Population pharmacokinetics and exploratory pharmacodynamics of ifosfamide according to continuous or short infusion schedules: an n = 1 randomized study.
BACKGROUND
* The optimal infusion duration for ifosfamide remains to be determined. * No differences according to time of infusion have been identified in traditional pharmacokinetic endpoints, such as area under the curve. * The impact on pharmacodynamics has never been modelled or correlated with pharmacokinetics.


CONCLUSIONS
* The pharmacokinetics and pharmacodynamics of ifosfamide and its main metabolites can both be modelled with no influence of infusion duration. * Pharmacodynamic modelling (renal and haematological toxicity) allows further simulations of new schedules with favourable toxicity profiles.


OBJECTIVE
To model the pharmacokinetics and pharmacodynamics of ifosfamide and its key metabolites. The pharmacodynamic parameters included were renal toxicity and myelosuppression measured using urinary beta(2)-microglobulin (BMG) and absolute neutrophil count (ANC), respectively.


METHODS
Seventeen patients were enrolled into an n = 1 randomized trial during two consecutive cycles of ifosfamide 9 g m(-2) during each cycle given by a 3 h or 72 h infusion. Data were analyzed using NONMEM.


RESULTS
Ifosfamide and metabolite concentration-time profiles were described by a one-compartment open-model with auto-induction of clearance. BMG and ANC time-courses were related to ifosfamide concentration via indirect response models.


CONCLUSIONS
This modelling allowed the simulation of weekly schedules of flat doses with favourable myelotoxic profiles.
Brain
Etienne G C
EG
Department of Medical Oncology, René Huguenin Cancer Centre, 35, rue Dailly, 92210 Saint-Cloud, France. e.brain@stcloud-huguenin.org
Rezai
Kevan
K
Lokiec
François
F
Gutierrez
Maya
M
Urien
Saïk
S
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000188:drug therapy*
D018906:Antineoplastic Agents, Alkylating; D007069:Ifosfamide