CLINICAL PHARMACOLOGY OF GO

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Pharmacokinetic studies in rats and monkeys identified the hepatobiliary system as the major excretion pathway for single and repeated doses of GO (101). In vitro, numerous metabolites of GO are formed, with biotransformation pathways involving both liver microsomes (oxygenation and demethylation) and the cytosol (acetylation of calicheamicin-g₁^I derivative) (101). In humans, most of the available information on pharmacokinetics and pharmacodynamics is from adult patients who received 1-2 doses of GO at 9 mg/m² given 14-28 days apart on the phase 2 monotherapy trials. A mean maximum plasma concentration of 2.86 ± 1.35 mg/L was measured shortly after the end of the first 2-hour infusion of GO, and near complete saturation of CD33 antigenic sites in the peripheral blood was reached within 3-6 hours (55, 124). The drug elimination half-life proved highly variable, ranging from 72.4 ± 42.0 hours to 45.1 ± 25.2 hours for hP67.6 and calicheamicin, respectively, after the first dose of GO (124). Even 2 weeks after drug administration, circulating levels of GO are sufficient to partially saturate CD33 sites in the peripheral blood (55). Consistently, the area under the curve (AUC) was found to be higher in the second dosing period, with a 94% increase relative to the first administration (239±196 vs. 123±105 mg x h/L) and a corresponding decrease in clearance (0.132±0.153 vs. 0.265±0.229 L/h), perhaps related to the decreased peripheral blood CD33 antigen load at the time of second dosing; the latter would imply that CD33 antigen binding impacts pharmacokinetics as the principal means of elimination of hP67.6 from the plasma. After the second dose of GO, maximum serum concentrations were higher (3.67±1.30 mg/L) and drug elimination longer (half-lives of 93.7±67.4 hours and 61.1±45.4 hours for hP67.6 and calicheamicin-g₁^I, respectively) than after the first dose. The nearly parallel time-concentration plasma curves for hP67.6 and total calicheamicin-g₁^I in most patients suggested that the toxic moiety remained largely bound to the antibody; indeed, free calicheamicin-g₁^I could only be measured for a relatively short time following the end of drug infusion (124). Of note, although inter-patient variability is high, the fundamental pharmacokinetics do not appear to differ in relationship to age, gender, or ethnicity (124-127), and, among a set of 59 patients, no relationship was found between the pharmacokinetic parameters and response (124).