Pharmacotherapeutic group: other antineoplastic agents, platinum compounds.
ATC code: L01XA03.
Pharmacology: Pharmacodynamics: Oxaliplatin is an antineoplastic agent belonging to a new class of platinum 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'] [ethanediato(2-)-kO
1, kO
2] platinum.
Oxaliplatin exhibits a wide spectrum of both
in vitro cytotoxicity and
in vivo antitumor activity in various tumor model systems, including human colorectal cancer models.
Oxaliplatin has also shown
in vitro and
in vivo efficacy in various cisplatin-resistant cell lines. Synergistic cytotoxic activity with 5-fluorouracil (5-FU) has been demonstrated both
in vitro and
in vivo.
Studies on the mechanism of action, which has however not been completely elucidated, have shown that the aqua derivatives resulting from the biotransformation of oxaliplatin interact with DNA to form both intra- and inter-strand cross-links, resulting in interruption of DNA synthesis, which underlies the cytotoxic and antitumor effects.
In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m
2 repeated every two weeks) in combination with 5-fluorouracil/folinic acid (5-FU/folinic acid) (5-FU/FA) has been reported in three clinical studies: as 1st-line treatment, in a 2-arm, comparative, phase III study (EFC2962), 420 patients were randomized either to 5-FU/FA alone (LV5FU2, N=210) or to oxaliplatin+5-FU/FA (FOLFOX4, N=210); in pretreated patients, in a 3-arm, comparative, phase III study (EFC4584), 821 patients, refractory to the irinotecan (CPT-11) + 5-FU/FA combination, were randomized to 5-FU/FA alone (LV5FU2, N=275), to single-agent oxaliplatin (N=275), or to oxaliplatin+5-FU/FA (FOLFOX4, N=271); finally, in a non-controlled phase II study (EFC2964), patients refractory to 5-FU/FA alone were treated with the oxaliplatin+5-FU/FA combination (FOLFOX4, N=57). (See Table 1, Table 2 and Table 3.)
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In pretreated patients who were symptomatic at baseline (EFC4584), a higher proportion of those treated with oxaliplatin + 5-FU/FA experienced a significant improvement of their disease-related symptoms, compared to those treated with 5-FU/FA alone (27.7% vs. 14.6%, p ≤ 0.0033).
In non-pretreated patients (EFC2962), no statistically significant difference between the two treatment groups was found in terms of quality of life.
However, the quality of life scores were generally better in the control group for overall performance status and pain, and less favorable in the oxaliplatin group for nausea/vomiting.
Concerning adjuvant treatment, the comparative, phase III MOSAIC study (EFC3313), included 2,246 patients (899 stage II/Dukes' B2 and 1,347 stage III/Dukes' C). After complete resection of the primary colon cancer tumor patients were randomized either to 5-FU/FA alone (LV5FU2, N=1,123 [B2/C = 448/675]) or to the combination of oxaliplatin + 5-FU/FA (FOLFOX4, N=1,123 [B2/C = 451/672]). (See Table 4.)
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The study demonstrated an overall significant superiority in 3-year disease-free survival for the oxaliplatin plus 5-FU/FA combination (FOLFOX4) compared to 5-FU/FA alone (LV5FU2). (See Table 5.)
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Overall Survival (ITT analysis): At the time of the 3-year disease-free survival analysis, which was the primary endpoint of the MOSAIC study, 85.1% of the patients were still alive in the FOLFOX4 arm versus 83.8% in the LV5FU2 arm. This showed an overall reduction in mortality risk of 10% in favor of FOLFOX4, without reaching statistical significance (hazard ratio = 0.90).
Results were 92.2% versus 92.4% in the stage II (Dukes' B2) sub-group (hazard ratio = 1.01) and 80.4% versus 78.1% in the stage III (Dukes' C) sub-group (hazard ratio = 0.87), for FOLFOX4 and LV5FU2, respectively.
Oxaliplatin as single-agent therapy was studied in children in 2 phase I studies (69 patients) and in 2 phase II studies (166 patients). A total of 235 pediatric patients (age range: 7 months to 22 years) with solid tumors were treated.
The efficacy of oxaliplatin administered alone was not established in the treated population. Enrollment in these two phase II studies was stopped due to lack of tumor response.
Pharmacokinetics: The pharmacokinetics of the various active metabolites have not been determined. The table as follows indicates the pharmacokinetic parameters of ultrafiltered platinum, i.e. all the unbound, active and inactive forms of platinum, following a two-hour infusion of oxaliplatin 130 mg/m
2 every three weeks for 1 to 5 cycles, and of oxaliplatin 85 mg/m
2 every two weeks for 1 to 3 cycles: See Table 6.
