Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties
Pharmacotherapeutic group: Other antineoplastic agents, platinum compounds.
ATC code: L01XA 03.

Mechanism of action
Oxaliplatin is an antineoplastic medicinal product 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, the cis-[oxalato(trans-l-1,2- DACH)platinum].
Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo antitumor activity in a variety of tumor 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 antitumor effects.
Clinical efficacy and safety
In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m 2 repeated every 2 weeks) combined with 5-fluorouracil/folinic acid (5-FU/FA) is reported in 3 clinical studies: 

- In a 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 3 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, who were treated with the oxaliplatin and 5-FU/FA combination (FOLFOX4, N=57).
The 2 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 versus 5-FU/FA did not reach statistical significance.

Response Rate Under FOLFOX4 versus LV5FU2
Response rate, % (95% CI)        LV5FU2           FOLFOX4                           Oxaliplatin independent radiological review                                                     single agent ITT analysis
Front-line treatment               22                 49
(EFC2962                          (16-27)           (42-56)
NA*
Response assessment every 8
P value = 0.0001 weeks
Pretreated patients                 0.7               11.1
(EFC4584                         (0.0-2.7)         (7.6-15.5)
1.1
(refractory to CPT-11+ 5-FU/FA)
(0.2-3.2)
Response assessment every 6           P value < 0.0001 weeks
Pretreated patients
EFC2964
23
(refractory to 5-FU/FA)            NA*                                                  NA* (13-36)
Response assessment every 12 weeks
*NA: Not applicable


Median Progression-free Survival (PFS) / Median Time to Progression (TTP) FOLFOX4 versus LV5FU2
Median PFS/TTP, months                LV5FU2           FOLFOX4             Oxaliplatin (95% CI)                                                                   single agent Independent radiological review
ITT analysis
Front-line treatment                     6.0               8.2
EFC2962 (PFS)                         (5.5-6.5)         (7.2-8.8)              NA* Log-rank P value = 0.0003
Pretreated patients                      2.6               5.3
2.1
EFC4584 (TTP)                         (1.8-2.9)         (4.7-6.1)
(1.6-2.7)
(refractory to CPT-11+ 5-FU/FA)        Log-rank P value < 0.0001
Pretreated patients
5.1
EFC2964                                 NA*                                    NA* (3.1-5.7)
(refractory to 5-FU/FA)
*NA: Not applicable

Median Overall Survival (OS) Under FOLFOX4 versus LV5FU2
Median OS, months                   LV5FU2        FOLFOX4                         Oxaliplatin (95% Cl) ITT analysis                                                             single agent 
  Front-line treatment                        14.7               16.2
EFC2962                                  (13.0-18.2)       (14.7-18.2)                  NA* Log-rank P value = 0.12
Pretreated patients                          8.8                9.9
8.1
EFC4584 (refractory to CPT-11+            (7.3-9.3)         (9.1-10.5) (7.2-8.7)
5-FU/FA)                                    Log-rank P value = 0.09
Pretreated patients                                            10.8
NA*                                         NA*
EFC2964 (refractory to 5-FU/FA)                             (9.3-12.8) *NA: Not applicable

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% vs. 14.6%, p = 0.0033).
In non-pretreated patients (EFC2962), no statistically significant difference between the 2 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 MOSAIC comparative phase III study (EFC3313) randomised 2,246 patients (899 stage II/Duke’s B2 and 1347 stage III/Duke’s C) further to complete resection of the primary tumor 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).

EFC 3313-3-year Disease-free Survival (ITT analysis)* for the Overall Population Treatment arm                                    LV5FU2                        FOLFOX4 Percent 3-year disease-free                         73.3                          78.7 survival (95% CI)                               (70.6-75.9)                    (76.2-81.1) Hazard ratio (95% CI)                                                0.76 (0.64-0.89)
Stratified log-rank test                                          P= 0.0008 * Median follow-up at 44.2 months (all patients followed for at least 3 years).

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).


EFC 3313-3-year Disease-free Survival (ITT analysis)* according to stage of disease Patient stage                                   Stage II (Duke’s B2)           Stage III (Duke’s C) Treatment arm                                  LV5FU2       FOLFOX4           LV5FU2       FOLFOX4 Percent 3-year disease-free survival             84.3           87.4            65.8           72.8 (95% CI)                                     (80.9-87.7) (84.3-90.5) (62.1-69.5) (69.4-76.2) Hazard ratio (95% CI)                                    0.79                           0.75 (0.57-1.09)                    (0.62-0.90)
Log rank test                                         P = 0.151                      P = 0.002 * Median follow-up at 44.2 months (all patients followed for at least 3 years).

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 (Duke’s B2) sub- population (hazard ratio = 1.01) and 80.4% versus 78.1% in the stage III (Duke’s 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 tumors 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 tumor response.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

The pharmacokinetics of individual active compounds has not been determined. The pharmacokinetics of ultrafiltrable platinum, representing a mixture of all unbound, active and inactive platinum species, following a 2-hour infusion of oxaliplatin at 130 mg/m2 every 3 weeks for 1 to 5 cycles and oxaliplatin at 85 mg/m2 every
2 weeks for 1 to 3 cycles is as follows:
Summary of Platinum Pharmacokinetic Parameter Estimates in Ultrafiltrate Following Multiple Doses of Oxaliplatin at 85 mg/m2 Every 2 Weeks or at 130 mg/m2 Every 3 Weeks Dose               Cmax     AUC0-48      AUC          t1/2α      t1/2β      t1/2γ       Vss       CL µg/ml     µg·h/ml µg·h/ml            h          h          h           l         l/h 85 mg/m2
Mean              0.814       4.19       4.68         0.43      16.8       391         440       17.4 
SD               0.193       0.647        1.40       0.35       5.74        406         199        6.35 130 mg/m2
Mean             1.21         8.20        11.9       0.28       16.3        273         582        10.1 
SD               0.10         2.40        4.60       0.06       2.90        19.0        261        3.07 
Mean AUC0-48 and Cmax values were determined on Cycle 3 (85 mg/m2) or Cycle 5 (130 mg/m2).
Mean AUC, Vss, CL and CLR0-48 values were determined on Cycle 1.
Cend, Cmax, AUC, AUC0-48, Vss and CL values were determined by non-compartmental analysis.
t1/2α, t1/2β, and t1/2γ were determined by compartmental analysis (Cycles 1-3 combined).

Distribution
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 2 weeks or 130 mg/m2 every 3 weeks and steady state was attained by cycle 1 in this matrix. Inter- and intra-subject variability is generally low.

Biotransformation
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 medicinal product was detectable in plasma ultrafiltrate at the end of a 2-hour 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.
.

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/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 65 mg/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 % Cl) 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 sections 4.2, 4.3 and 4.4).