Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products: 

  • Topoisomerase Inhibitors Type II:  Liposomal Doxorubicin (Pegylated liposomal doxorubicin, Doxil)

    • Overview:

    • Liposomal (Pegylated) Doxorubicin⁹

      Attribution: Sugiyama T Kumagai S Pegylated Liposomal Doxorubicin for Advance Ovarian Cancer in Women Who are Refractory to Both Platinum- and Paclataxel-Based Chemotherapy Regimens Clinical Medicine:  Therapeutics 2009:  1 1277-1236 https://www.ncbi.nlm.nih.gov/pubmed/238357629 Pegylated liposomal doxorubicin (PLD), shown above, consists of doxorubicin surrounded by N-(carbonyl-methoxpolyethylene glycol 2000)-1, 2-distearoyl-sn-glycero-3-phosphoethanolamine sodium salt (abbreviated in the diagram above as: MPEG-DSPE) coated liposome.9  Generally liposomes are advantageous with respect to formulation for IV use. However, such liposomes are rapidly taken up by the reticuloendothelial system thus removing them from circulation. This uptake process decreases tumor drug availability.9  The pegylated-derivative, given its hydrophilic character, prolongs drug circulation time with limited rapid uptake.9  Accordingly, liposomal doxorubicin exhibits a notably different pharmacokinetic profile compared to doxorubicin.

    • Administration of the pegylated form of doxorubicin (liposomal form) results in an extended duration of action as a liposomal form is not subject to appreciable uptake by the reticuloendothelial system.⁷ 

      • Accordingly, pharmacokinetics of the pegylated form is distinct from the non-liposomal drug preparation.

    • Liposomal doxorubicin administration is associated with a reduced side-effect profile compared to doxorubicin.⁷  

      • For example, nausea and vomiting occur less frequently with liposomal doxorubicin compared to doxorubicin.

      • Also, myelosuppression with doxorubicin is considerably more substantial compared to that observed with the liposomal drug formulation.

      • Two side effects appear unique to the pegylated liposomal doxorubicin form:

        • (1) Risk for hand-foot syndrome.

          • Hand-Foot Syndrome (Erythrodyseathesia)¹²

            "Grade I:  painless erythema or dysesthesia, no impairment."
            "Grade II: painful erythema, swelling, tingling, numbness, dryness, cracking, desquamation, activity is impaired."
            "Grade III: strong pain, ulceration, blistering, erythema, self-sufficiency is at risk."

        • (2) Acute infusion reaction.

          • The acute infusion reaction, dependent on infusion rate, presents with the following:

            • Flushing

            • Dyspnea

            • Fever

            • Edema

            • Chills

            • Bronchospasm

            • Rash Hypertension.

      • FDA-approved uses for pegylated liposomal doxorubicin (Doxil) include:

        • Ovarian cancer

        • AIDS-related Kaposi's sarcoma

        • Multiple myeloma.⁷

    • Pharmacokinetics and toxicities:

      • In preclinical experiments, liposomal doxorubicin elimination was characterized by a one-or two-phase plasma concentration-time curve.

        • Pegylated Liposomal Doxorubin (Doxil^®) and Free Doxorubicin¹⁰

          Attribution:  This figure corresponds to figure 7 in reference 10, https://www.ncbi.nlm.nih.gov/pubmed/12739982) Plasma mean concentration of doxorubicin in patients receiving a single intravenous dose of free doxorubicin (n=4) or Doxil (pegylated liposomal doxorubicin), (n= 14). This figure is second sourced from Gabizon et al, reference 11.

        • Drug elimination was characterized by half-life of about 25 hours.

        • The volume of distribution (V_d) approximated blood volume.

        • Tissue distribution studies suggested preferential concentration of drug in tumor, compared with free doxorubicin (non-pegylated liposomal form).

        • Pegylated liposomal doxorubicin has been the subject of clinical trials in patients with a variety of solid tumors including breast, ovarian and prostate carcinoma, well as in patients with AIDS-related Kaposi's sarcoma (ARKS).

        • Pharmacokinetic profiles determined in human subjects appeared similar to that observed in animals within a dose range of 10-80 mg/m2.

      • Toxicity of pegylated liposomal doxorubicin includes both dose-limiting mucosal and cutaneous toxicityand mild myelosuppression and reduced cardiotoxicity (compared with free doxorubicin) described earlier.

      • Despite mucocutaneous toxic reactions to liposomal doxorubicin, the reduced cardiotoxicity of the liposomal form permits an increased cumulative dose compared to free doxorubicin dosing.