Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products

  • Topoisomerase Inhibitors: Topotecan (Hycamtin)

    • Topotecan (Hycamtin)

     

    • Plant-Based Anti-Cancer Agents¹²

      Attribution Roose JL World Cancer Day:  What Do plants have to do with it.   New Under The Sun Blog. February 4, 2014 https://newunderthesunblog.wordpress.com/tag/topotecan/

       

      • Overview:

        • Topotecan (Hycamtin), a camptothecin derivative, began clinical trials in 1989.

          • This agent was approved as second-line treatment for:⁸  

            • Advanced ovarian cancer (1996)

            • Small cell lung cancer (SCLC), following failure of initial or later chemotherapy (1998)

            • Stage IVB recurrent/persistent cervical cancer not suitable for surgical and/or radiotherapy + cisplatin (2006, curative intent).⁸

          • Topotecan also exhibits pharmacologic activity in management of both:⁷

            • Acute myeloid leukemia and

            • Myelodysplastic syndrome⁷

      • Absorption, Distribution, Metabolism, Excretion:

        • Aborption:^7,8

          • Topotecan (Hycamtin), as noted with irinotecan, is administered using the intravenous (IV) route of administration.

            • Topotecan is rapidly eliminated from the systemic circulation (linear pharmacokinetics) and exhibits a t_1/2 of about 4 hours.¹ 

            • Topotecan penetrates the blood-brain barrier allowing for CSF drug concentrations to be about 1/3 of that observed in plasma.⁷

          • Oral formulations are undergoing testing.⁸ 

            • The oral formulation exhibits bioavailability of about 30%-40% and is sensitive to reduced absorption across intestinal walls if converted to the active carboxylate form.

            • Bioavailability may also be diminished by activity of transport systems that are outward-directed.

            • Lastly, bioavailability may be diminished by the binding of topotecan to food, proteins or by gastrointestinal fluid-mediated drug decomposition.

          • In pediatric patients and young adults, topotecan volume of distribution (V_d) is about 30 L/m² and exhibits protein binding on the order of about 35%.^1,9  

          • In pediatric patients and young adults from about six months of age to about 22 years old, significant interpatient variability (about 50%) in pharmacokinetic parameters has been reported as well as intrapatient variability on the order of 20% in these parameters.⁹

        • Metabolism:

          • Unlike irinotecan, topotecan (left, above) is not a prodrug and accordingly topotecan is the active form (right, above). However, topotecan undergoes a pH dependent lactone moiety hydrolysis rendering the ring-opened hydroxy acid form as prevalent at physiological pH.8  About 30% of plasma topotecan is present in the active lactone configuration.1

          •  

            pH-Dependent Interconversion between Topotecan Lactone (active) and Carboxylate Form (inactive)¹⁰

            About 30% of plasma topotecan is present in the active lactone configuration.1 Attribution: Tiwari AK Zhang R Gallo JM Overlapping Functions of ABC Transporters in Topotecan Disposition as Determined in Gene Knockout Mouse Models.  Mol Cancer Ther 2013 Jul; 12(7): 1343-1355. Adapted from Figure 1, reference 10. https://www.ncbi.nlm.nih.gov/pubmed/23635651 http://mct.aacrjournals.org/content/molcanther/12/7/1343.full.pdf

           

          • Topotecan is only minimally subject to hepatic metabolism.

            • As a consequence, patients with impaired liver function do not exhibit abnormal topotecan pharmacokinetics.

            • By contrast, about 1/3 of topotecan doses exhibit renal excretion.

              • Renal clearance is a significant factor in topotecan elimination requiring dosage modifications in those patients with impaired renal function.^7,8

              •  A 50% decrease in dose appears appropriate for patients exhibiting even moderate renal impairment defined as a creatinine clearance of about 20-39 mL/min).⁷

      • Mechanism of Action:

        • The mechanism of topotecan action follows from its effects on topoisomerase I enzyme function.¹  

          • Topoisomerase classes (I and II) act by promoting DNA strand breakage with subsequent resealing.

          • DNA topoisomerases modulate internal stress in supercoiled DNA such that particular regions are available for:¹

            • Replication

            • Repair

            • Transcription.

          • Topotecan is a camptothecin analog that alters topoisomerase I normal function.¹  

            • The camptothecins (irinotecan and topotecan) stabilize the normally unstable transient DNA-topoisomerase I cleavable complex, thus interfering with topoisomerase I normal function.

              • The specific site of interference is at the religation step, leaving the initial cleavage property of topoisomerase I unaffected.

