangre , Alanina Transaminasa/sangre , Antineoplásicos/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Evaluación de Medicamentos , Antagonistas del Ácido Fólico/administración & dosificación , Tasa de Filtración Glomerular/efectos de los fármacos , Enfermedades Hematológicas/inducido químicamente , Hiperbilirrubinemia/inducido químicamente , Enfermedades Renales/inducido químicamente , Leucil Aminopeptidasa/orina , Neoplasias/sangre , Neoplasias/fisiopatología , Quinazolinas/administración & dosificación , Enfermedades de la Piel/inducido químicamente
Cancer Chemother Pharmacol ; 9(3): 140-7, 1982.
Artículo en Inglés | MEDLINE | ID: mdl-6761010


cis-Diammine-1,1-cyclobutane dicarboxylate platinum II (CBDCA, JM8), an analogue of cisplatin showing reduced toxicity in preclinical studies, was evaluated in 60 patients. Doses were given initially every 3 weeks and escalated from 20 to 520 mg/m2. Following this, doses were given every 4 weeks and escalated from 300 to 500 mg/m2. The dose-limiting toxicity, thrombocytopoenia, occurred in four-fifths of patients treated at 520 mg/m2, with the nadir occurring 3 weeks after treatment. Leucopoenia and anaemia also occurred but were less severe. Vomiting occurred in all patients receiving over 120 mg/m2 but seldom persisted beyond 24 h. Serial measurements of 51Cr-EDTA clearances, urinary N-acetylglucosaminidase, urinary leucine aminopeptidase, and beta 2-microglobulin did not reveal significant evidence of nephrotoxicity. Detriment to the audiogram has not been seen in the first 13 patients studied. Pharmacological studies showed that most of the dose of platinum was excreted in the urine, and that impairment of renal function may be associated with drug retention and an increased risk of myelosuppression. The previous therapy and age of the patient also affected the tolerance of the drug. Clinical responses were seen in patients with ovarian carcinoma receiving greater than 120 mg/m2. A further dose escalation was performed on a 4-week schedule in patients under 65 with good renal function. The maximum dose it was possible to administer repeatedly without incurring myelosuppression was in the range 400-500 mg/m2. JM8 is not significantly nephrotoxic and is less emetic than cisplatin. It has antitumour activity in man and deserves wider evaluation, along with the other analogues under study in various centres, as an alternative to cisplatin.

Neoplasias/tratamiento farmacológico , Compuestos Organoplatinos/uso terapéutico , Adulto , Anciano , Anemia/inducido químicamente , Médula Ósea/efectos de los fármacos , Carboplatino , Femenino , Audición/efectos de los fármacos , Humanos , Riñón/efectos de los fármacos , Leucopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Náusea/inducido químicamente , Compuestos Organoplatinos/toxicidad , Parestesia/inducido químicamente , Trombocitopenia/inducido químicamente , Vómitos/inducido químicamente