Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, other antineoplastic agents: ATC code: L01XX17.
Mechanism of action

The anti-tumour activity of topotecan involves the inhibition of topoisomerase-I, an enzyme intimately involved in DNA replication as it relieves the torsional strain introduced ahead of the moving replication fork. Topotecan inhibits topoisomerase-I by stabilising the covalent complex of enzyme and strand-cleaved DNA which is an intermediate of the catalytic mechanism. The cellular sequela of inhibition of topoisomerase-I by topotecan is the induction of protein-associated DNA single-strand breaks.

Clinical efficacy and safety

Relapsed ovarian cancer
In a comparative study of topotecan and paclitaxel in patients previously treated for ovarian carcinoma with platinum-based chemotherapy (n = 112 and 114, respectively), the response rate (95 % CI) was 20.5 % (13 %, 28 %) versus 14 % (8 %, 20 %) and median time to progression 19 weeks versus 15

weeks (hazard ratio 0.7 [0.6, 1.0]), for topotecan and paclitaxel, respectively. Median overall survival was 62 weeks for topotecan versus 53 weeks for paclitaxel (hazard ratio 0.9 [0.6, 1.3]).

The response rate in the whole ovarian carcinoma programme (n = 392, all previously treated with cisplatin or cisplatin and paclitaxel) was 16 %. The median time to response in clinical studies was 7.6-11.6 weeks. In patients refractory to or relapsing within 3 months after cisplatin therapy (n = 186), the response rate was 10 %.

These data should be evaluated in the context of the overall safety profile of the medicinal product, in particular of the significant haematological toxicity (see section 4.8).

A supplementary retrospective analysis was conducted on data from 523 patients with relapsed ovarian cancer. Overall, 87 complete and partial responses were observed, with 13 of these occurring during cycles 5 and 6 and 3 occurring thereafter. Of the patients who received more than 6 cycles of therapy, 91 % completed the study as planned or were treated until disease progression, with only 3 % withdrawn for adverse events.

Relapsed SCLC

A Phase III study (Study 478) compared oral topotecan plus best supportive care (BSC) (n=71) with BSC alone (n=70) in patients who had relapsed following first-line therapy (median time to progression [TTP] from first-line therapy: 84 days for oral topotecan plus BSC, 90 days for BSC alone) and for whom re-treatment with intravenous chemotherapy was not considered appropriate.In the oral topotecan plus BSC group there was a statistically significant improvement in overall survival compared with the BSC alone group (Log-rank p=0.0104). The unadjusted hazard ratio for the oral topotecan plus BSC group relative to the BSC alone group was 0.64 (95 % CI: 0.45, 0.90). Median survival in patients treated with oral topotecan plus BSC was 25.9 weeks (95 % CI: 18.3, 31.6) compared to 13.9 weeks (95 % CI: 11.1, 18.6) for patients receiving BSC alone (p=0.0104).

Patient self-reports of symptoms using an unblinded assessment showed a consistent trend for symptom benefit for oral topotecan plus BSC.

One Phase II study (Study 065) and one Phase III study (Study 396) were conducted to evaluate the efficacy of oral topotecan versus intravenous topotecan in patients who had relapsed ≥ 90 days after completion of one prior regimen of chemotherapy (see Table 1). Oral and intravenous topotecan were associated with similar symptom palliation in patients with relapsed sensitive SCLC in patient self- reports on an unblinded symptom scale assessment in each of these two studies.

Table 1 Summary of survival, response rate, and time to progression in SCLC patients treated with oral or intravenous topotecan

Study 065                            Study 396
Oral              Intravenous        Oral topotecan      Intravenous topotecan         topotecan                              topotecan
(N = 52)          (N = 54)           (N = 153)           (N = 151)
Median survival (weeks)         32.3              25.1               33.0                35.0 (95 % CI)                 (26.3, 40.9)      (21.1, 33.0)       (29.1, 42.4)        (31.0, 37.1) Hazard ratio (95 %        0.88 (0.59, 1.31)                    0.88 (0.7, 1.11) CI)
Response rate (%)               23.1               14.8              18.3                21.9 (95 % CI)                 (11.6, 34.5)       (5.3, 24.3)       (12.2, 24.4)        (15.3, 28.5) Difference in response rate     8.3 (-6.6, 23.1)                     -3.6 (-12.6, 5.5) (95 % CI)
Median time to progression      14.9               13.1              11.9                14.6 (weeks)

(95 % CI)                (8.3, 21.3)       (11.6, 18.3)        (9.7, 14.1)         (13.3, 18.9) Hazard ratio (95 %       0.90 (0.60, 1.35)                     1.21 (0.96, 1.53) CI)
N = total number of patients treated.
CI = confidence interval.