              • A consequence of interference with the religation step is that interaction of a DNA replication fork with this affected DNA strand causes a permanent double-stranded DNA break, resulting in cell death.¹

          • Irinotecan and topotecan (campothecins) are classified as S-phase-specific agents since active DNA synthesis is required for drug-induced cytotoxicity.

            • A clinical consequence is that these cytotoxic agents must be exposed to tumor cells for an extended period of time, ensuring that the camptothecin is present when a given tumor cell is dividing and present at an appropriate therapeutic dose level.¹

      • Adverse/Toxic Effects:¹

        • The most common dose-limiting toxicity associated with topotecan is myelosuppression.¹ 

          • Topotecan -induced myelosuppression is more likely to occur if the patient has received significant previous radiotherapy or other anticancer agents which suppress bone marrow.

          • Neutropenia due to topotecan administration may present in the presence or absence of thrombocytopenia.¹ 

            • The incidence of neutropenia may reach 80% (dosing schedule:  1.5 mg/m² every day for 5 days every 3 weeks).

            • Febrile neutropenia may be associated with an incidence at about 25%.

          • For patients experiencing hematological cancers, G.I. side effects including mucositis and diarrhea may well be dose-limiting.¹ 

            • Other topotecan-related adverse effects include:

              • Nausea and vomiting

              • Fever

              • Fatigue

              • Alopecia⁷

              • Rash

              • Increased liver transaminase levels.¹

        •  

          Cancer Chemotherapy & Pharmacology Review¹¹

          Attribution:  Mascarenhas L Cancer Chemotherapy & Pharmacology:  Pediatric Hematology/Oncology Review Course, February 2017 (slide 23) https://slideplayer.com/slide/14539721/

           

      • Drug Resistance:

        • One mechanism involved in cellular resistance to anticancer effects for topoisomerase inhibitors is based on mechanisms that decrease cellular drug accumulation.¹  

          • For example, topotecan is a substrate for the P-glycoprotein multidrug transporter (P-glycoprotein (ABCB1) which supports efflux of a variety of hydrophobic agents including drugs.

            • This transporter is described as a 170 kDa (kilodalton) polypeptide and is important in blood-brain barrier function but also restricts intestinal drug uptake.¹³

            • Pgp substrates diffuse into the cell membrane because of their lipid-soluble properties and then, encountering the transporte, the drugs are translocated back into the aqueous phase (outside).

              • The Pgp transporte exhibits a large binding region sufficient to transport several substrate molecules at the same time.

                • Pgp activity appears dependent on ATP thriough ATP hydrolysis or ATP binding ¹³

          • By contrast, irinotecan is not a substrate for this transport system.

            • Cultured cells lacking carboxylesterase activity exhibit irinotecan resistance; however outside this model system, liver as well as blood cells may possess adequate carboxylesterase activity sufficient to catalyze conversion of irinotecan to the active metabolite SN-38.

              • As a class, camptothecin resistance could occur also from reduced expression or an abnormality (mutation) in its target, topoisomerase I.¹ 

      • Clinical Uses:

        • National Categories of Evidence and Consensus (NCCN)¹²

          Category 1: "Based upon high-level evidence there is uniform NCCN consensus that the intervention is appropriate." Category 2A: "Based upon lower-evidence there is uniform NCCN consensus that the intervention is appropriate." Category 2B: "Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate." Category 3: "Based upon any level of evidence, there is major NCCN disagreement at the intervention is appropriate."

          National Categories of Evidence and Consensus (NCCN) https://www.nccn.org/professionals/physician_gls/categories_of_consensus.aspx

        • Cervical cancer: topotecan (Hycamtin) has been FDA approved for treating stage IVB persistent, recurrent cervical carcinoma in patients in which curative surgical and/or radiotherapy with curative intent is not possible.⁷

        • Ovarian cancer

        • Small-cell lung cancer

        • Acute myeloid leukemia: topotecan may be used in treating AML (with a Class 2B designation).

        • Myelodysplastic syndrome: topotecan may be used in MDS (with the Class 2B designation).⁷

        • Phase II clinical trials have demonstrated topotecan antitumor activity when given as a single agent with various administration protocols in: ⁸

          • Ovarian cancer

          • Small-cell lung cancer

          • Non-small cell lung cancer

          • Breast cancer

          • Myelodysplastic syndrome

          • Chronic myelomonocytic leukemia.⁸

        • Some, limited anti-cancer activity has been noted in ⁸

          • Head and neck cancer

          • Pancreatic cancer

          • Gastric cancer

          • Esophageal cancer

          • Prostate cancer

          • Hepatocellular carcinoma

          • Recurring malignant glioma.⁸