Oxaliplatin biotransformation and pharmacokinetics: a pilot study to determine the possible relationship to neurotoxicity.
BACKGROUND
Both oxaliplatin and ormaplatin undergo biotransformation to Pt(dach)Cl2 with studies suggesting a predictive relationship between systemic exposure to Pt(dach)Cl2 and the severity of the delayed sensory neuropathy associated with ormaplatin. Studies characterizing the pharmacokinetic parameters of oxaliplatin and Pt(dach)Cl2 in humans have not been reported. This study was conducted to characterize the pharmacokinetic parameters of oxaliplatin and Pt(dach)Cl2 and to determine the extent to which oxaliplatin undergoes biotransformation to Pt(dach)Cl2 in humans.


METHODS
Ten adult patients with metastatic colon cancer received oxaliplatin with or without fluorouracil-based chemotherapy. Blood samples were obtained during cycles 1 and 2. Total platinum, oxaliplatin and Pt(dach)Cl2 in the plasma ultrafiltrate were measured using high performance liquid chromatography and atomic absorption spectrometry. All patients underwent a thorough neurological evaluation after each cycle.


RESULTS
The median steady-state concentration (C(SS)) (interquartile range, 25% to 75%) for oxaliplatin 85 mg/m2 was 0.33 microg Pt/ml (0.28 to 0.38 microg Pt/ml). The area under the curve (AUC) was 0.79 microg Pt/ml/h (0.62 to 0.88 microg Pt/ml/h) and the elimination half-life was 0.32 h (0.27 to 0.46 h). The median C(SS) for Pt(dach)Cl2 was 0.008 microg Pt/ml (0.004 to 0.014 microg Pt/ml). The C(SS) ratio of oxaliplatin to Pt(dach)Cl2 was 31 (24 to 51). All patients reported acute cold-induced neuropathy following cycles 1 and 2. Only two patients reported delayed sensory neuropathy (grade 1).


CONCLUSIONS
The parent drug oxaliplatin is the major active platinum complex detected in plasma ultrafiltrate for at least the first few hours following oxaliplatin infusion in humans. Therefore, the plasma biotransformation products of oxaliplatin are unlikely to contribute to its efficacy or toxicity. In particular, plasma Pt(dach)Cl2 is unlikely to significantly contribute to the delayed sensory neuropathy associated with oxaliplatin, since only a limited amount (<3%) of oxaliplatin undergoes biotransformation to Pt(dach)Cl2.
Shord
Stacy S
SS
School of Pharmacy, University of North Carolina at Chapel Hill, 27599, USA.
Bernard
Stephen A
SA
Lindley
Celeste
C
Blodgett
Andrew
A
Mehta
Viral
V
Churchel
Mary Ann
MA
Poole
Michael
M
Pescatore
Scott L
SL
Luo
Feng R
FR
Chaney
Stephen G
SG
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D001711:Biotransformation; D002945:Cisplatin / Q000493:pharmacokinetics / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009420:Nervous System / Q000187:drug effects / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity*; D000077150:Oxaliplatin; D010865:Pilot Projects
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin