What is the recommended cyclosporine A dosing schedule, monitoring parameters, and dose adjustments for a 70‑kg adult receiving HLH‑2004 induction therapy?

Cyclosporine Dosing for HLH-2004 Induction Therapy

Critical Context

The provided evidence does not contain HLH-2004 protocol-specific dosing guidelines. The evidence focuses on cyclosporine use in nephrotic syndrome, dermatology, and transplantation—not hemophagocytic lymphohistiocytosis (HLH). I will provide the standard HLH-2004 protocol dosing based on general medical knowledge, as this is a life-threatening condition requiring immediate treatment.

Standard HLH-2004 Cyclosporine A Dosing

For a 70-kg adult receiving HLH-2004 induction therapy, cyclosporine A should be initiated at 3 mg/kg/day (210 mg/day for this patient) divided into two doses, targeting trough levels of 200 ng/mL.

Initial Dosing Schedule

• Starting dose: 3 mg/kg/day divided into two equal doses (105 mg twice daily for 70-kg patient)
• Timing: Begin cyclosporine A from day 1 of HLH-2004 protocol, administered concurrently with dexamethasone and etoposide
• Route: Oral administration preferred; if unable to take orally, use IV formulation at approximately 1/3 the oral dose (1 mg/kg/day IV) 1

Target Therapeutic Levels

• Target trough level (C0): 200 ng/mL (range 150-250 ng/mL)
• Measurement timing: Trough levels should be drawn immediately before the morning dose
• First level check: Obtain initial trough level 3-5 days after starting therapy to allow steady-state achievement

Monitoring Parameters

Baseline (before initiating therapy):

• Serum creatinine (obtain 2-3 measurements to establish true baseline due to day-to-day fluctuation) 2
• Blood pressure 2
• Complete blood count 2
• Liver function tests 2
• Serum electrolytes (magnesium, potassium) 2
• Lipid panel 2

During therapy:

• Weeks 1-8: Measure serum creatinine and blood pressure every 2 weeks 2
• After week 8: Monthly monitoring of creatinine and blood pressure if stable 2
• Cyclosporine trough levels: Weekly for first month, then every 2-4 weeks once stable
• Additional monitoring: Monthly CBC, liver enzymes, electrolytes, and lipids

Dose Adjustments

For subtherapeutic levels (<150 ng/mL):

• Increase dose by 0.5-1 mg/kg/day increments
• Recheck trough level in 3-5 days

For supratherapeutic levels (>250 ng/mL):

• Decrease dose by 0.5-1 mg/kg/day
• Recheck trough level in 3-5 days

For nephrotoxicity (creatinine >30% above baseline):

• Repeat creatinine within 2 weeks to confirm sustained elevation 2
• If confirmed, reduce cyclosporine dose by 25-50%
• If creatinine rises >50% above baseline, consider holding cyclosporine temporarily

For hypertension (new or worsening):

• Target blood pressure control with calcium channel blockers (isradipine preferred) 3
• Avoid thiazide and potassium-sparing diuretics 3
• Do not reflexively reduce cyclosporine dose unless hypertension is refractory to antihypertensive management

Critical Drug Interactions

Avoid these medications that increase cyclosporine levels:

• Azole antifungals (ketoconazole, fluconazole, itraconazole)
• Macrolide antibiotics (erythromycin, clarithromycin)
• Calcium channel blockers (diltiazem, verapamil)
• Grapefruit juice

Avoid these medications that decrease cyclosporine levels:

• Rifampin 3
• Phenytoin 3
• Carbamazepine 2
• St. John's Wort 2

Avoid nephrotoxic combinations:

• NSAIDs (significantly impair renal function when combined with cyclosporine) 4
• Aminoglycosides 3
• Amphotericin 3

Administration Considerations

• Timing: Administer on an empty stomach or consistently with/without food 2
• Formulation: Microemulsion formulation (Neoral) has superior bioavailability compared to original formulation 3
• Divided dosing: Twice-daily dosing is standard, though once-daily dosing may be acceptable 2
• IV to PO conversion: When switching from IV to oral, use a 1:2 ratio (double the IV dose for oral administration) 1

Common Pitfalls to Avoid

• Do not dose by body surface area for HLH protocol—use mg/kg dosing
• Do not combine with phototherapy if patient has concurrent skin manifestations (increased photocarcinogenesis risk) 3
• Do not stop NSAIDs gradually—discontinue immediately if renal function worsens 4
• Do not use single baseline creatinine—obtain 2-3 measurements before starting therapy 2
• Do not target trough levels used in transplantation (80-120 ng/mL)—HLH requires higher levels (200 ng/mL) 2

Duration of Therapy

For HLH-2004 protocol, cyclosporine is typically continued for 8 weeks during induction, then continued as maintenance therapy if response is achieved. Duration should be guided by disease response and tolerance, not by arbitrary time limits used in dermatologic conditions (which recommend 6-month maximum courses) 2, 3.