Topoisomerase Inhibitors – Topotecan, Irinotecan, Etoposide, Teniposide

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What is Topoisomerase?

Topoisomerase are enzymes that help in preventing the DNA supercoiling by introducing single or double strand breaks in DNA.

Topoisomerases are of 2 types depending on the number of DNA strand breaks, Type I and Type II. Type I cause single-strand DNA breaks and Type II cause double-strand DNA breaks.


Role of Topoisomerases in Cell Cycle

Topoisomerases play a role in DNA Replication, Transcription, and Recombination. Here we discuss the role of Topoisomerase I and II in cell cycle.

Topoisomerase 1

It is encoded by a single copy gene located on Chromosome 20q. Through an ATP dependent process, it cleaves a single strand of DNA and forms a covalent intermediate by “Transesterification”, religates the DNA (“Reverese transesterification”) and relaxes supercoils generated during transcription.

Topoisomerase 2

It is encoded by copy gene located on chromosome 17q and 3p. It’s expression is increased during S phase of cell cycle and almost absent in quiescent cell. Through an ATP dependent process, it causes decatenation during DNA replication, DNA relaxation during transcription and facilitates remodeling of chromatin structure (knotting, unknotting), chromosome condensation, segregation of meiotic and mitotic chromosomes.


Classification of Topoisomerse Inhibitors

Topoisomerase I Inhibitors

  • CAMPTOTHECINS
    • Topotecan
    • Irinotecan

Topoisomerase II Inhibitors

  • EPIPODOPHYLLOTOXINS
    • Etoposide
    • Teniposide
  • ANTHRACYCLINES
  • ANTHRACENEDIONES
  • ACTINOMYCINS

Mechanism of Action of Topoisomerase Inhibitors

Topoisomerase 1 Inhibitors

These are partially Cell Cycle dependent and act mainly in S phase. They stabilize covalently liked enzyme-DNA complex and prevent religation of single strand nick in DNA replication fork.

Topoisomerase 2 Inhibitors

These are Cell Cycle dependent and act in late S and G2 phase of cell cycle. They form double strand DNA breaks and stabilize the cleavable complex, preventing religation of double strand DNA breaks.


Irinotecan

topoisomerase inhibitor irinotecan

Chemistry

Irinotecan is a prodrug containing a bulky dipiperidino side chain at C-10 that must be cleaved to generate the active metabolite, SN-38.

Pharmacokinetics

ABSORPTION

By oral route, bioavailability is 20%. This means only 20% of the drug reaches the systemic circulation when given orally. SN-38 generation is 3 fold higher (extensive first-pass metabolism in intestine and liver). Preferred route is intravenous as the bio-availability is higher.

DISTRIBUTION

Plasma protein binding is 50%. Half life of irinotecan is 6-7 hours, whereas, that of SN- 38 (active metabolite) is 10-20 hours. CSF penetration is poor but excellent penetration of pleural fluid compartment is there.

METABOLISM

Prodrug undergoes enzymatic cleavage of the C-10 side chain by irinotecan carboxylesterase converting enzyme into a biologically active metabolite SN-38. Irinotecan and SN-38 undergo non-enzymatic hydrolysis of the lactone ring to the open-ring carboxylate species.

Greater antitumor activity of irinotecan comapred to other camptothecin derivatives is due to longer half life of SN-38, higher plasma protien binding, slow conversion of irinotecan to SN-38, enterohepatic recirculation and topoisomerase I-DNA cleavable complexes induced by SN-38 being extremely stable.

Hepatic oxidation (CYP3A) of its dipiperidino side chain to form the inactive metabolite APC which then undergoes hepatic glucuronidation leading to biliary excretion.

EXCRETION

Mainly biliary excretion is the major route in 75% cases, renal excretion seen in only 25% cases.

Indications

Availability

  • Injection strengths available: 20 mg/mL (2 mL, 5 mL, 25 mL)

Dose

Various dose schedules that may be followed are as follows.

