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Objective: The population pharmacokinetics and pharmacodynamics of the cytostatic agent ifosfamide and its main metabolites 2- and 3-dechloroethylifosfamide and 4-hydroxyifosfamide were assessed in patients with soft tissue sarcoma., Methods: Twenty patients received 9 or 12 g/m2 ifosfamide administered as a 72-h continuous intravenous infusion. The population pharmacokinetic model was built in a sequential manner, starting with a covariate-free model and progressing to a covariate model with the aid of generalised additive modelling., Results: The addition of the covariates weight, body surface area, albumin, serum creatinine, serum urea, alkaline phosphatase and lactate dehydrogenase improved the prediction errors of the model. Typical pretreatment (mean +/- SEM) initial clearance of ifosfamide was 3.03 +/- 0.18 l/h with a volume of distribution of 44.0 +/- 1.8 l. Autoinduction, dependent on ifosfamide levels, was characterised by an induction half-life of 11.5 +/- 1.0 h with 50% maximum induction at 33.0 +/- 3.6 microM ifosfamide. Significant pharmacokinetic-pharmacodynamic relationships (P = 0.019) were observed between the exposure to 2- and 3-dechloroethylifosfamide and orientational disorder, a neurotoxic side-effect. No pharmacokinetic-pharmacodynamic relationships between exposure to 4-hydroxyifosfamide and haematological toxicities could be observed in this population.

An ELISA method was used to determine N7-methylguanine (N7-MeGua) adducts in DNA of white blood cells from cancer patients treated with the methylating antitumor drug dacarbazine by i.v. administration. From four patients who received dacarbazine only, at dosages of 250, 400 or 800 mg/m2, the blood samples were collected before and several days after administration, and from one patient also during the first few hours. N7-MeGua levels increased rapidly during the first hour after treatment, hardly changed during the following 7 h and decreased during the next days (half-life of approximately 72 h). The adduct levels appeared to be dose-dependent. Blood cells were also analyzed from three patients who received dacarbazine (225 mg/m2) in combination with other chemotherapeutic drugs during three successive days. One of these patients showed a larger initial level of N7-MeGua and a cumulative increase with the dacarbazine dose compared to the other two patients. For several patients adduct levels were monitored during two chemotherapy cycles, for which quite similar data were obtained.

Aims This study investigated the population pharmacokinetics of ifosfamide in 15 patients treated for soft tissue sarcoma with 9 or 12 g m-2 ifosfamide by means of a 72 h continuous i.v. infusion. Methods A model was developed using nonlinear mixed effects modelling (NONMEM) to describe the nonlinear pharmacokinetics of ifosfamide by linking the ifosfamide plasma concentrations to the extent of the autoinduction. Results The proposed model revealed the effect of autoinduction on the disposition of ifosfamide. The initial clearance, volume of distribution, rate constant for enzyme degradation, induction half-life of the enzyme and the ifosfamide concentration at 50% of the maximum inhibition of enzyme degradation were estimated at 2.94 ± 0.27 1 h-1, 43.5 ± 2.9 l, 0.0546 ± 0.0078 h-1, 12.7 h and 30.7 ± 4.8 µM, respectively. Interindividual variabilities of initial clearance, volume of distribution, rate constant for enzyme degradation were 24.5, 23.4 and 22.7%, respectively. Proportional and additive variability not explained by the model were 13.6% and 0.0763 µM, respectively. Conclusions The absence ora lag time for the autoinduction ofifosfamide metabolism could be the result of an immediate inhibition of the enzymatic degradation of CYP3A4 by ifosfamide. By application of the autoinduction model individual pharmacokinetic profiles of patients were described with adequate precision. This model may therefore be used in the future development of a model to individualize dose selection in patients. [ABSTRACT FROM AUTHOR]