title: Time-dependent pharmacodynamic models in cancer chemotherapy: population pharmacodynamic model for glutathione depletion following modulation by buthionine sulfoximine (BSO) in a Phase I trial of melphalan and BSO.
abstract: The development of time-dependent pharmacodynamic models in cancer chemotherapy has been extremely limited. A population approach was used to develop such a model to describe the effect of buthionine sulfoximine (BSO), via its active S-isomer (S-BSO), on glutathione (GSH) depletion in peripheral mononuclear cells. The Phase I trial utilized escalating doses of BSO, from 5 to 17 gm/m2, as a multiple infusion regimen. The population model consisted of a linear 2-compartment pharmacokinetic model coupled to an indirect response model. The indirect response model consisted of a GSH compartment with input and output rate processes that are modulated as a function of S-BSO and GSH concentrations. The model predicted the observed gradual depletion of GSH, a nadir at approximately 30 h after the last dose of BSO, and a return to baseline GSH levels. On the basis of an IC50 estimate of about 1.6 microM for inhibition of gamma-glutamylcysteine synthetase, the target enzyme of BSO, the population model predicted near identical GSH concentration time profiles over the dose range studied. Time-dependent pharmacodynamic models are seen as a powerful means to design dosing regimens and to provide a mathematical platform for mechanistic based models.
authors.affiliation: Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Gallo
authors.forename: J
authors.initials: J
authors.lastname: Brennan
authors.forename: T C
authors.initials: TC
authors.lastname: Hamilton
authors.forename: T
authors.initials: T
authors.lastname: Halbherr
authors.forename: P B
authors.initials: PB
authors.lastname: Laub
authors.forename: R F
authors.initials: RF
authors.lastname: Ozols
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019328:Buthionine Sulfoximine; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D008558:Melphalan / Q000008:administration & dosage*; D008717:Methionine Sulfoximine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D009369:Neoplasms / Q000188:drug therapy*; D009504:Neutrophils / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D004791:Enzyme Inhibitors; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D005978:Glutathione; D008558:Melphalan