Darzalex | Pharmacology Mentor

Generic Name

Darzalex

Mechanism

* CD38 binding – Daratumumab selectively binds the highly expressed CD38 ectoenzyme on malignant plasma cells.

* Direct cytotoxicity
• Antibody‑dependent cell‑mediated cytotoxicity (ADCC) via NK‑cell recruitment.
• Complement‑dependent cytotoxicity (CDC) leading to cell lysis.
• Antibody‑dependent cellular phagocytosis (ADCP) by macrophages.

* Indirect effects – Suppression of immunosuppressive myeloid‑related cells and induction of anti‑tumor immune responses.

* Prolonged cell depletion – Long half‑life allows durable remission in relapsed‑refractory disease.

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Pharmacokinetics

Parameter	Typical Values
Absorption	IV infusion; SC bioavailability ≈ 70‑77 %.
Distribution	Lasts in plasma; binds CD38‑positive cells; volume of distribution approx 10‑12 L.
Metabolism	Proteolytic catabolism to peptides; no hepatic clearance.
Elimination	Slow catabolism; terminal half‑life 18–20 days after cycle 4.
Clearance	~0.08 L/day; not significantly altered by renal/hepatic impairment.
Immunogenicity	Anti‑daratumumab antibodies in <1 % of patients; may shorten half‑life.

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Indications

* Relapsed or refractory multiple myeloma (RRMM) – as monotherapy or in combination with:
• Proteasome inhibitors (bortezomib, carfilzomib, ixazomib).
• Immunomodulatory drugs (lenalidomide, pomalidomide).
• For patients not eligible for autologous stem‑cell transplant (ASCT).

* New‑ly diagnosed MM – in combination with lenalidomide‑based regimens, often post‑ASCT.

* Subcutaneous Darzalex Epc – approved for RRMM per FDA label.

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Contraindications

* Hypersensitivity to daratumumab or any excipient.
* Severe pulmonary disease – risk of interstitial lung disease (ILD).
* Active systemic infection – can worsen immunosuppression.
* Pregnancy – no data; use is contraindicated.
* Concurrent severe cardiac disease – watch for heart failure.

Warnings
* Infusion reactions (fever, chills, dyspnea).
* Immunosuppression – opportunistic infections (fungi, CMV).
* Hypogammaglobulinemia – monitor immunoglobulin levels, consider IVIG if severe.
* Thromboembolic events – may increase risk, especially in older patients.
* Allergic contact dermatitis with SC formulation possible.

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Dosing

Formulation	Dose & Schedule	Notes
IV	1000 mg IV over 30‑120 min (first infusion)	First dose may be split (500 mg).
	1 mg/kg IV (max 1000 mg) weekly ×4, then every 2 weeks	Cycle 1: 4 weekly, cycles 2‑8: every 2 weeks; maintenance thereafter.
	Alternatively, 25 mg/m² IV (30‑120 min)	Same schedule if body‑surface‑area dosing preferred.
SC	20 mg/kg (max 1200 mg) SC 30‑60 s	One‑hour infusion recommended.
	Subsequent 20 mg/kg SC every 2 weeks (or monthly if rapid response)	Subcutaneous is well tolerated; less infusion‑related reactions.

Premedication (IV)

* Acetaminophen 1000 mg PO or IV 30 min pre‑infusion.

* H1 antagonist (diphenhydramine 25 mg PO/IV) and H2 antagonist (famotidine 20 mg PO/IV).

* Optional: 0.5 mg oral methylprednisolone pre‑infusion for high‑risk patients.

Premedication (SC)

* Diphenhydramine 25 mg PO 30 min prior.

* No steroids required.

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Adverse Effects

Adverse Effect	Frequency	Notes
Infusion‑related reactions	20–30 % (first infusion)	Pre‑medication/slow infusion necessary.
Fatigue, nausea, sore throat	10–20 %	Symptom‑managed.
Neutropenia & anemia	5–10 %	Monitor CBC.
Hypogammaglobulinemia	<5 %	Check IgG; consider IVIG if <5 g/L.
Infections (e.g., CMV, Candida)	<5 %	Prophylaxis per institutional protocol.
Pneumonitis/ILD	<2 %	Prompt discontinuation if suspected.
Hypertension, edema	2–5 %	Monitor BP.
Thromboembolism	<2 %	Consider LMWH prophylaxis in high‑risk pts.
Elevated transaminases	1–2 %	Rare; monitor liver function.

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Monitoring

Parameter	Timing	Rationale
CBC (Hgb, WBC, platelets)	Baseline, day 1 of cycle 1, then monthly	Detect cytopenias early.
CMP (renal & liver)	Baseline, every cycle	Identify hepatic or renal involvement.
Immunoglobulin levels	Baseline, every 3 months	Evaluate hypogammaglobulinemia.
Heart function (ECHO/NT‑proBNP)	Baseline, if cardiac history	Avoid exacerbation of heart failure.
Pulmonary assessment (spirometry/CT)	Baseline, if ILD risk	Early detection of lung toxicity.
CMV PCR	In transplant patients	Prevent CMV reactivation.
Vaccine serologies	Pre‑therapy	Identify need for revaccination.

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Clinical Pearls

* Loading Dose Strategy – A 1000 mg IV load simplifies calculations for most patients and reduces total infusion time, but body‑surface‑area dosing (25 mg/m²) is acceptable if precise dosing is required in weight‑based scenarios.

* Infusion Reaction Mitigation – Splitting the first infusion 500 mg followed by 500 mg 24 h later dramatically reduces grade‑III reactions while maintaining efficacy.

* SC Benefit for Home Therapy – Darzalex Epc allows outpatient or home subcutaneous injections, cutting infusion‑related reactions by >50 % and improving patient convenience.

* Combination Synergy – In RRMM, daratumumab combined with lenalidomide and dexamethasone (Dara‑LEN‑DEX) produces higher response rates than LEN‑DEX alone; the addition of bortezomib produces synergistic effect via enhanced complement activation.

* Hypogammaglobulinemia Management – Monitor IgG every 3–6 months; consider IVIG if IgG <5 g/L or if patient has frequent infections.

* Bleeding Risk – Daratumumab can prolong bleeding time; hold the drug 12 h prior to invasive procedures.

* Renal Function – No dose adjustment needed in CKD; however, monitor for neutropenia in patients with concurrent myelosuppressive drugs.

* Pregnancy Precautions – Store injectable forms at 2–8 °C; counsel patients to avoid pregnancy during treatment and for 90 days after last dose.

* Dermatologic Reaction – For SC formulation, apply a short‑acting antihistamine if rash appears, but steroids are usually unnecessary.

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