Hycamtin (Topotecan Hydrochloride) - Clinical Pharmacology

CLINICAL PHARMACOLOGY

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.

Pharmacokinetics:    The pharmacokinetics of topotecan have been evaluated in cancer patients following doses of 0.5 to 1.5 mg/m² administered as a 30-minute infusion. Topotecan exhibits multiexponential pharmacokinetics with a terminal half-life of 2 to 3 hours. Total exposure (AUC) is approximately dose-proportional. Binding of topotecan to plasma proteins is about 35%.

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. In vitro studies in human liver microsomes indicate that metabolism of topotecan to an N-demethylated metabolite represents a minor metabolic pathway.

In humans, about 30% of the dose is excreted in the urine and renal clearance is an important determinant of topotecan elimination (see Special Populations).

Special Populations: Gender:    The overall mean topotecan plasma clearance in male patients was approximately 24% higher than that in female patients, largely reflecting difference in body size.

Geriatrics:    Topotecan pharmacokinetics have not been specifically studied in an elderly population, but population pharmacokinetic analysis in female patients did not identify age as a significant factor. Decreased renal clearance, which is common in the elderly, is a more important determinant of topotecan clearance (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Race:    The effect of race on topotecan pharmacokinetics has not been studied.

Renal Impairment:    In patients with mild renal impairment (creatinine clearance of 40 to 60 mL/min.), topotecan plasma clearance was decreased to about 67% of the value in patients with normal renal function. In patients with moderate renal impairment (Cl_cr of 20 to 39 mL/min.), topotecan plasma clearance was reduced to about 34% of the value in control patients, with an increase in half-life. Mean half-life, estimated in 3 renally impaired patients, was about 5.0 hours. Dosage adjustment is recommended for these patients (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment:    Plasma clearance in patients with hepatic impairment (serum bilirubin levels between 1.7 and 15.0 mg/dL) was decreased to about 67% of the value in patients without hepatic impairment. Topotecan half-life increased slightly, from 2.0 hours to 2.5 hours, but these hepatically impaired patients tolerated the usual recommended topotecan dosage regimen (see DOSAGE AND ADMINISTRATION).

Drug Interactions:    Pharmacokinetic studies of the interaction of topotecan with concomitantly administered medications have not been formally investigated. In vitro inhibition studies using marker substrates known to be metabolized by human P450 CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, or CYP4A or dihydropyrimidine dehydrogenase indicate that the activities of these enzymes were not altered by topotecan. Enzyme inhibition by topotecan has not been evaluated in vivo.

Pharmacodynamics:    The dose-limiting toxicity of topotecan is leukopenia. White blood cell count decreases with increasing topotecan dose or topotecan AUC. When topotecan is administered at a dose of 1.5 mg/m²/day for 5 days, an 80% to 90% decrease in white blood cell count at nadir is typically observed after the first cycle of therapy.

CLINICAL STUDIES

Ovarian Cancer:    HYCAMTIN was studied in 2 clinical trials of 223 patients given topotecan with metastatic ovarian carcinoma. All patients had disease that had recurred on, or was unresponsive to, a platinum-containing regimen. Patients in these 2 studies received an initial dose of 1.5 mg/m² given by intravenous infusion over 30 minutes for 5 consecutive days, starting on day 1 of a 21-day course.

One study was a randomized trial of 112 patients treated with HYCAMTIN (1.5 mg/m²/day × 5 days starting on day 1 of a 21-day course) and 114 patients treated with paclitaxel (175 mg/m² over 3 hours on day 1 of a 21-day course). All patients had recurrent ovarian cancer after a platinum-containing regimen or had not responded to at least 1 prior platinum-containing regimen. Patients who did not respond to the study therapy, or who progressed, could be given the alternative treatment.

Response rates, response duration, and time to progression are shown in Table 1.

The median time to response was 7.6 weeks (range 3.1 to 21.7) with HYCAMTIN compared to 6.0 weeks (range 2.4 to 18.1) with paclitaxel. Consequently, the efficacy of HYCAMTIN may not be achieved if patients are withdrawn from treatment prematurely.

In the crossover phase, 8 of 61 (13%) patients who received HYCAMTIN after paclitaxel had a partial response and 5 of 49 (10%) patients who received paclitaxel after HYCAMTIN had a response (2 complete responses).

HYCAMTIN was active in ovarian cancer patients who had developed resistance to platinum-containing therapy, defined as tumor progression while on, or tumor relapse within 6 months after completion of, a platinum-containing regimen. One complete and 6 partial responses were seen in 60 patients, for a response rate of 12%. In the same study, there were no complete responders and 4 partial responders on the paclitaxel arm, for a response rate of 7%.

HYCAMTIN was also studied in an open-label, non-comparative trial in 111 patients with recurrent ovarian cancer after treatment with a platinum-containing regimen, or who had not responded to 1 prior platinum-containing regimen. The response rate was 14% (95% CI = 7% to 20%). The median duration of response was 22 weeks (range 4.6 to 41.9 weeks). The time to progression was 11.3 weeks (range 0.7 to 72.1 weeks). The median survival was 67.9 weeks (range 1.4 to 112.9 weeks).

Small Cell Lung Cancer:    HYCAMTIN was studied in 426 patients with recurrent or progressive small cell lung cancer in 1 randomized, comparative study and in 3 single-arm studies.

Randomized Comparative Study:    In a randomized, comparative, Phase 3 trial, 107 patients were treated with HYCAMTIN (1.5 mg/m²/day × 5 days starting on day 1 of a 21-day course) and 104 patients were treated with CAV (1,000 mg/m² cyclophosphamide, 45 mg/m² doxorubicin, 2 mg vincristine administered sequentially on day 1 of a 21-day course). All patients were considered sensitive to first-line chemotherapy (responders who then subsequently progressed >/=60 days after completion of first-line therapy). A total of 77% of patients treated with HYCAMTIN and 79% of patients treated with CAV received platinum/etoposide with or without other agents as first-line chemotherapy.

Response rates, response duration, time to progression, and survival are shown in Table 2.

The time to response was similar in both arms: HYCAMTIN median of 6 weeks (range 2.4 to 15.7) versus CAV median 6 weeks (range 5.1 to 18.1).

Changes on a disease-related symptom scale in patients who received HYCAMTIN or who received CAV 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 courses. Limitations in interpretation of the rating scale and responses preclude formal statistical analysis.

Single Arm Studies:    HYCAMTIN was also studied in 3 open-label, non-comparative trials in a total of 319 patients with recurrent or progressive small cell lung cancer after treatment with first-line chemotherapy. In all 3 studies, patients were stratified as either sensitive (responders who then subsequently progressed >/=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 studies and the comparative study.