Pharmacokinetics of oxaliplatin in patients with normal versus impaired renal function

Purpose: The pharmacokinetics (PK) of platinum was investigated and compare d in patients with normal (NRF) and impaired renal function (TRF), after th ey had received oxaliplatin at the recommended dose and delivery modality. Methods: Oxaliplatin was administered at 130 mg/m(2) as a 2-h infusion with out hydration. Patients were recruited and classified according to their cr eatinine clearance (CrCl > or < 60 ml/min), calculated using the Cockcroft and Gault formula. Blood was taken for PK analysis during and after the inf usion. Twenty-three patients were included in the PK analysis (13 NRF and 1 0 IRF). At inclusion, the median CrCls were 70.5 ml/min (range 63-136) for the NRF group and 42 ml/min (range 27-57) for the IRF group. Three patients underwent a second course of treatment and additional blood sampling for a nalysis. Platinum levels in the plasma, ultrafiltrate and red blood cells ( RBCs) were measured using flameless atomic absorption spectrophotometry (FA AS). Results: Following the administration of oxaliplatin, platinum binding to plasma proteins and RBCs was rapid and extensive; at the end of the 2-h infusion, 27% of the platinum in the plasma remained free (40% bound to RB Cs, 33% bound to plasma proteins). Neither the mean maximal concentration ( C-max) of total platinum in the plasma, the mean C-max of ultrafilterable p latinum in the plasma, nor the maximal platinum content in the RBCs differe d significantly between the two groups (2.59 vs 2.58 mu g/ml, 1.09 vs 1.28 mu g/ml and 2.06 vs 2.17 mu g/ml, respectively, for patients with NRF vs IR F). After the end of the infusion, levels of total and free (ultrafilterabl e) platinum in the:plasma declined biexponentially. The plasma clearance of both total and free platinum as well as the area under the curve (AUC) of the free platinum fraction correlate with the calculated CrCl (P = 9 x 10(- 3), P = 3.1 x 10(-5) and P = 9 x 10(-6), respectively). After a single cour se of oxaliplatin, toxicities reported in the two groups of patients were s imilar. Conclusions: Our results are in agreement with the in vitro data co ncerning the extensive binding of oxaliplatin to plasma proteins and RBCs. They also reveal a strong negative correlation between free drug plasma ava ilability and renal function, with a. corresponding positive correlation be tween clearance of the plasmatic platinum and renal function. Thus, renal i mpairment entails a greater overall exposure to platinum in the plasma. How ever, this study failed to elicit any relationship between moderate renal i mpairment and the acute toxicity associated with oxaliplatin.