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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 re-ligation of these singlestrand 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.
Following administration of HYCAMTIN capsules at doses of 1.2 to 3.1 mg/m² administered daily for 5 days in cancer patients, topotecan exhibited biexponential pharmacokinetics with a mean terminal half-life of 3 to 6 hours. Total exposure (AUC) increased approximately proportionally to dose.
Topotecan is rapidly absorbed with peak plasma concentrations occurring between 1 to 2 hours following oral administration. The oral bioavailability of topotecan is approximately 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 for topotecan lactone and from 3 to 4 hours for total topotecan. HYCAMTIN capsules can be given without regard to food.
Binding of topotecan to plasma proteins is approximately 35%.
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 drugrelated material following 5 daily doses of topotecan was 57% of the administered oral dose. In the urine, 20% of the orally 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 and Gender: 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.
Race: In patients with normal renal function, the exposures (geometric mean dose-normalized AUCinf) to topotecan lactone and total topotecan each were approximately 30% higher in Asian patients (n = 7) compared with Caucasian patients (n = 11).
In patients with mild renal impairment, the exposure was 30% higher for topotecan lactone in Asian (n = 7) compared with Caucasian (n = 12) patients, but the exposure to total topotecan was similar.
In patients with moderate renal impairment, the exposure was 60% higher for both topotecan lactone and total topotecan in Asian (n = 8) compared with Caucasian patients (n = 6).
In patients with severe renal impairment, the exposure was 112% higher for topotecan lactone and 70% higher for total topotecan in Asian (n = 3) compared with Caucasian patients (n = 4).
Renal Impairment: A trial was conducted in 59 patients with advanced cancer who were grouped based on the degree of their renal function and received HYCAMTIN capsules as shown in the table below.
Renal Function Groups With Initial Doses of HYCAMTIN Received
|Renal Function Group||Creatinine Clearance (CLcr) (mL/min)||N||Dose (mg/m ) Once Daily for 5 Days|
|Normal (without prior P-B CT)a||> 80||6||2.3|
|Normal (with prior P-B CT)||> 80||12||2.3|
|Mild renal impairment||50-79||19||1.9 or 2.3|
|Moderate renal impairment||30-49||14||1.2, 1.5 or 1.8|
|Severe renal impairment||< 30||8||0.6, 0.8 or 1.2|
|a P-B CT = platinum-based chemotherapy.|
The exposure (geometric mean dose-normalized AUCinf) for topotecan lactone increased by 34%, 80%, and 114% in Caucasian patients with mild, moderate, and severe renal impairment, respectively, compared with that in Caucasian patients with normal renal function. The corresponding values for total topotecan in Caucasian patients were 70%, 108%, and 227%, respectively. Asian patients with mild, moderate, and severe renal impairment had a 34%, 121%, and 247% higher exposure to topotecan lactone, respectively, than Asian patients with normal renal function. The corresponding values for total topotecan in Asian patients are 26%, 153%, and 331%, respectively. Prior platinum-based chemotherapy (P-B CT) had no effect on the systemic exposure to both total topotecan and topotecan lactone in patients with normal renal function.
No dosage adjustment is recommended for patients with mild renal impairment. Adjust the dosage of HYCAMTIN capsules in patients with moderate and severe renal impairment [see DOSAGE AND ADMINISTRATION, Use in Specific Populations].
Hepatic Impairment: In a population pharmacokinetic analysis involving oral topotecan administered at doses of 0.15 to 2.7 mg/m²/day to 118 cancer patients, the pharmacokinetics of total topotecan did not differ significantly based on patient serum bilirubin, ALT, or AST.
Effects of Topotecan on Drug-Metabolizing Enzymes: In vitro inhibition studies using marker substrates known to be metabolized by human cytochromes 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.
Drugs That Inhibit Drug Efflux Transporters: Following coadministration of escalating doses of a dual inhibitor of BCRP and P-gp with oral topotecan, the AUCinf of topotecan lactone and total topotecan increased approximately 2.5-fold compared with control [see DRUG INTERACTIONS].
Administration of oral cyclosporine A (15 mg/kg), an inhibitor of P-gp, multidrug-resistanceassociated protein (MRP-1), and cytochrome P450 3A4 (CYP3A4) within 4 hours of oral topotecan increased the dose-normalized AUC0.24h of topotecan lactone and total topotecan 2.0-to 3.0-fold compared with control [see DRUG INTERACTIONS].
Effect of pH-Elevating Agents: The pharmacokinetics of oral topotecan were unchanged when coadministered with ranitidine.
Small Cell Lung Cancer
The efficacy of HYCAMTIN capsules was studied in 141 patients with relapsed SCLC in a randomized, controlled, 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 treatment arms. Patients in the arm receiving HYCAMTIN capsules plus BSC received a median of 4 courses (range: 1 to 10) and maintained a median dose intensity of 3.77 mg/m²/week. The median patient age in the arm receiving HYCAMTIN capsules plus BSC and the BSC-alone treatment arm was 60 years and 58 years while the percentage of patients aged ≥ 65 years was 34% and 29%, respectively. The majority of patients were Caucasian (99.3%) and male (73%). Eighty percent of patients receiving HYCAMTIN capsules plus BSC previously received carboplatin or cisplatin, and 77% of patients in the BSC-alone arm received prior carboplatin or cisplatin. The arm receiving HYCAMTIN capsules plus BSC 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 arm receiving HYCAMTIN capsules plus BSC, 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 arm receiving HYCAMTIN capsules plus BSC 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 3 and Figure 1.
Table 4: Overall Survival in Patients With Small Cell
Lung Cancer With HYCAMTIN Capsules Plus BSC Comparet With BSC Alone
|HYCAMTIN Capsules + BSC
(N = 71)
(N = 70)
|Median (months) (95% CI)||6.0 (4.2, 7.3)||3.2 (2.6, 4.3)|
|Hazard ratio (95% CI)
|0.64 (0.45, 0.90)
|BSC = Best Supportive Care.
N = Total number of patients randomized.
CI = Confidence interval.
Figure 1: Kaplan-Meier Estimates for Survival
Last reviewed on RxList: 7/7/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Hycamtin Capsules Information
- Hycamtin Capsules Drug Interactions Center: topotecan oral
- Hycamtin Capsules Side Effects Center
- Hycamtin Capsules in detail including Side Effects and Drug Images
- Hycamtin Capsules FDA Approved Prescribing Information including Dosage
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