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Mechanism of Action

Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. The cytotoxicity of topotecan is thought to be due to double strand DNA damage produced during DNA synthesis, when replication enzymes interact with the ternary complex formed by topotecan, topoisomerase I, and DNA. Mammalian cells cannot efficiently repair these double strand breaks.

Pharmacodynamics

The dose-limiting toxicity of topotecan is leukopenia. White blood cell count decreases with increasing topotecan dose or topotecan AUC. There is a correlation between topotecan lactone AUC day 1 and percent decrease of leukocytes.

Pharmacokinetics

The pharmacokinetics of HYCAMTIN capsules after oral administration have been evaluated in cancer patients following doses of 1.2 to 3.1 mg/m² administered daily for 5 days. Topotecan exhibits biexponential pharmacokinetics with a mean terminal half-life of 3 to 6 hours. Total exposure (AUC) increases approximately proportionally with dose. Plasma protein binding of topotecan is about 35%.

Absorption

Topotecan is rapidly absorbed with peak plasma concentrations occurring between 1 to 2 hours following oral administration. The oral bioavailability of topotecan was about 40%. Following a high-fat meal, the extent of exposure was similar in the fed and fasted states, while tmax was delayed from 1.5 to 3 hours (topotecan lactone) and from 3 to 4 hours (total topotecan), respectively. HYCAMTIN capsules can be given without regard to food.

Following coadministration of the ABCG2 (BCRP) and ABCB1 (P-gp) inhibitor elacridar (GF120918) at 100 to 1,000 mg doses with oral topotecan, the AUC0-∞ of topotecan lactone and total topotecan increased approximately 2.5-fold.

Administration of oral cyclosporine A (15 mg/kg), an inhibitor of transporters ABCB1 (P-gp) and ABCC1 (MRP-1) as well as the metabolizing enzyme CYP3A4, within 4 hours of oral topotecan increased the dose-normalized AUC0-24 of topotecan lactone and total topotecan to 2.0- to 3-fold of control. [See DRUG INTERACTIONS.]

Metabolism and Elimination

Topotecan undergoes a reversible pH-dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. At pH ≤ 4, the lactone is exclusively present, whereas the ring-opened hydroxy-acid form predominates at physiologic pH. The mean metabolite:parent AUC ratio was < 10% for total topotecan and topotecan lactone.

In a mass balance study in 4 patients with advanced solid tumors, the overall recovery of drug-related material following 5 daily doses of topotecan was 57% of the administered oral dose. In the urine, 20% of the oral administered dose was excreted as total topotecan and 2% was excreted as N-desmethyl topotecan [see Use In Specific Populations]. Fecal elimination of total topotecan accounted for 33% while fecal elimination of N-desmethyl topotecan was 1.5%. Overall, the N-desmethyl metabolite contributed a mean of < 6% (range 4 to 8%) of the total drug-related material accounted for in the urine and feces. O-glucuronides of both topotecan and N-desmethyl topotecan have been identified in the urine.

Age, Gender, and Race

A cross-study analysis in 217 patients with advanced solid tumors indicated that age and gender did not significantly affect the pharmacokinetics of oral topotecan. There are insufficient data to determine an effect of race on pharmacokinetics of oral topotecan.

Clinical Studies

Small Cell Lung Cancer

HYCAMTIN capsules were studied in patients with relapsed SCLC in a randomized, comparative, open label trial. The patients were prior responders (complete or partial) to first line chemotherapy, were not considered candidates for standard intravenous chemotherapy, and had relapsed at least 45 days from the end of first-line chemotherapy. Seventy-one patients were randomized to HYCAMTIN capsules (2.3 mg/m²/day administered for 5 consecutive days repeated every 21 days) and Best Supportive Care (BSC) and 70 patients were randomized to BSC alone. The primary objective was to compare the overall survival between the 2 treatment arms. Patients in the HYCAMTIN capsules plus BSC group received a median of 4 courses (range 1 to 10) and maintained a median dose intensity of HYCAMTIN capsules, 3.77 mg/m²/week. The median patient age in the HYCAMTIN capsules plus BSC arm and the BSC alone treatment arm was 60 years and 58 years while the percentage of patients > 65 years of age was 34% and 29%, respectively. All but 1 patient were Caucasian. The HYCAMTIN capsules plus BSC treatment arm included 68% of patients with extensive disease and 28% with liver metastasis. In the BSC alone arm, 61% of patients had extensive disease and 20% had liver metastases. Both treatment arms recruited 73% males. In the HYCAMTIN capsules plus BSC arm, 18% of patients had prior carboplatin and 62% had prior cisplatin. In the BSC alone arm, 26% of patients had prior carboplatin and 51% had prior cisplatin.

The HYCAMTIN capsules plus BSC arm showed a statistically significant improvement in overall survival compared with the BSC alone arm (Log-rank p = 0.0104). Survival results are shown in Table 2 and Figure 1.

Table 2: Overall Survival in Small Cell Lung Cancer Patients With HYCAMTIN Capsules Plus BSC Compared With BSC Alone

Figure 1: Kaplan-Meier Estimates for Survival

Last reviewed on RxList: 10/28/2011
This monograph has been modified to include the generic and brand name in many instances.