  • 125 mg/m2 i.v. over 90 min weekly for 4 of every 6 weeks
  • 350 mg/m2 (240-350) i.v. over 60-90 min every 3 weekly
  • 100 mg/m2 every week or 150 mg/m2 every other week
  • FOLFIRI- 180mg/m2 q 2weekly
  • 65mg/m2 i.v. over 90 min weekly for 4 of every 6 weeks (Esophageal Cancer, Stomach Cancer, with cisplatin)
  • 60mg/m2 i.v. over 90 min weekly for 3 of every 4 weeks (lung cancer)
  • 20 mg/m2 i.v. over 60 min daily for 5 days (D1-5, D8-12, q4w) (Ewing’s Sarcoma)
  • Continous intravenous infusion over 4 days/ over 7 days/ over 14 days

Dose Modifications

Dose reduction of irinotecan may be required in the following conditions-

  • Grade 3 neutropenia or delayed diarrhea
  • Grade 4 neutropenia or diarrhea
  • Bilirubin >ULN to ≤2 mg/dL
  • Bilirubin >2 mg/dL: Use is not recommended

Adverse Effects/Toxicity

Early onset diarrhea

Early onset diarrhea within 24 hours of starting infusion, may be seen in 43% to 51% cases. Cholinergic symptoms may be accompanied in 47% of the patients, such as, GI cramps, nausea/vomiting, anorexia, asthenia, diaphoresis, chills, malaise, dizziness, visual accommodation disturbances, salivation, lacrimation, asymptomatic bradycardia. In patients experiencing cholinergic symptoms, Atropine 0.25 -1.0 mg subcutaneously or intravenously may be given. It may also be considered for prophylaxis if the patient had symptoms with previous cycles of chemotherapy.

Late onset diarrhea

Late onset diarrhea occurs after 24 hours of drug administration, and it is the major dose-limiting toxicity with irinotecan. It may be seen in 83% to 88% cases. Peak incidence is seen at 11 days with weekly schedule and at day 5 or 6 with 3 weekly regimen (less common). More intensity and frequency is seen at higher doses of irinotecan. The type of diarrhea is secretory.

Treatment is done with high-dose loperamide, initially 4 mg followed by 2 mg every 2 hourly during day and 4 mg every 4 hours during night. Start at the first sign of any loose stool, and continue until no bowel movements occur for 12 hours, for maximum 48 hours. For Persistent diarrhea (grade 1 to 2) after 12-24 hours of high dose loperamide, start oral antibiotics. For Persistent diarrhea (grade 1 to 2) after 48 hours or in case of grade 3 or 4 diarrhea, evaluate for infection and consider second line agent like octreotide (100-150mcg subcutaneous thrice a day or 25-50 mcg/hr i.v. infusion). In severe dehydration, dose may be increased till 500 mcg thrice a day. Prophylactic use of loperamide in recurrent cases decreases incidence of diarrhea by more than 50%.

Early use of oral broad-spectrum antibiotics (e.g., fluoroquinolone) may be considered for grade 4 diarrhea, febrile diarrhea, diarrhea with concomitant grade 3 or 4 neutropenia or failure of 48-hour high-dose loperamide therapy.

Factors associated with an increased risk for severe diarrhea are prior pelvic radiation, poor performance status, age 65 years or older, and Gilbert’s or Crigler-Najjar syndrome.

Myelosuppression

Neutropenia is more common tah thrombocytopenia although it is reversible, noncumulative and for short duration. Myelosuppression is dose-dependent and schedule-dependent, and ranges from14-47% in once every 3 weeks and 12-19% in the weekly schedule. Febrile Neutropenia may be seen in 2-6% cases.


Topotecan

topoisomerase inhibitor topotecan

Pharmacokinetics

ABSORPTION

Oral bioavailability ranges from 30 to 40 % as high pH of small intestine causes it’s conversion to carboxylate form, ABCG2 and ABCB1(Pgp) in intestinal wall cause outward transport of drug and binding to food, proteins, and intestinal fluids and/or decomposition in GI fluid reduces it’s absorption.

DISTRIBUTION

Plasma protein binding is 30 %, lower than other camptothecins. So it is safe to administer with malignant ascites and pleural effusion as it doesn’t get accumulated in these fluids.

METABOLISM

Topotecan mainly metabolizes through nonenzymatic hydrolysis of the lactone ring to open ring hydroxy carboxylic acid, major metabolites being N-desmethyl topotecan and glucuronide metabolites.

