The 2 most commonly used oxazaphosphorines are cyclophosphamide and ifosfamide, although other bifunctional mustard analogues continue to be investigated. The pharmacology of these agents is determined by their metabolism, since the parent drug is relatively inactive. For cyclophosphamide, elimination of the parent compound is by activation to the 4-hydroxy metabolite, although other minor pathways of inactivation also play a role. Ifosfamide is inactivated to a greater degree by dechloroethylation reactions. More robust assay methods for the 4-hydroxy metabolites may reveal more about the clinical pharmacology of these drugs, but at present the best pharmacodynamic data indicate an inverse relationship between plasma concentration of parent drug and either toxicity or antitumour effect. The metabolism of cyclophosphamide is of particular relevance in the application of high dose chemotherapy. The activation pathway of metabolism is saturable, such that at higher doses (greater than 2 to 4 g/m2) a greater proportion of the drug is eliminated as inactive metabolites. However, both cyclophosphamide and ifosfamide also act to induce their own metabolism. Since most high dose regimens require a continuous infusion or divided doses over several days, saturation of metabolism may be compensated for, in part, by auto-induction. Although a quantitative distinction may be made between the cytochrome P450 isoforms responsible for the activating 4-hydroxylation reaction and those which mediate the dechloroethylation reactions, selective induction of the activation pathway, or inhibition of the inactivating pathway, has not been demonstrated clinically. Mathematical models to describe and predict the relative contributions of saturation and autoinduction to the net activation of cyclophosphamide have been developed. However, these require careful validation and may not be applicable outside the exact regimen in which they were derived. A further complication is the chiral nature of these 2 drugs, with some suggestion that one enantiomer may have a favourable profile of metabolism over the other. That the oxazaphosphorines continue to be the subject of intensive investigation over 30 years after their introduction into clinical practice is partly because of their antitumour activity. Further advances in analytical and molecular pharmacological techniques may further optimise their use and allow rational design of more selective analogues.

Indisulam (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide, GOAL, E7070) is a novel anti-cancer drug currently in phase II clinical development for the treatment of solid tumors. Phase I dose-escalation studies were conducted comparing four treatment schedules. Neutropenia and thrombocytopenia were dose limiting in all schedules. The aim of this study was to describe the extent and the time course of the hematological toxicity and its possible schedule dependency using a semi-physiological model. Data from 142 patients were analyzed using NONMEM. The semi-physiological model comprised a progenitor blood cell compartment, linked to the central circulation compartment, through 3 transition compartments representing the maturation chain in the bone marrow. Plasma concentrations of the drug were assumed to reduce the proliferation rate in the progenitor compartment according to a linear function. A feedback mechanism was included in the model representing the rebound effect of endogenous growth factors. The model was validated using a posterior predictive check. The model adequately described the extent and time course of neutropenia and thrombocytopenia. The mean transition time (MTT, i.e. maturation time in bone marrow) of neutrophils was increased by 47% in patients who received indisulam as a weekly dose administered for four out of every six weeks. For platelets, MTT was increased by 33% in patients who received this schedule and also in patients who received a continuous 120-h infusion. The validation procedure indicated that the model adequately predicts the nadir value of neutrophils and platelets and the time to reach this nadir. A semi-physiological model was successfully applied to describe the time course and extent of the neutropenia and thrombocytopenia after indisulam administration for four treatment schedules.

1 Cyclophosphamide pharmacokinetics were measured in 38 children with cancer. 2 A high degree of inter-patient variation was seen in all pharmacokinetic parameters. Cyclophosphamide half-life varied between 1.1 and 16.8 h, clearance varied between 1.2 and 10.61 h-l m P 2 and volume of distribution varied between 0.26 and 1.48 1 kg-'. 3 The half-life of cyclophosphamide was prolonged at high dose levels (P = 0.008). 4 Children who had received prior treatment with dexamethasone showed a mean increase in clearance of 2.5 1 h-l m P 2 (P=O.OOl) presumably as a result of CYP450 enzyme induction. 5 Treatment with allopurinol or chlorpromazine was associated with a significant increase in cyclophosphamide half-life (P < 0.001 in both cases). 6 Dose and concurrent treatment may influence cyclophosphamide metabolism in vivo and thus potentially alter the drugs therapeutic effect.

Purpose: The purpose of our study was to determine whether variation in cyclophosphamide metabolism influences the incidence of recurrence among children receiving chemotherapy for B-cell non-Hodgkin's lymphoma.Experimental Design: The pharmacokinetics and metabolism of cyclophosphamide were studied during a single course of treatment in 36 children receiving a uniform chemotherapy regimen for B-cell non-Hodgkin's lymphoma and were analyzed in terms of disease recurrence and hematological toxicity.Results: At a median follow-up of 43 months (range, 17-98 months), six children had developed recurrent disease, giving an overall disease-free survival of 83%. The median clearance of cyclophosphamide in patients who remain free of B-cell non-Hodgkin's lymphoma was 3.7 liter/ h/m 2 (range, 2.3-5.0 liter/h/m 2 ), compared with 2.2 (range, 1.5-2.5 liter/h/m 2 ) in those with disease recurrence. Likelihood of recurrence was higher in patients with low clearance (<3.5 liter/h/m 2 ) of cyclophosphamide (P < 0.01) and positively related to detection of the inactive metabolites carboxyphosphamide and dechloroethylcyclophosphamide in plasma (P ‫؍‬ 0.01). There was no correlation between cyclophosphamide metabolism and hematological toxicity.Conclusions: Inadequate clearance of cyclophosphamide to active metabolites is associated with increased risk of recurrence of B-cell non-Hodgkin's lymphoma in children. Modified chemotherapy strategies should be considered in patients who exhibit low rates of clearance of the parent drug and/or extensive production of inactive metabolites.