Pharmacotherapeutic group: other antineoplastic agents, platinum compounds.
ATC code: L01XA 03.
Pharmacology: Pharmacodynamics: Mechanism of action: 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)-[(1
R,2
R)-Cyclohexane-1,2-diamine-k
N, k
N'] [ethanedioato(2-)-k
O1, k
O2] 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 (5-FU) 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.
Clinical efficacy and safety: In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m
2 repeated every two weeks) combined with 5-fluorouracil (5-FU)/folinic acid (5-FU/FA) is reported in three clinical studies: In front-line treatment, the 2-arm comparative phase III EFC2962 study randomised 420 patients either to 5-FU/FA alone (LV5FU2, N=210) or the combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=210); In pretreated patients, the comparative three arms phase III study EFC4584 randomised 821 patients refractory to an irinotecan (CPT-11) + 5-FU/FA combination either to 5-FU/FA alone (LV5FU2, N=275), oxaliplatin single agent (N=275), or combination of oxaliplatin with 5-FU/FA (FOLFOX4, N=271); Finally, the uncontrolled phase II EFC2964 study included patients refractory to 5-FU/FA alone, that were treated with the oxaliplatin and 5-FU/FA combination (FOLFOX4, N=57).
The two randomised clinical trials, EFC2962 in front-line therapy and EFC4584 in pretreated patients, demonstrated a significantly higher response rate and a prolonged progression free survival (PFS)/time to progression (TTP) as compared to treatment with 5-FU/FA alone.
In EFC4584 performed in refractory pretreated patients, the difference in median overall survival (OS) between the combination of oxaliplatin and 5-FU/FA did not reach statistical significance. (See Tables 1, 2 and 3.)
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Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In pretreated patients (EFC4584), who were symptomatic at baseline, a higher proportion of those treated with oxaliplatin and 5-FU/FA experienced a significant improvement of their disease-related symptoms compared to those treated with 5 FU/FA alone (27.7% versus 14.6% p = 0.0033).
In non-pretreated patients (EFC2962), no statistically significant difference between the two treatment groups was found for any of the quality of life dimensions.
However, the quality of life scores were generally better in the control arm for measurement of global health status and pain and worse in the oxaliplatin arm for nausea and vomiting.
In the adjuvant setting, the MOSAÏC comparative phase III study (EFC3313) randomised 2246 patients (899 stage II/Dukes B2 and 1347 stage III/Dukes C) further to complete resection of the primary tumour of colon cancer either to 5-FU/FA alone (LV5FU2, N=1123 (B2/C = 448/675) or to combination of oxaliplatin and 5-FU/FA (FOLFOX4, N=1123 (B2/C) = 451/672). (See Table 4.)
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The study demonstrated an overall significant advantage in 3-year disease free survival for the oxaliplatin and 5-FU/FA combination (FOLFOX4) over 5-FU/FA alone (LV5FU2). (See Table 5.)
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Overall Survival (ITT analysis): At time of the analysis of the 3-year disease free survival, which was the primary endpoint of the MOSAIC trial, 85.1% of the patients were still alive in the FOLFOX4 arm versus 83.8% in the LV5FU2 arm. This translated into an overall reduction in mortality risk of 10% in favour of FOLFOX4 not reaching statistical significance (hazard ratio = 0.90).
The figures were 92.2% versus 92.4% in the stage II (Dukes B2) sub-population (hazard ratio = 1.01) and 80.4% versus 78.1% in the stage III (Dukes C) sub-population (hazard ratio = 0.87), for FOLFOX4 and LV5FU2, respectively.
Paediatric population: Oxaliplatin single agent has been evaluated in paediatric population in 2 Phase I (69 patients) and 2 Phase II (166 patients) studies. A total of 235 paediatric patients (7 months-22 years of age) with solid tumours have been treated. The effectiveness of oxaliplatin single agent in the paediatric populations treated has not been established.
Accrual in both Phase II studies was stopped for lack of tumours response.
Pharmacokinetics: Adsorption and distribution: 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/m
2 every three weeks for 1 to 5 cycles and oxaliplatin at 85 mg/m
2 every two weeks for 1 to 3 cycles are as follows: See Table 6.
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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/m
2 every two weeks or 130 mg/m
2 every three weeks and steady state was attained by cycle one in this matrix. Inter- and intra-subject variability is generally low.
Biotransformations: 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 active substance 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.
Elimination: 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.
Special populations: Renal impairment: 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/m
2 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 65 mg/m
2 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 estimates (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 (see Dosage & Administration, Contraindications and Precautions).
Toxicology: Preclinical safety data: The target organs identified in preclinical species (mice, rats, dogs, and/or monkeys) in single- and multiple-dose studies included the bone marrow, the gastrointestinal system, the kidney, the testes, the nervous system, and the heart. The target organ toxicities observed in animals are consistent with those produced by other platinum-containing medicinal products and DNA-damaging, cytotoxic medicinal products used in the treatment of human cancers with the exception of the effects produced on the heart. Effects on the heart were observed only in the dog and included electrophysiological disturbances with lethal ventricular fibrillation. Cardiotoxicity is considered specific to the dog not only because it was observed in the dog alone but also because doses similar to those producing lethal cardiotoxicity in dogs (150 mg/m
2) were well-tolerated by humans.
Preclinical studies using rat sensory neurons suggest that the acute neurosensory symptoms related to Oxaliplatin may involve an interaction with voltage-gated Na
+ channels.
Oxaliplatin was mutagenic and clastogenic in mammalian test systems and produced embryo-fetal toxicity in rats. Oxaliplatin is considered a probable carcinogen, although carcinogenic studies have not been conducted.