other antineoplastic agents, platinum compounds. ATC Code:
Oxaliplatin is an antineoplastic active substance belonging to a new class of platinum-based compounds in which the platinum atom is complexed with 1,2-diaminocyclohexane ("DACH") and an oxalate group.
Oxaliplatin is a single enantiomer, (SP-4-2)-[(1R,2R)-Cyclohexane-1,2-diamine-kN, kN'] [ethanedioato(2-)-kO1
] platinum. Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo
antitumour activity in a variety of tumour model systems including human colorectal cancer models. Oxaliplatin also demonstrates in vitro
and in vivo
activity in various cisplatin resistant models. A synergistic cytotoxic action has been observed in combination with 5-fluorouracil both in vitro
and in vivo
Studies on the mechanism of action of oxaliplatin, although not completely elucidated, show that the aqua-derivatives resulting from the biotransformation of oxaliplatin, interact with DNA to form both inter and intra-strand cross-links, resulting in the disruption of DNA synthesis leading to cytotoxic and antitumour effects.
The pharmacokinetics of individual active compounds have not been determined. The pharmacokinetics of ultrafiltrable platinum, representing a mixture of all unbound, active and inactive platinum species, following a two-hour infusion of oxaliplatin at 130 mg /m2
every three weeks for 1 to 5 cycles and oxaliplatin at 85 mg/m2
every two weeks for 1 to 3 cycles are as follows: See Table 1.
Click on icon to see table/diagram/image
, and Cmax values were determined on Cycle 3 (85 mg/m2
) or cycle 5 (130 mg/m2
). Mean AUC, Vss and CL values were determined on Cycle 1.
, AUC, AUC0-48
, Vss and CL values were determined by non-compartmental analysis. t½
β, and t½
γ, were determined by compartmental analysis (Cycles 1-3 combined).
At the end of a 2-hour infusion, 15% of the administered platinum is present in the systemic circulation, the remaining 85% being rapidly distributed into tissues or eliminated in the urine. Irreversible binding to red blood cells and plasma, results in half-lives in these matrices that are close to the natural turnover of red blood cells and serum albumin. No accumulation was observed in plasma ultrafiltrate following 85 mg/m2
every two weeks or 130 mg/m2
every three weeks and steady state was attained by cycle one in this matrix. Inter- and intra-subject variability is generally low.
Biotransformation in vitro
is considered to be the result of non-enzymatic degradation and there is no evidence of cytochrome P450-mediated metabolism of the diaminocyclohexane (DACH) ring. Oxaliplatin undergoes extensive biotransformation in patients, and no intact drug was detectable in plasma ultrafiltrate at the end of a 2h-infusion. Several cytotoxic biotransformation products including the monochloro-, dichloro- and diaquo-DACH platinum species have been identified in the systemic circulation together with a number of inactive conjugates at later time points. Platinum is predominantly excreted in urine, with clearance mainly in the 48 hours following administration.
By day 5, approximately 54% of the total dose was recovered in the urine and <3% in the faeces. The effect of renal impairment on the disposition of oxaliplatin was studied in patients with varying degrees of renal function. Oxaliplatin was administered at a dose of 85 mg/m2
in the control group with a normal renal function (CLcr >80 ml/min, n=12) and in patients with mild (CLcr = 50 to 80 ml/min, n=13) and moderate (CLcr = 30 to 49 ml/min, n=11) renal impairment, and at a dose of 65mg/m2
in patients with severe renal impairment (CLcr <30 ml/min, n=5). Median exposure was 9, 4, 6, and 3 cycles, respectively, and PK data at cycle 1 were obtained in 11, 13, 10, and 4 patients respectively.
There was an increase in plasma ultrafiltrate (PUF) platinum AUC, AUC/dose and a decrease in total and renal CL and Vss with increasing renal impairment especially in the (small) group of patients with severe renal impairment: point estimate (90% CI) of estimated mean ratios by renal status versus normal renal function for AUC/dose were 1.36 (1.08, 1.71), 2.34 (1.82, 3.01) and 4.81 (3.49, 6.64) for patients with mild and moderate and in severe renal failure respectively.
Elimination of oxaliplatin is significantly correlated with the creatinine clearance. Total PUF platinum CL was respectively 0.74 (0.59, 0.92), 0.43 (0.33, 0.55) and 0.21 (0.15, 0.29) and for Vss respectively 0.52 (0.41, 0.65), 0.73 (0.59, 0.91) and 0.27 (0.20, 0.36) for patients with mild, moderate and severe renal failure respectively. Total body clearance of PUF platinum was therefore reduced by respectively 26% in mild, 57% in moderate, and 79% in severe renal impairment compared to patients with normal function.
Renal clearance of PUF platinum was reduced in patients with impaired renal function by 30% in mild, 65% in moderate, and 84% in severe renal impairment compared to patients with normal function.
There was an increase in beta half life of PUF platinum with increasing degree of renal impairment mainly in the severe group. Despite the small number of patients with severe renal dysfunction, these data are of concern in patients in severe renal failure and should be taken into account when prescribing oxaliplatin in patients with renal impairment.