Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function.
OBJECTIVE
To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function.


METHODS
Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, >or=60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m2 oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2.


RESULTS
Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r2 = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (Cmax) were consistent across all renal impairment groups. However, only the beta-half-life was significantly prolonged by renal impairment, with values of 14.0 +/- 4.3, 20.3 +/- 17.7, 29.2 +/- 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m2, the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 +/- 5.03, 39.7 +/- 11.5, and 44.6 +/- 14.6 mug.h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, -5.0 mL/min).


CONCLUSIONS
Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed.
Takimoto
Chris H
CH
Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78245-3217, USA. ctakimot@idd.org
Graham
Martin A
MA
Lockwood
Graham
G
Ng
Chee M
CM
Goetz
Andrew
A
Greenslade
Dennis
D
Remick
Scot C
SC
Sharma
Sunil
S
Mani
Sridhar
S
Ramanathan
Ramesh K
RK
Synold
Timothy W
TW
Doroshow
James H
JH
Hamilton
Anne
A
Mulkerin
Daniel L
DL
Ivy
Percy
P
Egorin
Merrill J
MJ
Grem
Jean L
JL
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D003404:Creatinine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077150:Oxaliplatin; D010984:Platinum / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010984:Platinum; D003404:Creatinine