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 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 % C.I. 18.3, 31.6) compared to 13.9 weeks (95 % C.I. 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           Intravenous topotecan            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 % CI)                0.88 (0.59, 1.31)                      0.88 (0.7, 1.11) 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                    8.3 (-6.6, 23.1)                     -3.6 (-12.6, 5.5) rate (95 % CI)
Median time to                        14.9               13.1               11.9                14.6 progression (weeks)
(95 % CI)                   (8.3, 21.3)       (11.6, 18.3)        (9.7, 14.1)        (13.3, 18.9) Hazard ratio (95 % CI)                0.90 (0.60, 1.35)                     1.21 (0.96, 1.53) N = total number of patients treated.
CI = confidence interval.

Paediatric population
The safety and effectiveness of oral topotecan in paediatric patients have not been established.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Distribution

The pharmacokinetics of topotecan after oral administration have been evaluated in cancer patients following doses of 1.2 to 3.1 mg/m2/day and 4 mg/m2/day administered daily for 5 days. The bioavailability of oral topotecan (total and lactone) in humans is approximately 40 %. Plasma concentrations of total topotecan (i.e. lactone and carboxylate forms) and topotecan lactone (active moiety) peak at approximately 2.0 hours and 1.5 hours, respectively, and decline bi-exponentially with mean terminal half-life of approximately 3.0 to 6.0 hours. Total exposure (AUC) increases approximately proportionally with dose. There is little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change in 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
A major route of clearance of topotecan is by hydrolysis of the lactone ring to form the ring-opened carboxylate. Other than hydrolysis, topotecan is cleared predominantly renally, with a minor component metabolised to the N-desmethyl metabolite (SB-209780) identified in plasma, urine and faeces.

Elimination

Overall recovery of topotecan-related material following five daily doses of topotecan was 49 to 72 % (mean 57 %) of the administered oral dose. Approximately 20 % was excreted as total topotecan and 2 % was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for 33 % while faecal elimination of N-desmethyl topotecan was 1.5 %. Overall, the N- desmethyl metabolite contributed a mean of less than 6 % (range 4-8 %) of the total topotecan related material accounted for in the urine and faeces. O-glucuronides of both topotecan and N-desmethyl topotecan have been identified in the urine. The mean metabolite: parent plasma AUC ratio was less than 10 % for both total topotecan and topotecan lactone.

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.

Following co-administration of the ABCB1 (P-gp) and ABCG2 (BCRP) inhibitor, elacridar (GF120918) at 100 to 1,000 mg with oral topotecan, the AUC0-∞ of topotecan lactone and total topotecan increased approximately 2.5-fold (see section 4.5 for guidance).

Administration of oral cyclosporine A (15 mg/kg), an inhibitor of transporters ABCB1 (P-gp) and ABCC1 (MRP-1) as well as the metabolising enzyme CYP3A4, within 4 hours of oral topotecan increased the dose normalised AUC0-24h of topotecan lactone and total topotecan approximately 2.0- and 2.5-fold, respectively (see section 4.5).

The extent of exposure was similar following a high-fat meal and in the fasted state, while tmax was delayed from 1.5 to 3 hours (topotecan lactone) and from 3 to 4 hours (total topotecan).

Special populations

Hepatic impairment
The pharmacokinetics of oral topotecan have not been studied in patients with hepatic impairment (see section 4.2 and 4.4).

Renal impairment

Results of a cross-study analysis suggest that the exposure to topotecan lactone, the active moiety following topotecan administration, increases with decreased renal function. Geometric mean topotecan lactone dose-normalised AUC(0-∞) values were 9.4, 11.1 and 12.0 ng*h/ml in subjects with creatinine clearance values of more than 80 ml/min, 50 to 80 ml/min and 30 to 49 ml/min, respectively. In this analysis, creatinine clearance was calculated using the Cockcroft-Gault method.
Similar results were obtained if glomerular filtration rate (ml/min) was estimated using the MDRD formula corrected for body weight. Patients with creatinine clearance >60 ml/min have been included in efficacy/safety studies of topotecan. Therefore, use of the normal starting dose in patients with a mild decrease in renal function is considered established (see section 4.2).

Korean patients with renal impairment had generally higher exposure than non-Asian patients with the same degree of renal impairment. The clinical significance of this finding is unclear. Geometric mean topotecan lactone dose-normalised AUC(0-∞) values for Korean patients were 7.9, 12.9 and 19.7 ng*h/ml in subjects with creatinine clearance values of more than 80 ml/min, 50 to 80 ml/min and 30 to 49 ml/min, respectively (see section 4.2 and 4.4). There are no data from Asian patients with renal impairment other than Koreans.

Gender
A cross-study analysis in 217 patients with advanced solid tumours indicated that gender did not affect the pharmacokinetics of HYCAMTIN capsules to a clinically relevant extent.