Chemical formula: C₂₃H₂₃N₃O₅ Molecular mass: 421.446 g/mol PubChem compound: 60700
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.
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.
Following intravenous administration of topotecan at doses of 0.5 to 1.5 mg/m² as a 30-minute infusion daily for five days, topotecan demonstrated a high plasma clearance of 62 l/h (SD 22), corresponding to approximately ⅔ of liver blood flow. Topotecan also had a high volume of distribution, about 132 l (SD 57), and a relatively short half-life of 2-3 hours. Comparison of pharmacokinetic parameters did not suggest any change in pharmacokinetics over the 5 days of dosing. Area under the curve increased approximately in proportion to the increase in dose. There is little or no accumulation of topotecan with repeated daily dosing and there is no evidence of a change in the 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.
The elimination of topotecan has only been partly investigated in man. A major route of clearance of topotecan was by hydrolysis of the lactone ring to form the ring-opened carboxylate.
Metabolism accounts for <10% of the elimination of topotecan. An N-desmethyl metabolite, which was shown to have similar or less activity than the parent in a cell-based assay, was found in urine, plasma and faeces. The mean metabolite:parent AUC ratio was <10% for both total topotecan and topotecan lactone. An O-glucuronidation metabolite of topotecan and N-desmethyl topotecan has been identified in the urine.
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.
Overall recovery of topotecan-related material following five daily doses of topotecan was 71 to 76% of the administered IV dose. Approximately 51% was excreted as total topotecan and 3% was excreted as N-desmethyl topotecan in the urine. Faecal elimination of total topotecan accounted for 18% while faecal elimination of N-desmethyl topotecan was 1.7%. Overall, the N-desmethyl metabolite contributed a mean of less than 7% (range 4-9%) of the total topotecan-related material accounted for in the urine and faeces. The topotecan-O-glucuronide and N-desmethyl topotecan-O-glucuronide in the urine were less than 2.0%.
In vitro data using human liver microsomes indicate the formation of small amounts of Ndemethylated topotecan. 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.
When given in combination with cisplatin (cisplatin day 1, topotecan days 1 to 5), the clearance of topotecan was reduced on day 5 compared to day 1 (19.1 l/h/m² compared to 21.3 l/h/m² [n=9]).
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 1000 mg 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 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.
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).
Plasma clearance in patients with hepatic impairment (serum bilirubin between 1.5 and 10 mg/dl) decreased to about 67% when compared with a control group of patients. Topotecan half-life was increased by about 30% but no clear change in volume of distribution was observed. Plasma clearance of total topotecan (active and inactive form) in patients with hepatic impairment only decreased by about 10% compared with the control group of patients.
The pharmacokinetics of oral topotecan have not been studied in patients with hepatic impairment.
Plasma clearance in patients with renal impairment (creatinine clearance 41-60 ml/min) decreased to about 67% compared with control patients. Volume of distribution was slightly decreased and thus half-life only increased by 14%. In patients with moderate renal impairment topotecan plasma clearance was reduced to 34% of the value in control patients. Mean half-life increased from 1.9 hours to 4.9 hours.
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.
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. There are no data from Asian patients with renal impairment other than Koreans.
A cross-study analysis in 217 patients with advanced solid tumours indicated that gender did not affect the pharmacokinetics of topotecan capsules to a clinically relevant extent.
In a population study, a number of factors including age, weight and ascites had no significant effect on clearance of total topotecan (active and inactive form).
The pharmacokinetics of topotecan given as a 30-minute infusion for 5 days were evaluated in two studies. One study included a dose range of 1.4 to 2.4 mg/m² in children (aged 2 up to 12 years, n=18), adolescents (aged 12 up to 16 years, n=9) and young adults (aged 16 to 21 years, n=9) with refractory solid tumours. The second study included a dose range of 2.0 to 5.2 mg/m² in children (n=8), adolescents (n=3) and young adults (n=3) with leukaemia. In these studies there were no apparent differences in the pharmacokinetics of topotecan among children, adolescents and young adult patients with solid tumours or leukaemia, but data are too limited to draw definite conclusions.
Resulting from its mechanism of action, topotecan is genotoxic to mammalian cells (mouse lymphoma cells and human lymphocytes) in vitro and mouse bone marrow cells in vivo. Topotecan was also shown to cause embryo-foetal lethality when given to rats and rabbits.
In reproductive toxicity studies with topotecan in rats there was no effect on male or female fertility; however, in females super-ovulation and slightly increased pre-implantation loss were observed.
The carcinogenic potential of topotecan has not been studied.
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