In another randomised Phase III study which compared intravenous (IV) topotecan to cyclophosphamide, doxorubicin and vincristine (CAV) in patients with relapsed, sensitive SCLC, the overall response rate was 24.3 % for topotecan compared to 18.3 % for the CAV group. Median time to progression was similar in the two groups (13.3 weeks and 12.3 weeks, respectively). Median survivals for the two groups were 25.0 and 24.7 weeks, respectively. The hazard ratio for survival with IV topotecan relative to CAV was 1.04 (95 % CI: 0.78, 1.40).

The response rate to topotecan in the combined small cell lung cancer programme (n = 480) for patients with relapsed disease sensitive to first-line therapy was 20.2 %. Median survival was 30.3 weeks (95 % CI: 27.6, 33.4).

In a population of patients with refractory SCLC (those not responding to first-line therapy), the response rate to topotecan was 4.0 %.

Cervical carcinoma

In a randomised, comparative Phase III study conducted by the Gynecologic Oncology Group (GOG 0179), topotecan plus cisplatin (n = 147) was compared with cisplatin alone (n=146) for the treatment of histologically confirmed persistent, recurrent or Stage IVB carcinoma of the cervix where curative treatment with surgery and/or radiation was not considered appropriate. Topotecan plus cisplatin had a statistically significant benefit in overall survival relative to cisplatin monotherapy after adjusting for interim analyses (Log-rank p =0.033).



Table 2 Study results Study GOG-0179

ITT population
Cisplatin            Cisplatin
50 mg/m2 on day,     50 mg/m2 on day 1 +
1 every 21 days      Topotecan
0.75 mg/m2 on days 1-
3, every
21 days
Survival (months)             (n= 146)             (n = 147)
Median (95 % CI)              6.5 (5.8, 8.8)       9.4 (7.9, 11.9)
Hazard ratio (95 % CI)        0.76 (0.59,0.98)
Log rank p-value              0.033
Patients without prior cisplatin chemoradiotherapy
Cisplatin          Topotecan/Cisplatin
Survival (months)              (n= 46)            (n = 44)
Median (95 % CI)               8.8 (6.4, 11.5)    15.7 (11.9, 17.7)
Hazard ratio (95 % CI)         0.51 (0.31, 0.82)

Patients with prior cisplatin chemoradiotherapy
Cisplatin           Topotecan/Cisplatin
Survival (months)            (n= 72)             (n = 69)
Median (95 % CI)             5.9 (4.7, 8.8)      7.9 (5.5, 10.9)
Hazard ratio (95 % CI)       0.85 (0.59, 1.21)

In patients (n=39) with recurrence within 180 days after chemoradiotherapy with cisplatin, the median survival in the topotecan plus cisplatin arm was 4.6 months (95 % CI: 2.6, 6.1) versus 4.5 months (95 %CI: 2.9, 9.6) for the cisplatin arm with a hazard ratio of 1.15 (0.59, 2.23). In those patients (n=102) with recurrence after 180 days, median survival in the topotecan plus cisplatin arm, was 9.9 months (95 % CI: 7, 12.6) versus 6.3 months (95 %CI: 4.9, 9.5) for the cisplatin arm with a hazard ratio of 0.75 (0.49, 1.16).


Paediatric population
Topotecan was also evaluated in the paediatric population; however, only limited data on efficacy and safety are available.

