Pharmacokinetics of oxaliplatin (NSC 266046) alone and in combination with paclitaxel in cancer patients.
Oxaliplatin (OPT), a third-generation platinating agent, is currently being evaluated in a phase II clinical trial in head and neck cancer patients and in a phase I clinical trial in combination with paclitaxel (TXL).


OBJECTIVE
The aim of this study was to investigate the pharmacokinetics and biological correlates of OPT alone as well as the potential pharmacokinetic interaction between OPT and TXL.


METHODS
In the phase II study, OPT was given alone as a 2-h i.v. infusion at 60 mg/m(2) weekly for 4 weeks with the cycle repeated after a 2-week rest. In the concurrent phase I combination trial OPT was also given as a 2-h i.v. infusion, but followed by a 1-h i.v. infusion of TXL, weekly for 4 weeks with the cycle repeated after a 2-week rest. The clinical pharmacokinetics of OPT alone and in combination with TXL were investigated in the first cycle of each treatment protocol. The platinum levels in plasma, plasma ultrafiltrate (PUF) and urine were measured by a fully validated inductively coupled plasma mass spectrometry (ICPMS) method.


RESULTS
In the ten patients receiving OPT alone, the concentration-time profiles of total platinum exhibited a biexponential decline both in plasma and in PUF. The peak levels of platinum were 2.72+/-0.41 microg/ml in plasma and 1.36+/-0.42 microg/ml in PUF at the end of the OPT infusion, and the platinum levels were still detectable at >10 ng/ml 94 h after the OPT infusion. The mean terminal t(1/2) values of total platinum in plasma and in PUF were 58.9 h and 22.8 h, respectively. The AUC of ultrafilterable platinum represented about 10% of that of the total plasma platinum. The platinum levels in the DNA fraction of peripheral white blood cells (WBC) correlated with the platinum levels in PUF ( r=0.77, P<0.01). In the phase I combination study, the dose level of OPT was escalated from 35 mg/m(2) to 60 mg/m(2). The concentration-time profiles of platinum in the combination trial also showed biexponential decay in plasma and in PUF as exhibited by OPT alone. However, the terminal elimination rate constant (beta) of total plasma platinum increased at all dose levels of OPT when combined with TXL at 45 mg/m(2) ( P<0.05). A concomitant increase in clearance (CL) of total plasma platinum was observed at the OPT dose level of 45 mg/m(2) in combination with TXL at 45 mg/m(2). No statistically significant difference in the 24-h urinary elimination of total platinum was detected between the combination groups and the single-agent group. The AUC values of total platinum in PUF were proportional to OPT doses ranging from 35 to 60 mg/m(2), whether OPT was given alone or in combination with TXL.


CONCLUSIONS
OPT clearance may be enhanced by TXL when the two agents are used in combination in patients. The Pt-DNA adduct level in peripheral WBC was found to be a good indicator for oxaliplatin exposure in patients, and should be further exploited for potential tumor drug exposure.
Liu
Jing
J
College of Pharmacy, Ohio State University, Columbus, OH 43210, USA.
Kraut
Eric
E
Bender
Jonathan
J
Brooks
Rebecca
R
Balcerzak
Stanley
S
Grever
Michael
M
Stanley
Harriet
H
D'Ambrosio
Steven
S
Gibson-D'Ambrosio
Ruth
R
Chan
Kenneth K
KK
D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D019540:Area Under Curve; D018736:DNA Adducts / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006258:Head and Neck Neoplasms / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000737:chemistry; D013058:Mass Spectrometry; D009369:Neoplasms / Q000378:metabolism*; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics*; D000077150:Oxaliplatin; D017239:Paclitaxel / Q000493:pharmacokinetics*; D010984:Platinum / Q000097:blood / Q000652:urine; D015203:Reproducibility of Results
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D018736:DNA Adducts; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum; D017239:Paclitaxel