Oxaliplatin biotransformation and pharmacokinetics: A pilot study to determine the possible relationship to neurotoxicity

Background: Both oxaliplatin and ormaplatin undergo biotransformation to Pt(dach)Cl-2 with studies suggesting a predictive relationship between systemic exposure to Pt(dach)Cl-2 and the severity of the delayed sensory neuropathy associated with ormaplatin (1-3). Studies characterizing the pharmacokinetic parameters of oxaliplatin and Pt(dach)Cl-2 in humans have not been reported. This study was conducted to characterize the pharmacokinetic parameters of oxaliplatin and Pt(dach)Cl-2 and to determine the extent to which oxaliplatin undergoes biotransformation to Pt(dach)Cl-2 in humans. Materials and 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)Cl-2 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/m(2) was 0.33 mug Pt/ml (0.28 to 0.38 mug Pt/ml). The area under the curve (AUC) was 0.79 mug Pt/ml/h (0.62 to 0.88 mug 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)Cl-2 was 0.008 mug Pt/ml (0.004 to 0.014 mug Pt/ml). The C-ss ratio of oxaliplatin to Pt(dach)Cl-2 was 31 (24 to 51). All patients reported acute cold-induced neuropathy following cycles I and 2. Only two patients reported delayed sensory neuropathy (grade 1). Conclusion: 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)Cl-2 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)Cl-2.