Topotecan (Page 3 of 4)

12.3 Pharmacokinetics

Following administration of topotecan at doses of 0.5 to 1.5 mg/m2 (0.3 to 1 times the recommended dose) administered as a 30-minute infusion, area under the curve (AUC) increases approximately proportional with dose.

Distribution

Protein binding of topotecan is approximately 35%.

Elimination

The terminal half-life of topotecan is 2 to 3 hours following intravenous administration.

Metabolism

Topotecan undergoes a reversible pH-dependent hydrolysis of its pharmacologically active lactone moiety. At pH ≤ 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. Topotecan is metabolized to an N-demethylated metabolite in vitro. The mean metabolite: parent AUC ratio was about 3% for total topotecan and topotecan lactone following intravenous administration.

Excretion

The overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73% ± 2% following an intravenous dose. Mean values of 51% ± 3% as total topotecan and 3% ± 1% as N-desmethyl topotecan were excreted in the urine. Fecal elimination of total topotecan accounted for 18% ± 4% while fecal elimination of N-desmethyl topotecan was 1.7% ± 0.6%. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine.

Specific Populations

No clinically significant differences in the pharmacokinetics of topotecan were observed based on age, sex, or hepatic impairment following intravenous administration.

Patients with Renal Impairment

Compared to patients with CLcr > 60 mL/min (calculated by the Cockcroft-Gault method using ideal body weight), plasma clearance of topotecan lactone decreased by 33% in patients with CLcr 40 to 60 mL/min and decreased by 65% in patients with CLcr 20 to 39 mL/min. The effect on topotecan pharmacokinetics in patients with CLcr < 20 mL/min is unknown [see Dosage and Administration (2.4)].

Drug Interaction Studies

Clinical Studies

No clinically significant changes in topotecan pharmacokinetics were observed when coadministered cisplatin.

No clinically significant changes in the pharmacokinetics of free platinum were observed in patients coadministered cisplatin with topotecan.

In Vitro Studies

Topotecan does not inhibit CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity testing of topotecan has not been performed. Topotecan is known to be genotoxic to mammalian cells and is a probable carcinogen. Topotecan was mutagenic to L5178Y mouse lymphoma cells and clastogenic to cultured human lymphocytes with and without metabolic activation. It was also clastogenic to mouse bone marrow. Topotecan did not cause mutations in bacterial cells.

Topotecan given to female rats prior to mating at an intravenous dose of 1.4 mg/m2 (about equal to the 1.5 mg/m2 clinical dose based on BSA) caused superovulation possibly related to inhibition of follicular atresia. This dose given to pregnant female rats also caused increased pre-implantation loss. A one month study in dogs given a daily intravenous topotecan dose of 0.4 mg/m2 (about 0.25 times the 1.5 mg/m2 clinical dose based on BSA) suggests that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.

14 CLINICAL STUDIES

14.1 Small Cell Lung Cancer

The efficacy of topotecan was studied in 426 patients with recurrent or progressive SCLC in a randomized, comparative trial and in 3 single-arm trials.

Randomized Comparative Trial

In a randomized, comparative trial, 211 patients were randomized 1:1 to received topotecan (1.5 mg/m2 once daily intravenously for 5 days starting on Day 1 of a 21-day cycle) or CAV (cyclophosphamide 1,000 mg/m2 , doxorubicin 45 mg/m2 , vincristine 2 mg administered sequentially on Day 1 of a 21-day cycle). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed greater than or equal to 60 days after completion of first-line therapy). A total of 77% of patients treated with topotecan and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy. The efficacy outcome measures were overall response rate, response duration, time to progression and overall survival (OS).

The results of the trial did not show statistically significant improvements in response rates, response duration, time to progression, and OS as shown in Table 2.

Table 2. Efficacy Results in Patients with Small Cell Lung Cancer Sensitive to First-Line Chemotherapy in Study 090
Parameter Topotecan
(n = 107)
CAV *
(n = 104)
Abbreviations: CI = confidence interval.
*
CAV = cyclophosphamide, doxorubicin and vincristine.
The calculation for duration of response was based on the interval between first response and time to progression.
Overall response rate (95% CI) 24% (16% to 32%) 18% (11% to 26%)
Complete response rate 0% 1%
Partial response rate 24% 17%
Response duration (months)
Median (95% CI) 3.3 (3.0 to 4.1) 3.5 (3.0 to 5.3)
Time to progression (months)
Median (95% CI) 3.1 (2.6 to 4.1) 2.8 (2.5 to 3.2)
Hazard ratio (95% CI) 0.92 (0.69 to 1.22)
Overall survival (months)
Median (95% CI) 5.8 (4.7 to 6.8) 5.7 (5.0 to 7.0)
Hazard ratio (95% CI) 1.04 (0.78 to 1.39)

The median time to response was similar in both arms: topotecan 6 weeks (2.4 weeks to 3.6 months) versus CAV 6 weeks (5.1 weeks to 4.2 months).

Changes on a disease-related symptom scale are presented in Table 3. It should be noted that not all patients had all symptoms, nor did all patients respond to all questions. Each symptom was rated on a 4-category scale with an improvement defined as a change in 1 category from baseline sustained over 2 cycles. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.

Table 3. Symptom Improvement * in Patients with Small Cell Lung Cancer in Study 090
Symptom Topotecan
(n = 107)
CAV
(n = 104)
n % n %
*
Defined as improvement sustained over at least 2 cycles compared with baseline.
CAV = cyclophosphamide, doxorubicin and vincristine.
Number of patients with baseline and at least 1 post-baseline assessment.
Shortness of breath 68 28 61 7
Interference with daily activity 67 27 63 11
Fatigue 70 23 65 9
Hoarseness 40 33 38 13
Cough 69 25 61 15
Insomnia 57 33 53 19
Anorexia 56 32 57 16
Chest pain 44 25 41 17
Hemoptysis 15 27 12 33

Single-Arm Trials

Topotecan was also studied in 3 open-label, non-comparative trials (Studies 014, 092 and 053) in a total of 319 patients with recurrent or progressive SCLC after treatment with first-line chemotherapy. In all 3 trials, patients were stratified as either sensitive (responders who then subsequently progressed greater than or equal to 90 days after completion of first-line therapy) or refractory (no response to first-line chemotherapy or who responded to first-line therapy and then progressed within 90 days of completing first-line therapy). Response rates ranged from 11% to 31% for sensitive patients and 2% to 7% for refractory patients. Median time to progression and median survival were similar in all 3 trials and the comparative trial.

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