Pemetrex, consists of Pegylated liposomal doxorubicin (PLD) is a specialized formulation of doxorubicin, an anthracycline chemotherapy drug used to treat various types of cancer. The pegylation (attachment of polyethylene glycol molecules) and liposomal encapsulation enhance the drug's pharmacokinetics, improving efficacy while reducing toxicity.

PLD is primarily used in the treatment of:

• Ovarian Cancer (Platinum-resistant or recurrent cases)

• Breast Cancer (Particularly in HER2-negative, metastatic cases)

• Multiple Myeloma (In combination with bortezomib)

• Kaposi’s Sarcoma (Especially in HIV-associated cases)

Doxorubicin works by intercalating into DNA, inhibiting topoisomerase II, and generating free radicals, leading to cell cycle arrest and apoptosis (cell death) in rapidly dividing cancer cells. However, the liposomal pegylation alters its properties:

Liposomal Encapsulation:

• Protects doxorubicin from being rapidly cleared from circulation.

• Reduces uptake by healthy tissues, minimizing cardiotoxicity.

Pegylation (Attachment of Polyethylene Glycol - PEG):

• Increases circulation time in the bloodstream.

• Enhances tumor penetration via the Enhanced Permeability and Retention (EPR) effect, where leaky tumor vasculature allows drug accumulation.

This formulation reduces the classic cardiotoxicity of doxorubicin while maintaining its anti-cancer efficacy. However, it introduces hand-foot syndrome (palmar-plantar erythrodysesthesia, PPE) as a notable side effect.

Pegylated liposomal doxorubicin (PLD) represents a significant advancement in chemotherapy, offering improved tumor targeting and reduced toxicity, especially in terms of cardiac side effects. It has established itself as a key treatment in ovarian cancer, breast cancer, multiple myeloma, and Kaposi’s sarcoma. However, hand-foot syndrome and myelosuppression remain dose-limiting toxicities, requiring careful monitoring and supportive care. Overall, PLD is a valuable option for patients requiring doxorubicin therapy but with a need for reduced toxicity and better tolerability.

Pharmacokinetics & Advantages:

• Half life : 50-60 hours

• Clearance : Slow (liposomes prevent rapid metabolism)

• Tissue accumulation : Higher in tumors, lower in heart tissue

• Cardiotoxicity risk : Lower

• Dosing schedule : Less frequent due to extended half-life

The pegylated formulation allows for higher drug concentration at the tumor site while sparing healthy organs, particularly the heart, from toxic effects.

Indications & Clinical Use

1. Ovarian Cancer

• Indicated for platinum-resistant ovarian cancer (when cancer recurs within six months of platinum-based chemotherapy).

• Administered as monotherapy or in combination with bevacizumab.

• Shows better tolerability and similar efficacy compared to topotecan or paclitaxel.

2. Breast Cancer

• Used in HER2-negative metastatic breast cancer, particularly in patients at risk for cardiotoxicity.

• Sometimes used as an alternative to conventional anthracyclines to reduce heart damage.

• PLD reduces alopecia (hair loss) compared to standard doxorubicin.

3. Multiple Myeloma

• Combined with bortezomib in relapsed/refractory multiple myeloma.

• Improves progression-free survival (PFS) without significantly increasing toxicity.

4. Kaposi’s Sarcoma (KS)

• First-line treatment for AIDS-related Kaposi’s sarcoma.

• Preferred due to better skin penetration and lower systemic toxicity.

• Effective in reducing lesion size and improving quality of life in KS patients.

Dosing & Administration

PLD is administered via intravenous infusion with a slow infusion rate to minimize infusion reactions.

Typical Dosage Guidelines:

• Ovarian Cancer & Breast Cancer: 40-50 mg/m² every 4 weeks.

• Multiple Myeloma (with Bortezomib): 30 mg/m² every 3 weeks.

• Kaposi’s Sarcoma: 20 mg/m² every 3 weeks.

Dose adjustments may be needed in patients with:

• Hepatic impairment (as doxorubicin is metabolized in the liver).

• Severe myelosuppression (to reduce the risk of neutropenia and infections).

Side Effects & Toxicity

Common Side Effects:

• Fatigue

• Nausea/Vomiting

• Mucositis (Mouth Sores)

• Hand-Foot Syndrome (PPE)

• Neutropenia (Low WBCs)

Serious Side Effects & Warnings:

Cardiotoxicity (Heart Damage)

• Risk lower than conventional doxorubicin, but still present.

• Cumulative lifetime dose should not exceed 450-500 mg/m².

• Monitor Left Ventricular Ejection Fraction (LVEF) regularly.

Hand-Foot Syndrome (PPE)

• A characteristic toxicity of PLD.

• Presents as redness, swelling, pain, or peeling on palms and soles.

• Managed by dose modification, emollients, cooling therapy.

Myelosuppression (Bone Marrow Suppression)

• May cause neutropenia (low white blood cells), increasing infection risk.

• Requires regular blood monitoring and dose adjustments.

Infusion-Related Reactions

• Includes fever, chills, rash, and hypotension.

• Pre-treatment with antihistamines and corticosteroids may reduce risk.

Contraindications

PLD is contraindicated in:

• Severe cardiac disease (heart failure, low LVEF).

• Severe hepatic dysfunction (as metabolism occurs in the liver).

• Pregnancy & Breastfeeding (potential teratogenic effects).

• Severe bone marrow suppression.