Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products: 

  • Topoisomerase Inhibitors Type II: Idarubicin (Idamycin)

    • Overview:

      •  Idarubicin (Idamycin)

      • Idarubicin (Idamycin), like epirubicin, intercalates between DNA base pairs and for steric reasons, this intercalation results in DNA and RNA synthesis inhibition.⁹ 

        • The combination of idarubicin binding to DNA (intercalation) and inhibition of DNA repair (topoisomerase II inhibition) results in DNA and RNA synthesis blockade and DNA fragmentation.

        • Clinically, Idamycin has a role in treating acute myeloid leukemia in adults (AML).⁹  

          • This therapy typically is in the context of combination treatment with cytarabine.¹⁰

            • When used in combination with cytarabine, idarubicin may be more effective compared to daunorubicin with the endpoint of complete remissions and improved survival in AML patients.³

          • Idarubicin also exhibits activity in acute lymphoid leukemia (ALL).⁷

    • Absorption, Distribution, Biotransformation, Excretion:

      • Idarubicin is mainly cleared from the system by combination of hepatic metabolism and biliary excretion and by a reduced extent by renal excretion.^1,7 

        • Idarubicin exhibits of half-life (t_1/2) of about 15 hours and an active metabolite, idarubicinol exhibits a t_1/2 of about 40 hours.

        • Idarubicin volume of distribution (Vd) is about 1500 L/m² with the clearance of about 60 L/h/m².

        • Idarubicin undergoes metabolic biotransformation into idarubicinol (a 13-dihydro derivative) exhibiting comparable activity to idarubicin.¹¹ 

          • Idarubicin pharmacokinetics is characterized by a 2-or 3-compartment model exhibiting plasma disappearance with half-lives (t_1/2) of about 10 minutes, 2.5h, 16h respectively for the 3 compartments.

          • Idarubicin elimination t_1/2 is considered very long at 55h¹¹  (>45 h idarubicinol)⁹.

          • In children (equal to are older than one year of age and adolescents) the half-life is about 17h = +/- 7 h.⁹

          • Idarubicin may be administered orally and the oral route of administration exhibits similar pharmacokinetics as described for intravenous administration.

          • Bioavailability of idarubicin is about 25% (idarubicin + idarubicinol bioavailability = about 40%).

            • About 10% of an IV dose is found in urine (idarubicin + idarubicinol) with slightly more found in bile.¹¹

        • Idarubicin (along with the other anthracyclines noted earlier) has ready access to most organs e.g. heart, kidneys, liver, lungs, and spleen but the drug cannot access the central nervous system (CNS) due to the blood-brain barrier.¹

    • Clinical Uses:

      • Idarubicin is FDA approved as part of a combination chemotherapy protocol for acute myeloid leukemia and exhibits activity as well in acute lymphoid leukemia.

        • Given the role of the liver in biotransformation as well as the kidney in drug excretion, dose adjustments are appropriate in patients who exhibit hepatic and/or renal dysfunction.

          • In the case of hepatic dysfunction, a dose reduction of 50% may be appropriate in cases in which serum bilirubin levels range between 2.6 to 5 mg/dL.

            • If bilirubin levels exceed 5 mg/dL, idarubicin administration may be contraindicated.

            • Dose reductions in cases of renal dysfunction may also be appropriate.

        • In the pediatric setting, AML patients typically receive induction chemotherapy utilizing cytarabine along with a topoisomerase II inhibitor, such as idarubicin, doxorubicin or mitoxantrone, sometimes a third drug such as etoposide or 6-thioguanine may also be used.¹² 

          • Remission induction rates, based on recent clinical trials, range from about 75% to about 95%.

          • Changes in remission induction therapy are attempted not only to improve remission rates but also its "quality."¹²

           

        • Nivolumab with cytarabine and idarubicin in Newly Diagnosed AML¹⁴

          Attribution: Ravandi F Nivolumab with cytarabine & idarubicin in newly diagnosed AML https://www.youtube.com/watch?v=RKJKKE16hwo (published 12/2017) AML Hub,Youtube Channel:  https://www.youtube.com/channel/UCZo7Wi8rd6P710nNXDJEB3A

    • Toxicities:

      • Some acute toxicities associated with idarubicin include:

        • Myelosuppression

        • Alopecia

        • Mucositis

        • G.I. disturbances (nausea/vomiting).⁹ 

      • Cardiotoxicity, a delayed toxicity, may also be observed.⁹

      • Late-onset treatment-related leukemia has been associated with both alkylating-type anticancer agents as well as topoisomerase II inhibitors (anthracyclines and epipodophyllotoxins).¹³

       

  • Topoisomerase Inhibitors Type II: Valrubicin (Valstar) \

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    • Overview:^1,15

      • Valrubicin (Valstar) is a fluorinated, synthetic doxorubicin analog.

        • Valrubicin clinical use is for intravesicular bladder cancer.

          • This agent is used in the context of BCG (bacille Calmette-Guerin)-refractory bladder carcinoma in situ under the circumstances in which cystectomy would be contraindicated.

          • BCG Unresponsive Disease:  A Roadmap for Drug Development and Novel Therapies¹⁶

            Attribution:  Lerner S BCG Unresponsive Disease:  A Roadmap for Drug Development and Novel Therapies https://www.youtube.com/watch?v=sPKenDA-QW8 (2/18) "Seth Lerner, MD, defines what places a bladder cancer patient into the BCG unresponsive category and treatment options in these cases. He touches on valrubicin, summarizes data regarding off-trial options such as gemcitabine, docetaxel, and the gem/doce combination, and discusses clinical trials for CG0070, Ad-IFN and atexolizumab." Grand Rounds in Urology Youtube Channel:  https://www.youtube.com/channel/UCJ9wfEDgPFNQ3Lnrg-u0vCg

        • The agent is introduced into the bladder with limited drug systemically absorbed.

          • The principal side effects have to do with bladder irritation.

        • Valrubicin inhibits DNA double polymerase II; however by contrast to other anthracyclines it exhibits limited or no DNA intercalation.