Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Platinum compounds, ATC code: L01XA 03

Mechanism of action

Oxaliplatin is an antineoplastic drug 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 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.

Clinical efficacy and safety
In patients with metastatic colorectal cancer, the efficacy of oxaliplatin (85 mg/m2 repeated every two weeks) combined with 5-fluorouracil/folinic acid (5-FU/FA) is reported in three clinical studies: 
-   In front-line treatment, a 2-arm comparative phase III study (de Gramont, A et al., 2000) 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, a comparative three arms phase III study (Rothenberg, ML et al., 2003) 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, an uncontrolled phase II study (André, T et al., 1999) 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 in front-line therapy (de Gramont, A et al.) and in pretreated patients (Rothenberg ML et al.), 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 the study of Rothenberg et al. 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.


Table 5: Response rate under FOLFOX4 versus LV5FU2
Response rate, % (95%                 LV5FU2                 FOLFOX4                  Oxaliplatin CI)
independent radiological                                                              Single agent review ITT analysis
Front-line treatment                     22                       49                      NA* (de Gramont, A et al.,                 (16-27)                  (42-46) 2000)
Response assessment every                    P value = 0.0001
8 weeks
Pretreated patients                      0.7                     11.1                      1.1 (Rothenberg, ML et al.,               (0.0-2.7)               (7.6-15.5)                (0.2-3.2) 

2003)
(refractory to                          P value = 0.0001
CPT-11 + 5-FU/FA)
Response assessment every
6 weeks
Pretreated patients               NA*                        23             NA* (André, T et al., 1999)                                    (13-36)
(refractory to 5-FU/FA)
Response assessment every
12 weeks
* NA: Not applicable.


Table 6: Median Progression Free Survival (PFS) / Median Time to Progression (TTP) FOLFOX4 versus LV5FU2

Median PFS/TTP,                 LV5FU2                FOLFOX4            Oxaliplatin Months (95% CI)                                                          Single agent independent radiological
review ITT analysis
Front-line treatment               6.0                    8.2               NA* (de Gramont, A et al.,          (5.5-6.5)              (7.2-8.8)
2000) (PFS)                       Log-rank P value = 0.0003
Pretreated patients
(Rothenberg, ML et al.,            2.6                    5.3                 2.1 2003) (TTP)                     (1.8-2.9)              (4.7-6.1)           (1.6-2.7)
(refractory to                    Log-rank P value = 0.0001
CPT-11 + 5-FU/FA)
(Pretreated patients
(André, T et al., 1999)           NA*                     5.1               NA* (refractory to 5-FU/FA)                                (3.1-5.7)

* NA: Not applicable.

Table 7:       Median Overall Survival (OS) under FOLFOX4 versus LV5FU2 
Median OS, months                 LV5FU2              FOLFOX4            Oxaliplatin (95% CI)                                                                 Single agent ITT analysis
Front-line treatment                14.7                 16.2               NA* (de Gramont, A et al., 2000)     (13.0-18.2)          (14.7-18.2)
Log-rank P value = 0.12

Pretreated patients                  8.8                  9.9                 8.1 (Rothenberg, ML et al., 2003)     (7.3-9.3)           (9.1-10.5)           (7.2-8.7) (TTP)                                 Log-rank P value = 0.09
(refractory to
CPT-11 + 5-FU/FA)
Pretreated patients                 NA*                   10.8              NA* (André, T et al., 1999)                                (9.3-12.8)
(refractory to 5-FU/FA)

* NA: Not applicable.

In pretreated patients (Rothenberg, ML et al., 2003), 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 (de Gramont, A et al., 2000), 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 MOSAIC comparative phase III study randomised 2246 patients (899 stage II / Duke's B2 and 1347 stage III / Duke's 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).


Table 8: MOSAIC-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)                               (70.6-75.6)                          (76.2-81.1) Hazard ratio (95% CI)                                                 0.76 (0.64-0.89)
Stratified log rank test                                          P = 0.0008 
* median follow up 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).


Table 9: MOSAIC-3-year Disease Free Survival (ITT analysis)* according to Stage of                  Disease 
Patient stage                                  Stage II                               Stage III (Duke's B2)                             (Duke's C)
Treatment arm                           LV5FU2         FOLFOX4                  LV5FU2       FOLFOX4 
Percent 3-year disease free               84.3                87.4               65.8             72.8 survival (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)

Stratified log rank test                          P = 0.151                            P = 0.002 
* median follow up 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 the 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 tumour response.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties
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/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: 

Table 10:       Summary of Platinum Pharmacokinetic Parameter Estimates in Ultrafiltrate following Multiple Doses of Oxaliplatin at 85 mg/m2 Every Two Weeks or at 130 mg/m2 Every Three 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, t1/2γ 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
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.

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.

A significant decrease in clearance from 17.6 ± 2.18 l/h to 9.95 ± 1.91 l/h in renal impairment was observed together with a statistically significant decrease in distribution volume from 330 ± 40.9 to 241 ± 36.1 l. The effect of severe renal impairment on platinum clearance has not been evaluated.