Pharmacokinetics of Arsenic Trioxide (As2O3) in Chinese Primary Hepatocarcinoma Patients


Background: Arsenic trioxide (As2O3) induces growth inhibition and apoptosis in human hepatocarcinoma celllines, but little is known about its pharmacology with this cancer in vivo. Pharmacokinetics after As2O3 injectioninto patients with a primary hepatocarcinoma (PHC) were therefore investigated.
Methods: Fourteen patientswere enrolled after providing informed consent and given daily intravenous doses of 10mg for 14 days. ThreemL blood samples were collected before and 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 8 h, 12 h and 24h after the drug infusionon days 1 and 14, as well as once every other day from day 2, for measurement of plasma concentrations usingan atom fluorescent assay and analysis of pharmacokinetic parameters with the PKBP-N1 program.
Results:Data from 13 cases were evaluable, 1 case being excluded due to an insufficient blood sample. Pharmacokineticswere consistent with the characteristics of the two-compartment model, parameters on days 1 and 14 beingclosely similar. The mean plasma maximal peak concentration (Cpmax) was 136.4±89.4μg/L, lasma distributionhalf-life time (T1/2α) was 0.071±0.027 hours, plasma elimination half-life time (T1/2β) was 23.9±18.4 hours,apparent distribution volume (Vd) was 335.1±387.0L, entry distribution volume (Vc) was 20.3±21.3L, systemclearance(CLs) was 8.65±4.26L/h, area under curve (AUC0-t) of concentration-time was 1128.5±510.3 μg·h/L.From days 2 to 14, minimal steady state plasma drug concentration (Cssmin) was in the range of 31.7±9.27μg/Lto 55.6±32.3μg/L for 10 detected patients.
Conclusions: The data suggested that a two-compartment model mostaccurately reflects As2O3 pharmacokinetics in PHC patients. The apparent distribution volume was comparativelylarge and the plasma drug concentration was a little low, with a comparatively long drug elimination half-life,so clinical administration of the drug should be individualized for the best clinical efficacy and prevention ofside effects.