EXCRETION

Half-life of topotecan is 2 to 3 hours through intravenous route and 3 to 6 hours through oral route. 30% to 40% of the drug is excreted unchanged over 24 hours through renal excretion and 33% fecal excretion of oral drug.

Indications

FDA approved indications are as follows-

  • Metastatic Ovarian cancer (1996)
  • Recurrent/ Resistant Cervical cancer (2006)
  • Relapsed/ Refractory Small cell lung cancer (2007)

Other off-label indications of topotecan-

  • Non-small cell lung cancer
  • Breast cancer
  • AML, MDS, CMML
  • CNS metastasis from lung cancer, PCNSL, neuroblastoma
  • Ewing’s sarcoma, osteosarcoma, rhabdomyosarcoma
  • Merkel cell cancer

Availability

  • Capsule, oral: 0.25 mg, 1 mg
  • Injection, powder for reconstitution, solution: 4 mg

Doses

  • Ovarian and Lung Cancer : 1.5 mg/m2 i.v. over 30 minutes daily for 5 days q3w for minimum 4 cycles
  • Cervical Cancer : 0.75mg/m2 daily (followed by cisplatin 50 mg/m2 on day 1 only) for 3 days q3w
  • Hematological malignancies : 2.0 mg/m2 contnous infusion daily for 5 days
  • Through oral route, dose is 3 mg/m2 per day (round dose to the nearest 0.25 mg) for 5 days every 3 weekly. It may be taken any time without regards to meals. It is mainly indicated for relapsed ovarian cancer and lung cancer.

Dose Modifications

Hematological Toxicity in the form of grade 4 neutropenia, grade 3 neutropenia with fever and/or infection, complicated grade 3 or 4 thrombocytopenia may require dose modification. Consider G-CSF support prior to instituting dose reduction.

  • Reduce by 0.25 mg/m2/d (Ca lung & Ovary)
  • Reduce dose to 0.6 mg/m2/day (Cervical Ca)
  • Reduce dose by 0.4 mg/m2/day for oral dosing

Renal impairment may require 50% dose reduction for intravenous dose if creatinine clearance (CrCl) is less than 40 mL/min and contraindicated if  CrCl <20 mL/min. Oral dose to be decreased to 1.8 mg/m2 if CrCl <50 ml/min and avoid when CrCl< 30 ml/min.

Adverse Effects/Toxicities

Myelosuppression is dose-related, reversible and noncumulative. Neutropenia is more common than thrombocytopenia or anemia. Nadir occurs at day 9, lasting for 7-10 days. Extensive prior carboplatin treatment increases the risk of thrombocytopenia. Extensive prior radiation or previous bone marrow-suppressive chemotherapy increases risk of myelosuppression.

Secondary Malignancy such as Myelodysplastic syndrome or AML may be seen as a long term toxicity with the drug. This mayoccur due to chimeric fusion protein that includes NUP98 (nucleoporin gene), created by t(11,20)(p15,q11).

Drug Interactions

Cisplatin given before topotecan leads to decreased clearance of topotecan (subclinical renal tubular toxicity) and more hematological toxicity.

Topotecan before Docetaxel  may cause decreased clearance of docetaxel by 50% and increased neutropenia.


Etoposide

topoisomerase inhibitor etoposide

Pharmacokinetics

ABSORPTION

Oral form has significant variable bioavailability (average 50%). Upto 75% bioavailability for lower doses at 50 mg/m2 and less than 50% bioavailability at higher doses (more than 100mg/m2). This is mainly due to saturable absorptive mechanism in the GI tract, very low aqueous solubility and low stability at acid pH. 25% to 75% is the bioavailability through intravenous route.

DISTRIBUTION

Plasma protein binding is 96%. Poor CSF (5% of plasma), pleural fluid, ascitic fluid penetration. Low albumin levels increase free drug concentration and increased toxicity. High bilirubin competes with albumin binding of drug causing increased toxicity.

METABOLISM

Main metabolite is etoposide-glucuronide that is predominantly eliminated in the urine.

EXCRETION

Half life of etoposide is 6-8 hours (ranging from 3-12 hours). 40 to 60% of the drug is excreted unchanged through kidney, and biliary excretion is minimal.

