RESUMEN
The nitrosourea, fotemustine, was given intravenously in 1 h constant-rate infusion to 66 patients in a multicentric study to assess both fotemustine pharmacokinetic behaviour and the pharmacokinetic-pharmacodynamic relationships. Depending on the tumour type treated, two administration and sampling protocols were used: 100 mg/m2/week as a conventional dose (six samples, 44 patients) and 300-500 mg/m2/day as a high dose (10 samples, 22 patients). The 91 time-concentration curves were best described by either a one-(55) or a two-compartment (36) model, and their mean clearance values did not differ significantly (85.3 +/- 6.5 and 101.3 +/- 9.5 l/h, respectively, P = 0.1727). Fotemustine pharmacokinetics were not influenced by repeated treatment (time-independence) nor by dose level (dose-independence). The pharmacodynamic effect observed on white blood cell count was expressed by a logit regression model involving the area under the curve mainly and the total administered dose. White blood cell toxicity could be predicted as a function of the dose for a given patient with a known fotemustine clearance value.
Asunto(s)
Antineoplásicos/farmacocinética , Compuestos de Nitrosourea/farmacocinética , Compuestos Organofosforados/farmacocinética , Adulto , Anciano , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Compuestos de Nitrosourea/uso terapéutico , Compuestos de Nitrosourea/toxicidad , Compuestos Organofosforados/uso terapéutico , Compuestos Organofosforados/toxicidad , Estudios Prospectivos , Factores de TiempoRESUMEN
Docetaxel, a novel anticancer agent, was given to 26 patients by short i.v. infusion (1-2 h) at various dose levels (70-115 mg/m2, the maximum tolerated dose) during 2 phase I studies. Two population analyses, one using NONMEM (nonlinear mixed-effect modeling) and the other using NPML (nonparametric maximum-likelihood), were performed sequentially to determine the structural model; estimate the mean population parameters, including clearance (Cl) and interindividual variability; and find influences of demographic covariates on them. Nine covariates were included in the analyses: age, height, weight, body surface area, sex, performance status, presence of liver metastasis, dose level, and type of formulation. A three-compartment model gave the best fit to the data, and the final NONMEM regression model for Cl was Cl = BSA(Theta1 + Theta02 x AGE), expressing Cl (in liters per hour) directly as a function of body surface area. Only these two covariates were considered in the NPML analysis to confirm the results found by NONMEM. Using NONMEM [for a patient with mean AGE (52.3 years) and mean BSA (1.68 m2)] and NPML, docetaxel Cl was estimated to be 35.6 l/h (21.2 lh-1 m-2) and 37.2 l/h with interpatient coefficients of variations (CVs) of 17.4% and 24.8%, respectively. The intraindividual CV was estimated at 23.8% by NONMEM; the corresponding variability was fixed in NPML in an additive Gaussian variance error model with a 20% CV. Discrepancies were found in the mean volume at steady state (Vss; 83.21 for NPML versus 1241 for NONMEM) and in terminal half-lives, notably the mean t1/2 gamma, which was shorter as determined by NPML (7.89 versus 12.2 h), although the interindividual CV was 89.1% and 62.7% for Vss and t1/2 gamma, respectively. However, the NPML-estimated probability density function (pdf) of t1/2 gamma was bimodal (5 and 11.4 h), probably due to the imbalance of the data. Both analyses suggest a similar magnitude of mean Cl decrease with small BSA and advanced age.
Asunto(s)
Antineoplásicos Fitogénicos/farmacocinética , Paclitaxel/análogos & derivados , Taxoides , Adulto , Anciano , Docetaxel , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Paclitaxel/farmacocinéticaRESUMEN
The pharmacokinetics of pefloxacin (PF) were investigated in a population of 74 intensive care unit patients receiving 400 mg bid as 1-hr infusion using (i) Bayesian estimation (BE) of individual patient parameters followed by multiple linear regression (MLR) analysis and (ii) NONMEM analysis. The data consisted of 3 to 9 PF plasma levels per patient measured over 1 to 3 dosage intervals (total 113) according to four different limited (suboptimal) sampling 3-point protocols. Twenty-nine covariates (including 15 comedications) were considered to explain the interpatient variability. Predicted PF CL for a patient with median covariates values was similar in both BE/MLR and NONMEM analysis (4.02 and 3.92 L/hr, respectively). Bilirubin level and age were identified as the major determinants of PF CL by both approaches with similar predicted magnitude of effects (about 40 and 30% decrease of median CL, respectively). Confounding effects were observed between creatinine clearance (26% decrease of PF CL in the BE/MLR model), simplified acute physiology score (a global score based on 14 biological and clinical variables) (18% decrease of median CL in the NONMEM model) and age (entered in both models) which were highly correlated in our data base. However, both models predicted similar PF CL for actual subpopulations by using actual covariate values. Finally, the NONMEM analysis allowed identification of an effect of weight on CL (decrease of CL for weight < 65 kg) whereas the BE/MLR analysis predicted an increase of CL in patients treated with phenobarbital. In conclusion, both approaches allowed identification of the major risk factors of PF pharmacokinetics in ICU patients. Their potential use at different stages of drug development is discussed.
Asunto(s)
Teorema de Bayes , Pefloxacina/farmacocinética , Farmacocinética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento , Bilirrubina/sangre , Cuidados Críticos , Estudios de Evaluación como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Análisis de Regresión , Programas InformáticosRESUMEN
We have studied the pharmacokinetics of mitoxantrone in cancer patients. Two regimens were used: eight women (10 kinetics) received a 10 min i.v. infusion of 12 mg m-2 of mitoxantrone; seven women (seven kinetics) received high-dose mitoxantrone associated to high-dose alkylating agents and underwent autologous bone marrow transplantation (BMT). High-dose mitoxantrone was administered according to two different protocols. The drug was quantified in plasma with an HPLC assay and pharmacokinetic analysis was performed with the APIS software. Mitoxantrone pharmacokinetics were best described by an open two- (six kinetics) or an open three compartment model (11 kinetics). A large interindivual variability was observed in pharmacokinetic parameters. In the first group of patients, mean +/- s.d. values of clearance, half-life and total distribution volume were 21.41 +/- 14.59 1 h-1, 19.83 +/- 23.95 h, 165.89 +/- 134.75 1 respectively. In the high-dose group, these values were 21.68 +/- 7.30 1 h-1, 50.26 +/- 20.62 h, 413.70 +/- 194.81 1 respectively. Results showed that identification through the open 2-compartment model is certainly related to the small number of late time-points. We therefore think that mitoxantrone pharmacokinetics is generally best described by an open 3-compartment model. Clearance values showed that there was no saturation in mitoxantrone elimination, even at the highest doses. Terminal elimination half-life was probably underestimated because of the lack of late time-points in some kinetics. The half-life is long for patients receiving high-dose mitoxantrone (mean value was 50 h) and it would be hazardous to perform BMT too early after mitoxantrone infusion. Mitoxantrone metabolites were detected in the plasma of five patients receiving high-dose mitoxantrone and in one with hepatic impairment.