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Following a 2-hour infusion, 15% of administered platinum is found in the systemic circulation, the remaining 85% having been rapidly distributed into tissues or excreted in 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 of platinum was observed in plasma ultrafiltrate following an 85 mg/m
2 infusion every 2 weeks or a 130 mg/m
2 infusion every 3 weeks, and steady state was reached in cycle 1 in this matrix. Inter- and intra-individual variability was generally low.
In vitro, metabolites result from non-enzymatic degradation and there is no evidence of cytochrome P450-mediated biotransformation of the diaminocyclohexane (DACH) ring.
Oxaliplatin is highly metabolized in humans; no parent drug was detectable in plasma ultrafiltrate following a 2-hour infusion. Several cytotoxic metabolites including the monochloro-, dichloro- and diaquo-DACH platinum forms have been identified in the systemic circulation, as have a number of inactive metabolites at later timepoints.
Platinum is primarily excreted in the urine, with clearance mainly occurring in the 48 hours following administration.
At Day 5, approximately 54% of the dose is recovered in the urine and less than 3% in the feces.
A significant decrease in clearance from 17.6 ± 2.18 l/h to 9.95 ± 1.91 l/h has been observed in patients with renal failure together with a statistically significant decrease in volume of distribution from 330 ± 40.9 to 241 ± 36.1 l. The effect of severe renal failure on platinum clearance has not been studied.
The effect of renal failure on the bioavailability of oxaliplatin has been studied in patients with varying degrees of renal impairment. Oxaliplatin was administered at a dose of 85 mg/m
2 in the control group with normal renal function (creatinine clearance >80 ml/min, n = 12) and in patients with mild renal failure (creatinine clearance = 50 to 80 ml/min, n = 13) and moderate renal failure (creatinine clearance = 30 to 49 ml/min, n = 11) and at a dose of 65 mg/m
2 in patients with severe renal failure (creatinine clearance <30 ml/min, n = 5).
Median exposure was 9, 4, 6, and 3 cycles, respectively, and pharmacokinetic data at cycle 1 were obtained in groups of 11, 13, 10 and 4 patients, respectively.
There was an increase in plasma ultrafiltrate (PUF) platinum AUC, AUC/dose and a decrease in CL and total and renal Vss with increased renal impairment, particularly in the (small) group of patients with severe renal failure: point estimates (90% CI) of estimated mean ratios by renal function 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 to moderate renal failure and severe renal impairment, respectively.
Elimination of oxaliplatin is significantly correlated with 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 impairment. Total body clearance of PUF platinum was therefore reduced by 26% in patients with mild failure, 57% in patients with moderate renal failure, and 79% in patients with severe renal failure, compared with patients with normal function.
Renal clearance of PUF platinum was reduced by 30% in patients with mild renal failure, 65% in moderate renal failure, and 84% in severe renal failure, compared with patients with normal function.
There was an increase in the beta-half-life of PUF platinum with increased renal failure, mainly in the severe renal failure group. Despite the small number of patients with severe renal failure, these data should be taken into account when prescribing oxaliplatin to patients with renal failure (see Dosage & Administration, Contraindications and Precautions).
Toxicology: Preclinical safety data: The target organs identified in the species used in preclinical studies (mice, rats, dogs and/or monkeys) in single-dose and repeated-dose studies included bone marrow, the gastrointestinal system, the kidney, the testes, the nervous system and the heart. The toxicities in the target organs observed in animals are similar to those observed with other platinum-based agents and other cytotoxic drugs, which interact with DNA, used in the treatment of cancer in humans, with the exception of those on the heart. Effects on the heart were only observed in the dog and included electrophysiological abnormalities with lethal ventricular fibrillation. Cardiotoxicity is considered to be specific to dogs, not only because it was only observed in this species, but also because doses similar to lethal doses in the dog (150 mg/m
2) were well tolerated in humans. Preclinical studies using rat sensory neurons suggested that the oxaliplatin-induced acute neurosensory symptoms may be related to an interaction with voltage-gated Na+ channels.
Oxaliplatin is mutagenic and clastogenic in mammalian cells and has demonstrated embryo-fetal toxicity in rats. Although no studies have been performed concerning its carcinogenic potential, oxaliplatin is considered to be probably carcinogenic.