Indications

As first-line therapy in combination with cisplatin

  • Germ-cell malignancies
  • Small cell lung cancer
  • Poorly differentiated carcinomas
  • Poorly differentiated endocrine tumors

Second-line regimens or salvage therapies in

  • Non Hodgkin’s Lymphoma, including HIV-associated NHLs, Cutaneous T cell Lymphoma
  • Hodgkin’s Lymphoma
  • High-risk metastatic gestational trophoblastic tumors
  • Kaposi’s sarcomas
  • Osteosarcomas, Ewing’s sarcomas
  • Neuroblastomas, Retinoblastoma
  • NSCLC
  • Gastric Cancer
  • Endometrial Cancer
  • Leukemias- ALL, AML
  • Multiple Myeloma
  • MDS

Availability

  • Etoposide
      • oral form : 50-mg capsules,
      • parenteral form : solution of 20 mg/mL (5ml, 25ml, 50ml)
  • Etoposide phosphate :
      • 100-mg single-dose vials as lyophilized powder

Administration

  • Oral doses more than 200 mg should be given in 2-4 divided doses with or without food
  • Intravenous infusion should be over at least 30 to 60 minutes (risk of hypotension). Administration through non-PVC tubing should be done to prevent Polysorbate 80 leaching of diethylhexyl phthalate (DEHP). Concentrations greater than 0.4 mg/mL are very unstable and may precipitate within a few minutes, so large doses of undiluted drug should be given through a running NS/5D/DNS infusion or use of etoposide phosphate should be preferred in such cases.
  • Intraperitoneal infusion upto 100-600mg/m2 is tolerated for peritoneal carcinometosis.
  • Intrapleural route may be used for recurrent malignant pleural effusion.
  • Intraventricular dose is 5 mg daily for 5 days, followed by a second course with two injections per day of the same dose.
  • Intraarterial route used for brain tumors (carotid or vertebral arteries) , liver metastasis in testicular tumors.

Dose Modification

Dose modification is mainly required for renal dysfunction. For creatinine clearance 15-50 mL/min, administer 75% of dose and consider further dose reductions to 50% when creatinine clearance is 15 mL/min or less.


Teniposide

topoisomerase inhibitor teniposide

Pharmacokinetics

  • Oral bioavailability is similar to Etoposide.
  • Available only as intravenous formulation, but same formulation can be used orally.
  • High plasma protein binding (>99%), high volume of distribution, half life is 5 hours.
  • Significant Hepatic metabolism.
  • Renal excretion is low, only 10-20% excreted through urine.

Indications

Teniposide is mainly used in pediatrics and neuro-oncology

  • Retinoblastoma
  • Neuroblastoma, Oligodendroglioma, PCNSL
  • AML
  • ALL-as salvage therapy
  • NHL-second line
  • SCLC

Availability

Solution of 10-mg/mL solution containing 50 mg of drug.

Dose Modification

In cases of renal dysfunction, administer 75% of dose when creatine clearance is15-50 mL/min and consider further dose reductions to 50% with clearance <15 mL/min.

In cases of hepatic dysfunction, consider 50% dose reduction with bilirubin 1.5-3 mg/dL or AST >3 times ULN, 75% dose reduction with bilirubin 3-5 mg/dL and avoid when bilirubin >5mg/dL.


Second Malignancy with Topoisomerase Inhibitors

Greatest risk is with Topoisomerase II inhibitors, 6 year cmulative risk being upto 4% (0.7-4%). Cumulative dose of the drug plays a major role, with the risk being highest with high cumulative doses (>3 g/m2) as compared to low (<1.5 g/m2) and moderate (1.5 to 2.99 g/m2) doses.

Most commonly secondary malignancy is acute myeloid leukemia, with Myelomonocytic (FAB M4 ) and monoblastic (FAB M5) variants being the commonest. Less frequently it may cause AML-M3 or other realted disorders like chrnic myelomonocytic leukemia (CMML) and myelodysplastic syndrome (MDS).

Secondary malignancies are causes by balanced chromosomal translocations involving MLL (ALL-1, HRX) gene at 11q23 or AML1 gene at 21q22. It has a short latency period, with a median of 24 to 30 months and administration of L-asparaginase prior to etoposide might increase risk of leukemia.

 

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