In an open-label study involving children (n = 108, age range: infant to 16 years) with recurrent or progressive solid tumours, topotecan was administered at a starting dose of 2.0 mg/m2 given as a 30- minute infusion for 5 days repeated every 3 weeks for up to one year depending on response to therapy. Tumour types included were Ewing’s sarcoma/primitive neuroectodermal tumour, neuroblastoma, osteoblastoma and rhabdomyosarcoma. Anti-tumour activity was demonstrated primarily in patients with neuroblastoma. Toxicities of topotecan in paediatric patients with recurrent and refractory solid tumours were similar to those historically seen in adult patients. In this study, forty-six (43 %) patients received G-CSF over 192 (42.1 %) courses; sixty-five (60 %) received transfusions of packed red blood cells and fifty (46 %) of platelets over 139 and 159 courses (30.5 % and 34.9 %), respectively. Based on the dose-limiting toxicity of myelosuppression, the maximum tolerated dose (MTD) was established at 2.0 mg/m2/day with G-CSF and 1.4 mg/m2/day without G- CSF in a pharmacokinetic study in paediatric patients with refractory solid tumours (see section 5.2).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Distribution
Following intravenous administration of topotecan at doses of 0.5 to 1.5 mg/m2 as a 30-minute infusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/h (SD 22), corresponding to approximately 2/3 of liver blood flow. Topotecan also had a high volume of distribution, about 132 l (SD 57), and a relatively short half-life of 2-3 hours. Comparison of pharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of dosing. Area under the curve increased approximately in proportion to the increase in dose. There is little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change in the pharmacokinetics after multiple doses. Preclinical studies indicate plasma protein binding of topotecan is low (35 %) and distribution between blood cells and plasma was fairly homogeneous.

Biotransformation

The elimination of topotecan has only been partly investigated in man. A major route of clearance of topotecan was by hydrolysis of the lactone ring to form the ring-opened carboxylate.

Metabolism accounts for < 10 % of the elimination of topotecan. An N-desmethyl metabolite, which was shown to have similar or less activity than the parent in a cell-based assay, was found in urine, plasma and faeces. The mean metabolite:parent AUC ratio was <10 % for both total topotecan and topotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine.
Elimination

Overall recovery of topotecan-related material following five daily doses of topotecan was 71 to 76 % of the administered IV dose. Approximately 51 % was excreted as total topotecan and 3 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for 18 % while faecal elimination of N-desmethyl topotecan was 1.7 %. Overall, the N-desmethyl metabolite contributed a mean of less than 7 % (range 4-9 %) of the total topotecan-related material accounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyl topotecan-O- glucuronide in the urine were less than 2.0 %.

In vitro data using human liver microsomes indicate the formation of small amounts of N- demethylated topotecan. In vitro, topotecan did not inhibit human P450 enzymes CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A or CYP4A, nor did it inhibit the human cytosolic enzymes dihydropyrimidine or xanthine oxidase.

When given in combination with cisplatin (cisplatin day 1, topotecan days 1 to 5), the clearance of topotecan was reduced on day 5 compared to day 1 (19.1 l/h/m2 compared to 21.3 l/h/m2 [n=9]) (see section 4.5).

Special populations

Hepatic impairment
Plasma clearance in patients with hepatic impairment (serum bilirubin between 1.5 and 10 mg/dl) decreased to about 67 % when compared with a control group of patients. Topotecan half-life was increased by about 30 % but no clear change in volume of distribution was observed. Plasma clearance of total topotecan (active and inactive form) in patients with hepatic impairment only decreased by about 10 % compared with the control group of patients.

Renal impairment
Plasma clearance in patients with renal impairment (creatinine clearance 41-60 ml/min.) decreased to about 67 % compared with control patients. Volume of distribution was slightly decreased and thus half-life only increased by 14 %. In patients with moderate renal impairment topotecan plasma clearance was reduced to 34 % of the value in control patients. Mean half-life increased from 1.9 hours to 4.9 hours.

Age/weight
In a population study, a number of factors including age, weight and ascites had no significant effect on clearance of total topotecan (active and inactive form).

Paediatric population
The pharmacokinetics of topotecan given as a 30-minute infusion for 5 days were evaluated in two studies. One study included a dose range of 1.4 to 2.4 mg/m2 in children (aged 2 up to 12 years, n = 18), adolescents (aged 12 up to 16 years, n = 9) and young adults (aged 16 to 21 years, n = 9) with refractory solid tumours. The second study included a dose range of 2.0 to 5.2 mg/m2 in children (n = 8), adolescents (n = 3) and young adults (n = 3) with leukaemia. In these studies there were no apparent differences in the pharmacokinetics of topotecan among children, adolescents and young adult patients with solid tumours or leukaemia, but data are too limited to draw definite conclusions.