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Pharmacokinetics and Pharmacodynamics of Mesna‐Mediated Plasma Cysteine Depletion
Author(s) -
Smith Patrick F.,
Booker Brent M.,
Creaven Patrick,
Perez Raymond,
Pendyala Lakshmi
Publication year - 2003
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270003260332
Subject(s) - mesna , pharmacokinetics , pharmacodynamics , ifosfamide , glutathione , chemistry , pharmacology , cysteine , medicine , biochemistry , cisplatin , chemotherapy , enzyme
Cellular glutathione (GSH) levels are related to the resistance of tumor cells to platinum and alkylating agents, and depletion of GSH may enhance the activity of these drugs. The pharmacodynamic effects of mesna on depleting plasma cysteine, a GSH precursor, were evaluated in 22 patients as part of a Phase I study. Escalating doses of ifosfamide and mesna were administered; carboplatin was administered to achieve an AUC of 4 mg·min/mL. Plasma samples were collected and assayed by reverse‐phase high‐performance liquid chromatography (HPLC) for total mesna and total cysteine concentrations at 0, 1, 3, 6, 24, 25, 28, and 48 hours. A one‐compartment pharmacokinetic model was fit to the mesna plasma concentrations, using M.A.P. Bayesian estimation (ADAPT II). Pharmacodynamics were evaluated by fitting an inhibitory E max model to the cysteine concentration data. Both the pharmacokinetic (median R 2 = 0.95; range = 0.85–0.98) and pharmacodynamic (median R 2 = 0.96; range = 0.74–1.0) models fit the data well. Mean (coefficient of variation [CV%]) mesna pharmacokinetic parameter estimates were as follows: V ss of 15.3 (29) L/m 2 , CL of 4.6 (29) L/h/m 2 , and half‐life of 2.2 (37) hours. Mean (CV%) pharmacodynamic parameter estimates were as follows: E max of 31.7 (19) μg/mL and EC 50 of 10.3 (52) μg/mL. Mesna produced a rapid, concentration‐dependent reduction in plasma cysteine concentrations that could be adequately characterized by an inhibitory E max pharmacodynamic model. The depletion of plasma cysteine was facilitated by ifosfamide, suggesting a pharmacodynamic interaction between these two agents. Further increases in mesna doses beyond those administered in this study would be unlikely to provide additional benefit.